Drug interactions between common dermatological medications and the oral anti-COVID-19 agents nirmatrelvir-ritonavir and molnupiravir

ABSTRACT

Introduction: The oral antiviral agents nirmatrelvir-ritonavir (NMV/r) and molnupiravir are used to treat mild-to-moderate COVID-19 infection in outpatients. However, the use of NMV/r is complicated by significant drug-drug interactions (DDIs) with frequently prescribed medications. Healthcare professionals should be aware of the possible risk of DDIs, given the emergence of COVID-19 variants and the widespread use of oral COVID-19 treatments. We reviewed available data on DDIs between NMV/r, molnupiravir and common dermatological medications; summarised the potential side effects; and suggest strategies for safe COVID-19 treatment.

Method: A systematic review using PubMed was conducted on data published from inception to 18 July 2022 to find clinical outcomes of DDIs between NMV/r, molnupiravir and dermatological medications. We also searched the Lexicomp, Micromedex, Liverpool COVID-19 Drug Interactions database and the National Institutes of Health COVID-19 Treatment Guidelines for interactions between NMV/r and molnupiravir, and commonly used dermatological medications.

Results: NMV/r containing the cytochrome P-450 (CYP) 3A4 inhibitor ritonavir has DDIs with other medications similarly dependent on CYP3A4 metabolism. Dermatological medications that have DDIs with NMV/r include rifampicin, clofazimine, clarithromycin, erythromycin, clindamycin, itraconazole, ketoconazole, fluconazole, bilastine, rupatadine, dutasteride, ciclosporin, cyclophosphamide, tofacitinib, upadacitinib, colchicine and systemic glucocorticoids. With no potential DDI identified yet in in vitro studies, molnupiravir may be an alternative COVID-19 therapy in patients taking medications that have complicated interactions with NMV/r, which cannot be stopped or dose adjusted.

Conclusion: NMV/r has significant DDIs with many common dermatological medications, which may require temporary discontinuation, dosage adjustment or substitution with other anti-COVID-19 agents such as molnupiravir.

In December 2021, an Emergency Use Authorisation was issued by the U.S. Food and Drug Administration (FDA) for the use of the orally active antiviral medications nirmatrelvir-ritonavir (NMV/r, PAXLOVID) and molnupiravir (LAGEVRIO) in the treatment of patients with mild COVID-19, who are at risk of developing severe disease resulting in hospital admission or mortality.^1,2

Unfortunately, the use of oral COVID-19 therapies is complicated by their significant drug-drug interactions (DDIs) with many medications. With the emergence of highly transmissible dominant variants such as the Omicron strain and its new subvariants BA.2.12.1, BA.4 and BA.5, coupled with the increasing use of oral COVID-19 therapies and the widespread use of dermatological medications by patients, it is crucial for physicians to recognise DDIs involving the most widely used COVID-19 oral agent, NMV/r, and dermatological medications. This can help to support safe decision-making and initiation of COVID-19 treatment as soon as possible after diagnosis, preferably within 5 days of symptom onset.

We aimed to consolidate and review available data on DDIs between NMV/r, molnupiravir and dermatological medications. We also aimed to provide a summary of potential adverse events, details of the expected duration of the CYP3A4 gene-related inhibitory effect of ritonavir; and to suggest appropriate management of co-medications that can potentially interact with NMV/r and molnupiravir.

METHOD

A systematic review (protocol registered with PROSPERO, CRD 42022346065) was conducted to identify the clinical outcomes of DDIs between NMV/r, molnupiravir and dermatological medications, using PubMed from inception to 18 July 2022. The search terms used were: dermatology* AND (nirmatrelvir OR ritonavir OR molnupiravir OR Paxlovid OR Lagevrio). Clinical studies reporting DDI between dermatological drugs and NMV/r or molnupiravir were included in the review. Articles without mention of DDI in the title or abstract were excluded. Conference articles, clinical images/photographic quizzes, as well as pharmacokinetic investigations without clinical outcomes were also excluded. Two authors independently reviewed the titles and abstracts, and the relevant papers were then selected for full-text review. Any disagreement was resolved by discussion with a third author.

