Cutaneous adverse reactions to the new oral antiviral drugs against SARS‐CoV‐2

Dear Editor,

Currently, there are two oral antivirals directed to SARS‐CoV‐2: molnupiravir (Lagevrio^®), which induces an antiviral effect via viral error catastrophe, and nirmatrelvir–ritonavir (Paxlovid™) (nirmatrelvir inhibits an enzyme needed for coronavirus replication and ritonavir decreases metabolism of nirmatrelvir, maintaining its antiviral activity at higher levels). Both are indicated for the treatment of mild to moderate COVID‐19 in adults who do not require supplemental oxygen and who are at increased risk for progressing to severe COVID‐19.

Given the recent approval of both drugs, this letter aims to raise awareness of possible cutaneous adverse effects (AEs) related to their administration. These effects may be due to the COVID infection alone, the drug alone, or to the interaction between the virus and the drug (or one of its metabolites).

In Phase 1, 2 and 3 clinical trials, molnupiravir has demonstrated good efficacy and safety. AEs related to skin and subcutaneous tissue were mild to moderate and uncommon (≥ 1 in 1000 to < 1 in 100). ¹ (Table 1). The reported cutaneous adverse reactions were rash, acne, pruritus and skin exfoliation in a Phase 1 trial, ² and rash, pruritus, urticarial and allergic dermatitis, in a Phase 2/3 study. ¹ In the Phase 1 trial, one participant discontinued the drug because of an AE of a mildly maculopapular pruritic rash of the trunk, which resolved with topical steroids and oral antihistamines. ²

Table 1.

Reported cutaneous adverse events with molnupiravir and nirmatrelvir/ritonavir.

Adverse effect, n (%)	Phase 1		Phase 2		Phase 2/3
	NCT04392219 a		NCT04575597: MOVE‐OUT b		NCT04960202: 1005 EPIC HR c
	Active (n = 110)	Placebo (n = 30)	Active (n = 86)	Placebo (n = 379)	Active (n = 1109)	Placebo (n = 1115)
Rash
Unspecified	2 (1.8)	0 (0.0)	3 (0.8)	1 (0.3)	2 (0.2)	3 (0.3)
Maculopapular	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	1 (0.1)	0 (0.0)
Pruritus	1 (0.9)	0 (0.0)	1 (0.3)	0 (0.0)	1 (0.1)	0 (0.0)
Urticaria	0 (0.0)	0 (0.0)	1 (0.3)	1 (0.3)	0 (0.0)	2 (0.2)
Allergic dermatitis	0 (0.0)	0 (0.0)	1 (0.3)	0 (0.0)	0 (0.0)	0 (0.0)
Skin exfoliation	1 (0.9)	0 (0.0)	0 (0.0)	0 (0.0)	2 (0.2)	0 (0.0)
Skin oedema	0 (0.0)	0 (0.0)	0 (0.0)	1 (0.3)	1 (0.1)	0 (0.0)
Hyperkeratosis	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	1 (0.1)	0 (0.0)
Hyperhidrosis	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	1 (0.1)	0 (0.0)
Acne	1 (0.9)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	1 (0.1)
Alopecia	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	1 (0.1)	1 (0.1)
Erythema	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	4 (0.4)

^a COVID‐19 first in human study to evaluate safety, tolerability and pharmacokinetics of molnupiravir in healthy volunteers.

^b Efficacy and safety of molnupiravir in nonhospitalized adult participants with COVID‐19 (Cl).

^c EPIC HR: treatment in patients COVID‐19 positive at high risk with nirmatrelvir/ritonavir: Pfizer preliminary data up to 19 January 2022.

Nirmatrelvir/ritonavir reduces hospitalization rates and deaths by 80%–90% among patients with COVID‐19 who are at high risk for severe illness. ³ AEs related to skin and subcutaneous tissue are uncommon (≥ 1 in 1000 to < 1 in 100) or rare (≥ 1 in 10 000 to < 1 in 1000) ³ (Table 1).

In the Phase 2/3 Study 1005 EPIC HR, nirmatrelvir–ritonavir was administered to 1109 patients (data up to 19 January 2022). According to the preliminary data, adverse skin reactions are mild–moderate in severity and include rash (maculopapular), skin exfoliation, pruritus, skin oedema, hyperkeratosis, hyperhidrosis and alopecia. ³

Adverse cutaneous drug reactions occur much more frequently in HIV‐infected patients than in the general population. ⁴ Ritonavir use in patients with chronic HIV infection requires a higher dose and longer duration than the precluded therapeutic 5‐day course of paxlovid, thus previously known data regarding the cutaneous AEs of its administration in this population are not generalizable to paxlovid.

In patients with COVID‐19 treated exclusively with lopinavir–ritonavir, there was one report of acute generalized exanthematous pustulosis with erythema multiforme‐like lesions and a prevalence of 1.8%–3.2% of patients with a mild, self‐limiting maculopapular rash. ⁵ This drug did not demonstrate clinical benefit in patients with COVID‐19.

In summary, the new oral antivirals against SARS‐CoV‐2 appear to have a low frequency and severity of cutaneous AES, with a favourable risk–benefit ratio for use. However, further clinical studies are needed to better characterize these AEs with regard to their type, morphology and treatment. More reports are expected after the commercialization of both drugs, which will help clarify these reactions. To date, the number of patients exposed to the drugs are too small to predict the incidence of severe AEs, which nevertheless seem to be rare. In addition, all studies demonstrating clinical benefit of these drugs in patients with COVID‐19 patients were conducted in unvaccinated individuals and most in unimmunized individuals with no previous infection. Considering the current high immunization status in some countries, a clinical and cost–benefit advantage of these drugs is still to be demonstrated.