The Lexicomp, Micromedex, Liverpool COVID-19 Drug Interactions database, and the National Institutes of Health COVID-19 Treatment Guidelines were also searched for DDIs between NMV/r and molnupiravir with commonly used dermatological medications from the time of inception to 18 July 2022. Lexicomp and Micromedex were selected as the drug interaction resources because of their completeness, accuracy and ease of use.^3,4 The Liverpool COVID-19 Drug Interactions⁵ checker is a user-friendly and leading database for DDI with anti-COVID-19 drugs. Apart from their extensive DDI databases, these sources also conduct regular surveillance of ongoing pharmacovigilance and pharmaceutical publications, as well as announcements on new drug developments. In view of the inconsistency among drug interaction resources, we used more than one drug interaction resource.⁶

To predict potential drug interactions with NMV/r or molnupiravir concerning drugs without information in all 4 drug interaction resources, we referred to the pertinent drug monograph to determine whether the drug is an inhibitor, inducer, or substrate of the drug-metabolising enzymes (expressed by the following genes: CYP3A4, CYP2D6, CYP2B6, CYP2C19, CYP2C9 and CYP1A2) and the P-glycoprotein. P-glycoprotein—also known as multidrug resistance protein 1, adenosine triphosphate (ATP)-binding cassette subfamily B member 1, and cluster of differentiation 243—is an important ATP-dependent efflux pump with broad substrate specificity, which transports many foreign substances out of the cells.

For drugs identified independently by 2 authors to have clinically significant interactions with NMV/r or molnupiravir, the individual drug prescribing information was reviewed for recommended actions, including the need for withdrawal, dosage reduction or continued use with close monitoring. Any disagreement was resolved by discussion, and further issues were escalated to a third author.

RESULTS

A total of 54 studies were screened, but none of the studies was relevant to be included in the systematic review. The published drug interaction resources, however, generated sufficient data to support our analysis, based on the drug monographs associated with NMV/r and molnupiravir, and on inferences from studies on ritonavir and other CYP450 3A4 enzyme inhibitors.

DISCUSSION

Nirmatrelvir-ritonavir (NMV/r)

Nirmatrelvir is an orally effective SARS-CoV-2 3-chymotrypsin-like protease inhibitor involved in the prevention of viral replication in COVID-19 and other coronavirus infections. It is co-administered with ritonavir, a pharmaco-enhancer and strong CYP450 3A4 enzyme inhibitor, to inhibit the metabolism of nirmatrelvir, a CYP3A4 substrate, to maintain the plasma drug concentration at therapeutic levels.⁷

NMV/r is currently the most effective oral antiviral therapy for COVID-19.⁸ However, NMV/r might not be suitable for all patients due to its potential for significant DDIs with co-administered medications.

Drug-drug interactions

The main target molecules of DDIs of NMV/r include other CYP3A4 substrates, with ritonavir-mediated CYP3A4 inhibition, maximal within 48 hours from the first dose of NMV/r, producing an increase in drug plasma concentration, and in the risk of concentration-dependent toxicity.⁹ The concomitant administration of NMV/r with CYP3A4 inhibitors raises the risk of adverse effects from NMV/r. In contrast, CYP3A4 inducers cause a significant reduction of antiviral therapeutic effect, with a potential for the development of viral resistance.

As ritonavir is an irreversible CYP3A4 inhibitor, these DDIs persist even after its discontinuation because time is required for the reduction in CYP3A4 inhibition through the synthesis of new CYP3A4 enzyme in the microsomes of liver cells. A significant 80% resolution of CYP3A4 inhibition occurs by 48 hours and 72 hours after the last dose of NMV/r, in adults aged 20–50 years and >60 years, respectively.¹⁰ Hence, in most individuals, a 3-day rule can effectively guide the management of DDI with NMV/r, since medications that interact with NMV/r may be safely restarted, or alternatively restored to their original dose, 3 days after the last dose of NMV/r.¹⁰

As the duration of NMV/r treatment for COVID-19 is only 5 days, many long-term dermatological medications with known drug interactions may be withdrawn or dose adjusted, where clinically appropriate, for a short 8 days to allow for safe treatment with NMV/r. Since NMV/r is currently the only highly effective oral antiviral therapy against COVID-19, DDI should be managed where feasible to allow its use.⁸

Systemic glucocorticoids

Short courses of oral glucocorticoids are used to treat severe acute exacerbations of atopic dermatitis. Many commonly used glucocorticoids, such as prednisolone and prednisone, are dependent on CYP3A4-mediated metabolism. Thus, co-administration with NMV/r can increase systemic glucocorticoid exposure and the risk of adverse effects, such as hyperglycaemia, adrenal suppression and Cushing’s syndrome.¹¹ Recommendations include careful monitoring for the adverse effects.

Systemic immunomodulators

Ciclosporin is a calcineurin inhibitor used to prevent organ rejection. It is also used to treat severe resistant atopic dermatitis and psoriasis. As ciclosporin is primarily metabolised by hepatic and intestinal CYP3A4 enzymes, ritonavir-mediated CYP3A4 inhibition during concomitant administration will greatly elevate its plasma concentrations, with a significantly increased risk of ciclosporin toxicity, including nephrotoxicity, systemic hypertension and hepatotoxicity.¹² Vogel et al. demonstrated the interaction between ritonavir-boosted antiretroviral therapy and ciclosporin in liver transplant human immunodeficiency virus-infected patients.¹³ They were observed to have flattening of absorption/elimination curves with little changes in plasma levels of ciclosporin over 12 hours and an increase of terminal half-life from 4–6 hours up to 38 hours.¹³ Even though ciclosporin doses in liver-transplant patients are much higher than those for dermatology patients, elevated ciclosporin levels due to slower clearance is expected with dermatological use of ciclosporin. In view of a significantly increased risk of ciclosporin toxicity during concomitant administration with NMV/r, it is recommended to discontinue ciclosporin during NMV/r treatment, and resume it 3 days after the last dose of NMV/r.

Cyclophosphamide, an alkylating agent, is used in cytotoxic chemotherapy for cutaneous T-cell lymphomas and in the treatment of severe, refractory autoimmune skin conditions.¹⁴ It is administered as a prodrug requiring activation by hepatic CYP450 enzymes, including CYP2B6 and to a lesser extent, CYP3A4. As ritonavir is a CYP2B6 inducer, the concomitant use of cyclophosphamide with NMV/r results in increased risk for toxic effects such as oral mucositis and neutropaenia, for which patients must be monitored carefully.¹⁵ Patients with genetic variants associated with reduced CYP2B6 function may be less affected than those with increased CYP2B6 function.¹⁶

Janus kinase (JAK) inhibitors are a relatively new treatment for autoimmune diseases such as psoriatic arthritis, for which tofacitinib and upadacitinib have both been approved for use—the latter recently approved by FDA for atopic dermatitis as well.^17,18 The metabolism of both tofacitinib and upadacitinib is mediated primarily by hepatic CYP3A4, hence elevated plasma concentrations of the active drugs occur in co-administration with NMV/r via ritonavir-mediated CYP3A4 inhibition. For tofacitinib, a maximum of 5mg once-daily dosing of the immediate-release formulation is recommended.¹⁷ For upadacitinib, a maximum daily dose of 15mg is recommended.¹⁸ Dose reductions should be carried out throughout the NMV/r treatment and for another 3 days from completion of the last NMV/r dose.

Abrocitinib, another JAK inhibitor recently approved for use in atopic dermatitis, is less dependent on CYP3A4 metabolism. Although elevated plasma concentrations are expected in co-administration of abrocitinib with NMV/r, their interaction has not been identified as clinically significant and there are no recommendations for dose adjustments or additional monitoring.¹⁹

Acitretin, apremilast, azathioprine, dimethyl fumarate, methotrexate, mycophenolate mofetil and sulfasalazine may be safely co-administered with NMV/r without expected clinically significant interaction. However, the risk of immunosuppressants such as azathioprine, methotrexate and mycophenolate mofetil exacerbating the COVID-19 infection should be weighed against the risk of a flare-up of the dermatological condition, before deciding whether to continue immunosuppressants during the COVID-19 infection.²⁰

Biologicals

Treatment with biologicals (Table 1) may be safely continued during treatment with NMV/r, without dose adjustment or additional clinical monitoring, if the patient is clinically indicated to continue biologicals during the COVID-19 infection.

Table 1. Preferred systemic dermatologic medications during nirmatrelvir-ritonavir use^a

^a Consult the Liverpool COVID-19 Drug Interactions website⁵ for updated drugs
Superscript number: refer to REFERENCES

Antibacterial drugs

Macrolides such as clarithromycin and erythromycin are indicated for use in acne, rosacea, and staphylococcal skin infections. When co-administered with NMV/r, the CYP3A4-mediated metabolism of clarithromycin and erythromycin is inhibited by ritonavir, and the raised plasma concentration of these macrolides increases the risk of side effects (e.g. hepatotoxicity and QT-interval prolongation).^21,22 For erythromycin, it is recommended to stop use and replace it with other antibacterial drugs with less interaction with NMV/r. Examples include replacing erythromycin with tetracycline-class drugs for acne and rosacea, and penicillins or cephalosporins for staphylococcal skin infections, barring any drug hypersensitivity. For clarithromycin, which is less dependent on CYP3A4 metabolism than erythromycin, careful monitoring for adverse effects is suggested, with dose reduction required only in patients with renal impairment (Kidney Disease Improving Global Outcomes stage ≥3, with creatinine clearance [CrCl] ≤60mL/min). Clarithromycin prescribing information suggests dose reduction by 50% and 75% in patients with CrCl 30–60mL/min and <30mL/min, respectively.²²

However, on use of clarithromycin in non-tuberculous mycobacterial infections, replacement by another antibiotic is recommended. Although co-administration of clarithromycin and ritonavir in NMV/r increases the plasma concentration of clarithromycin, there is a reduction in plasma concentration of the active metabolite 14-OH-clarithromycin. The efficacy of clarithromycin treatment might thus be compromised, and the physician should consider replacement with other antibiotics as appropriate.²²

Clindamycin and clofazimine are 2 other antibacterials that depend on CYP3A4 metabolism, and therefore require careful monitoring for adverse effects.

Rifampicin, an anti-tuberculosis agent, is also used in patients with hidradenitis suppurativa, as well as in staphylococcal and non-tuberculous mycobacterial infections.²³ As a potent CYP3A4 inducer, the co-administration of rifampicin with NMV/r would produce decreased plasma concentrations of ritonavir, a CYP3A4 substrate. This can significantly decrease the therapeutic effect of NMV/r, leading to poor treatment outcomes and promoting the development of viral resistance to NMV/r.²⁴ Also, as the induction of CYP3A4 by rifampicin persists for a long time after discontinuation, it is not sufficient to stop rifampicin use before starting NMV/r therapy.⁷ Therefore, it is recommended to consider an alternative COVID-19 treatment, such as molnupiravir, for patients on rifampicin.

Table 1 shows antibacterial drugs often used in skin disorders. The drugs lack an expected interaction with NMV/r, and may be safely continued during NMV/r treatment without dose adjustments or additional monitoring.

Antifungal agents

Systemic azoles, including fluconazole, itraconazole and ketoconazole, are commonly prescribed as oral treatment in extensive or resistant dermatophyte infections, pityriasis versicolor, and other cutaneous fungal infections. All the 3 azoles have significant DDIs with NMV/r as they inhibit CYP3A4 and would produce both raised plasma concentrations of NMV/r, and an increased risk of NMV/r adverse effects. Moreover, itraconazole and ketoconazole are also substrates of CYP3A4, and ritonavir-mediated CYP3A4 inhibition increases the bioavailability and plasma concentrations of these 2 azoles. This raises the risk of side effects, including gastrointestinal symptoms, transaminitis and QT-interval prolongation due to ketoconazole.

The recommendations for fluconazole include careful electrocardiogram (ECG) monitoring, as both fluconazole and ritonavir are known to prolong the QT interval; their concomitant use therefore increases the risk of an additive effect.²⁵ For itraconazole and ketoconazole, dose reduction to a maximum of 200mg daily is suggested, on top of monitoring for side effects.^26,27

Antiparasitic agents

The antihelminthic agent albendazole, when co-administered with ritonavir, decreases the plasma albendazole concentration.²⁸ Thus, monitoring for a reduced clinical response to albendazole therapy is proposed in co-administration with NMV/r.

Antihistamines

Antihistamines are one of the most commonly prescribed drugs in dermatology, ranging from use in pruritic skin dermatoses to cutaneous hypersensitivity reactions, such as urticaria and angioedema.

Hydroxyzine is dependent on hepatic CYP3A4 metabolism; co-administration with the CYP3A4-inhibitor ritonavir will result in elevated hydroxyzine plasma concentrations, increasing the risk of adverse effects, such as QT-interval prolongation.²⁹ Recommendations include close ECG monitoring for a prolonged QT interval.

Bilastine and rupatadine are second-generation antihistamines with significant drug interactions with NMV/r, as they are dependent on P-glycoprotein-mediated efflux and CYP3A4 metabolism, respectively—both processes which are inhibited by ritonavir. The resultant increase in plasma concentrations of these antihistamines increases the risk of side effects like QT-interval prolongation. The Lexicomp Drug Interactions resource lists both bilastine and rupatadine as contraindicated for concomitant use during ritonavir administration.^30,31 Discontinuation of these antihistamines during the NMV/r treatment course and for an additional 3 days after the last dose of NMV/r is recommended.

Other second-generation antihistamines, such as cetirizine, fexofenadine and loratadine are also dependent on P-glycoprotein-mediated efflux and CYP3A4 metabolism. Drug interaction with ritonavir may result in increased central antihistaminic effects, including drowsiness and prolonged reaction times, but with a minimal risk of severe adverse effects such as QT-interval prolongation. As such, no dosage adjustment or additional monitoring is suggested.

The preferred choices of antihistamines during NMV/r treatment include desloratadine, chlorpheniramine, diphenhydramine and buclizine, for which no clinically significant interactions are expected.

Anti-acne agents

Oral contraceptives with anti-androgenic properties are widely used in treating acne and hirsutism, and in polycystic ovarian syndrome with underlying hyperandrogenism and adult female acne. The synthetic oestrogen ethinyloestradiol is contained in combined oral contraceptive pills (COCPs) with various progestogens (progestins). In co-administration with ritonavir, the bioavailability and plasma concentration of ethinyloestradiol decrease, probably via ritonavir-mediated induction of CYP2C9 and CYP1A2. On the other hand, progestogen is primarily metabolised by CYP3A4, and elevated plasma progestogen results from the drug interaction with ritonavir, thus raising the risk of side effects, including irregular menstrual bleeding and venous thrombosis. Other side effects with certain progestogens include the risk of hyperkalaemia with drospirenone, as well as hepatotoxicity and hot flashes with cyproterone acetate. Recommendations for co-administration of progestogen-only pills or COCPs with NMV/r include careful monitoring for adverse effects. Patients taking COCPs should be advised to consider additional non-hormonal (i.e. barrier) contraceptives for the prevention of pregnancy during and up to 1 menstrual cycle after completing the course of NMV/r,⁷ although a clinically significant reduction in contraceptive efficacy is unlikely to result from a decreased plasma concentration of ethinyloestradiol during the standard short course of NMV/r.

Hair agents

Dutasteride and finasteride have been shown to be effective in the treatment of male androgenetic alopecia via the inhibition of dihydrotestosterone production. Of these 2 medications, dutasteride depends on CYP3A4 metabolism; drug interaction with the CYP3A4 inhibitor ritonavir elevates the plasma dutasteride concentration, and increases the risk of side effects, including erectile dysfunction and libido reduction. Close monitoring for the adverse effects is suggested for dutasteride, if used concomitantly with NMV/r.³² For finasteride, no additional monitoring is needed.

Topical and oral minoxidil are also used in the treatment of androgenetic alopecia. Minoxidil is not expected to have DDI with NMV/r, and systemic treatment may be safely continued without dosage adjustment or additional monitoring.

Other drugs commonly prescribed for dermatology patients

Colchicine is an anti-gout agent, and also used in treating skin disorders (e.g. leukocytoclastic and urticarial vasculitis, and neutrophilic dermatoses, including Sweet’s syndrome). Colchicine is primarily dependent on hepatic CYP3A4 metabolism; co-administration with the potent CYP3A4 inhibitor ritonavir greatly increases plasma colchicine concentrations, thereby risking potentially life-threatening acute colchicine toxicity, which encompasses severe gastrointestinal symptoms, seizures, bone marrow suppression and multiorgan failure.³³ The use of colchicine during NMV/r treatment is therefore contraindicated. If colchicine therapy is required in a patient who is taking or has taken NMV/r within the last 14 days, and there are no appropriate alternatives, dose reduction of colchicine is recommended (Table 2).³⁴

Table 2. Summary of drug interactions between nirmatrelvir-ritonavir (NMV/r) and dermatologic medications

Dyslipidaemia is common in the general population. In dermatology, abnormal plasma lipoproteins occur particularly in patients with psoriasis and hidradenitis suppurativa, which are conditions linked to the metabolic syndrome; and in patients receiving medications such as retinoids (e.g. isotretinoin and acitretin) and ciclosporin, which predispose to dyslipidaemia.³⁵ As the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors lovastatin, simvastatin and to a lesser degree, atorvastatin, primarily depend on CYP3A4 metabolism, their co-administration with the CYP3A4-inhibitor ritonavir can increase risks of statin-related myopathy and rhabdomyolysis. Lovastatin and simvastatin intake should cease at least 12 hours before the first dose of NMV/r, during NMV/r treatment, and for another 3 days after the last NMV/r dose.³⁶ For atorvastatin, brief cessation, or dose reduction to 10mg daily with resumption of its usual dose 3 days after completing NMV/r treatment, is recommended. Rosuvastatin is known to have an elevated plasma concentration when co-administered with ritonavir.³⁶ Thus, recommendations for rosuvastatin are similarly to stop temporarily or reduce dose to 10mg daily until 3 days after completing NMV/r treatment. Neither pravastatin nor fluvastatin are expected to have clinically significant interactions with NMV/r.

Molnupiravir

As of December 2022, the use of molnupiravir is still under Emergency Use Authorisation by FDA.³⁷ Molnupiravir has yet to be authorised for use in the European Union.³⁸ In Singapore, molnupiravir (LAGEVRIO) has been granted interim authorisation for the treatment of mild to moderate COVID-19 in patients aged ≥18 years, and are at risk of progression to severe COVID-19 and/or hospitalisation, as well as in cases when alternative COVID-19 treatment cannot be used.³⁹

Molnupiravir is administered as a prodrug, subsequently converted to the active metabolite β-D-N⁴-hydroxycytidine (NHC), phosphorylated, and incorporated by viral ribonucleic acid (RNA) polymerase into viral RNA, thereby inhibiting viral replication.⁴⁰ Further studies are needed to explore any potential long-term mutagenic effects of molnupiravir to the host.⁴¹

Currently, no DDIs involving molnupiravir have been identified. In vitro studies show that molnupiravir and its metabolite NHC are not substrates, inhibitors or inducers of major drug metabolising CYP450 enzymes. Also, they are not substrates of P-glycoprotein or breast cancer resistance protein efflux transporters, which are important mediators of intestinal absorption and subsequent excretion of drugs.³⁷ Therefore, molnupiravir can be an option for alternative COVID-19 therapy in patients who are clinically indicated for oral COVID-19 antiviral therapy, but are contraindicated for NMV/r. Molnupiravir is contraindicated during pregnancy, and men and women of childbearing potential should practise contraception for 3 months after the last dose.

Limitations

This present review has 4 main limitations. First, the list of drugs reviewed within this article is not exhaustive, and might not include newer drugs still pending approval by the European Medicines Agency and FDA. To the best of our knowledge, this is the most comprehensive and in-depth review of drug interactions between dermatological medications and the 2 current oral COVID-19 medications. Second, some of the drugs were not listed on the Liverpool COVID-19 Drug Interactions checker at the time of our literature search, and cannot be assumed to be safe to co-administer with NMV/r, although we attempted to corroborate with the individual product monographs. Third, given that NMV/r interacts with many medications, the focus on dermatological medications may be too specialised for generalists and other specialists. However, as patients in the community often present with comorbidities including dermatological conditions, information on DDIs between NMV/r and dermatological agents can be useful for physicians. Moreover, some of the medications discussed here are frequently prescribed by generalists and/or specialists (e.g. systemic glucocorticosteroids, antibiotics, statins, immunomodulators and biologicals). Lastly, information contained within our review is based on our literature search ending on 18 July 2022—recommendations and practices may vary between regions and with time.

CONCLUSION

Clinically significant DDIs exist between NMV/r and numerous dermatological medications, mostly due to CYP3A4 inhibition caused by ritonavir. Genetic variations in the CYP450 genes encoding the drug metabolising enzymes may also influence the extent of drug interaction between NMV/r and concomitant medication. Long-term dermatological medications linked to potential drug interactions should be withdrawn or dose-adjusted as appropriate, for 8 days to enable safe and timely access to treatment with NMV/r. Molnupiravir may be considered as an alternative COVID-19 therapy for patients who take medications that have complicated drug interactions with NMV/r, and are not suitable for temporary cessation or dose reduction.

Funding

This study is supported by the Singapore National Medical Research Council Centre Grant II Seed funding and National Skin Centre Medical Department Fund.

Disclosure

HH Oon is a speaker, advisory board member and researcher for Galderma, Janssen and Novartis. She has also been a clinical investigator for Pfizer, as well as a speaker and advisory board member for AbbVie and Eli Lilly.

REFERENCES

1. U.S. Food and Drug Administration. Coronavirus (COVID-19) Update: FDA Authorizes First Oral Antiviral for Treatment of COVID-19, 22 December 2021. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-first-oral-antiviral-treatment-covid-19. Accessed 18 July 2022.
2. U.S. Food and Drug Administration. Coronavirus (COVID-19) Update: FDA Authorizes Additional Oral Antiviral for Treatment of COVID-19 in Certain Adults, 23 December 2021. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-additional-oral-antiviral-treatment-covid-19-certain. Accessed 6 December 2022.
3. Patel RI, Beckett RD. Evaluation of resources for analyzing drug interactions. J Med Libr Assoc 2016;104:290-5.
4. Kheshti R, Aalipour M, Namazi S. A comparison of five common drug-drug interaction software programs regarding accuracy and comprehensiveness. J Res Pharm Pract 2016;5:257-63.
5. University of Liverpool. Liverpool COVID-19 Drug Interactions. https://www.covid19-druginteractions.org/checker. Accessed 18 July 2022.
6. Monteith S, Glenn T. Comparison of potential psychiatric drug interactions in six drug interaction database programs: A replication study after 2 years of updates. Hum Psychopharmacol 2021;36:e2802.
7. Paxlovid (nirmatrelvir and ritonavir) [package insert on the Internet]. New York, NY: Pfizer Laboratories Div Pfizer Inc; 2021. https://labeling.pfizer.com/ShowLabeling.aspx?id=16474. Accessed 18 July 2022.
8. Ritonavir-Boosted Nirmatrelvir (Paxlovid), updated 1 December 2022. https://www.covid19treatmentguidelines.nih.gov/therapies/antiviral-therapy/ritonavir-boosted-nirmatrelvir–paxlovid-/. Accessed 18 July 2022.
9. Katzenmaier S, Markert C, Riedel KD, et al. Determining the time course of CYP3A inhibition by potent reversible and irreversible CYP3A inhibitors using a limited sampling strategy. Clinical Pharmacol Ther 2011;90:666-73.
10. 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;75:3084-6.
11. UpToDate. Prednisolone: Drug information. https://www.uptodate.com/contents/prednisone-drug-information. Accessed 18 July 2022.
12. Neoral (cyclosporine) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2009.
13. Vogel M, Voigt E, Michaelis HC, et al. Management of drug-to-drug interactions between cyclosporine A and the protease-inhibitor lopinavir/ritonavir in liver-transplanted HIV-infected patients. Liver Transpl 2004;10:939-44.
14. Kim J, Chan JJ. Cyclophosphamide in dermatology. Australas J Dermatol 2017;58:5-17.
15. Cyclophosphamide [package insert]. Deerfield, IL: Baxter Healthcare Corporation; 2013.
16. Lexicomp Drug Interactions (Wolters Kluwer Health). Cyclophosphamide/CYP2B6 Inducers (Moderate). Accessed 18 July 2022.
17. Xeljanz (tofacitinib) [package insert]. New York, NY: Pfizer Inc; 2018.
18. Rinvoq (upadacitinib) [package insert]. North Chicago, IL: AbbVie Inc; 2022.
19. Cibinqo (abrocitinib) [package insert]. New York, NY: Pfizer Inc; 2021.
20. Lim ZV, Lim YL. Impact of COVID-19 on Clinical Operations and Management of Patients in a Singapore Immunodermatology Unit during the ‘Circuit-Breaker’ Period and Beyond. Ann Acad Med Singap 2020;49:919-21.
21. Erythro-base (erythromycin) [package insert]. Vaughan, ON: AA Pharma Inc; 2014.
22. Biaxin (clarithromycin) [package insert]. North Chicago, IL: AbbVie Inc; 2017.
23. Rifampin (rifampicin): Drug information. In: UpToDate. Waltham, MA.
24. U.S. Food and Drug Administration. Fact Sheet for Healthcare Providers: Emergency Use Authorisation for PAXLOVID™, revised 26 September 2022. https://www.fda.gov/media/155050/download. Accessed 18 July 2022.
25. Diflucan (fluconazole) [package insert on the Internet]. New York, NY: Roerig Div Pfizer Inc; 2022.
26. Sporanox (itraconazole) [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc; 2001.
27. Nizoral (ketoconazole) [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc; 2014.
28. Corti N, Heck A, Rentsch K, et al. Effect of ritonavir on the pharmacokinetics of the benzimidazoles albendazole and mebendazole: an interaction study in healthy volunteers. Eur J Clin Pharmacol 2009;65:999-1006.
29. Hydroxyzine (hydroxyzine) [package insert]. Vaughan, ON: AA Pharma Inc; 2018.
30. Lexicomp Drug Interactions (Wolters Kluwer Health). Bilastine/P-glycoprotein/ABCB1 Inhibitors. Accessed 18 July 2022.
31. Lexicomp Drug Interactions (Wolters Kluwer Health). Rupatadine/CYP3A4 Inhibitors (Strong). Accessed 18 July 2022.
32. Avodart (dutasteride) [package insert]. Mississauga, ON: GlaxoSmithKline Inc; 2013.
33. Davis MW, Wason S, Digiacinto JL. Colchicine-antimicrobial drug interactions: what pharmacists need to know in treating gout. Consult Pharm 2013;28:176-83.
34. Colcrys (colchicine) [package insert]. Deerfield, IL: Takeda Pharmaceuticals America, Inc; 2012.
35. Shenoy C, Shenoy MM, Rao GK. Dyslipidemia in Dermatological Disorders. N Am J Med Sci 2015;7:421-8.
36. Kiser JJ, Gerber JG, Predhomme JA, et al. Drug/Drug interaction between lopinavir/ritonavir and rosuvastatin in healthy volunteers. J Acquir Immune Defic Syndr 2008;47:570-8.
37. U.S. Food and Drug Administration. Fact Sheet for Healthcare Providers: Emergency Use Authorisation for LAGEVRIO™ (molnupiravir) Capsules. https://www.fda.gov/media/155054/download. Accessed 18 July 2022.
38. European Medicines Agency. COVID-19 treatments. https://www.ema.europa.eu/en/human-regulatory/overview/public-health-threats/coronavirus-disease-covid-19/treatments-vaccines/covid-19-treatments. Accessed 20 December 2022.
39. Health Sciences Authority, Singapore. HSA Grants Interim Authorisation for LAGEVRIO (Molnupiravir) for Treatment of COVID-19 Infection, 19 April 2022. https://www.hsa.gov.sg/announcements/press-release/interimauth-lagevrio-molnupiravir. Accessed 20 December 2022.
40. Extance A. Covid-19: What is the evidence for the antiviral molnupiravir? BMJ 2022;377:o926.
41. Rahmah L, Abarikwu SO, Arero AG, et al. Oral antiviral treatments for COVID-19: opportunities and challenges. Pharmacol Rep 2022;1255-78.