Ensitrelvir

Ensitrelvir (500 mg single dose) increased the C_max and AUC_0-inf of the BCRP substrate rosuvastatin by 1.97- and 1.65-fold, thus ensitrelvir is an inhibitor of BCRP. Caution should be exercised in case of concomitant treatment with sensitive BCRP substrates with narrow therapeutic index.

Based on in vitro studies, there is a potential for ensitrelvir to inhibit OAT3 at clinically relevant concentrations. No in vivo study has been performed. Caution should be exercised when OAT3 substrates with a narrow therapeutic index (e.g., methotrexate) are given concomitantly.

Concomitant use of moderate CYP3A inducers with ensitrelvir is not recommended, but in case it is necessary, the prescriber should be aware that this may lead to a decreased exposure of ensitrelvir and a potential loss of virologic response.

Ensitrelvir is a strong CYP3A inhibitor since ensitrelvir 375/125 mg increased C_max and AUC of midazolam by 2.80- and 6.77-fold, respectively and increases plasma concentrations of medicinal products that are primarily metabolised by CYP3A. Co-administration of ensitrelvir with medicinal products highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated. Co-administration of other CYP3A substrates that may lead to potentially significant interactions should be considered only if the benefit outweighs the risk.

In vitro studies with ensitrelvir showed inhibitory effects on CYP2C8 and inductive effects on CYP2B6, CYP2C8, CYP2C9 and CYP2C19. No in vivo studies have been performed. Ensitrelvir might decrease exposure of substrates of CYP2B6 (e.g. bupropion), CYP2C9 (e.g. S-warfarin) and CYP2C19 (e.g. omeprazole). Additionally, ensitrelvir might either increase or decrease exposure of substrates of CYP2C8 (e.g. repaglinide).

Ensitrelvir (500 mg single dose) increased the C_max and AUC_0-inf of the P-gp substrate digoxin by 2.17- and 1.31-fold, thus ensitrelvir is an inhibitor of P-gp. Caution should be exercised in case of concomitant treatment with sensitive P-gp substrates with narrow therapeutic index (e.g. digoxin, dabigatran). Close drug monitoring for safety and efficacy should be performed, and the dose may be adjusted accordingly.

Ensitrelvir is not recommended for use in patients with severe hepatic impairment.

Concomitant use with ensitrelvir is not recommended since alfuzosin blood levels may be increased.

Ensitrelvir inhibits CYP3A and as a result is expected to increase the plasma concentrations of aprepitant and loperamide.

Ensitrelvir inhibits CYP3A and as a result is expected to increase the plasma concentrations of atorvastatin (refer to atorvastatin SmPC).

• Axitinib
• Bortezomib
• Bosutinib
• Cabazitaxel
• Crizotinib
• Dasatinib
• Docetaxel
• Erlotinib
• Gefitinib
• Imatinib
• Irinotecan
• Lapatinib
• Nilotinib
• Panobinostat
• Ponatinib
• Ruxolitinib
• Sunitinib
• Temsirolimus

Ensitrelvir may increase plasma concentrations, resulting in the potential for increased incidence of adverse events. Refer to the individual SmPC for more information.

Ensitrelvir inhibits CYP3A and as a result is expected to increase the plasma concentrations of bromocriptine.

Ensitrelvir inhibits CYP3A and increases the plasma concentrations of dexamethasone. It is also expected to increase the plasma concentrations of budesonide, ciclesonide, and methylprednisolone. Caution is recommended in case of concomitant use, refer to individual SmPCs.

Ensitrelvir inhibits CYP3A and as a result is expected to increase the plasma concentrations of cyclosporine and tacrolimus. This co-administration should only be considered with close and regular monitoring of immunosuppressant blood concentrations, to reduce the dose of the immunosuppressant in accordance with the latest guidelines and to avoid over-exposure and subsequent increase of serious adverse reactions of the immunosuppressant. It is important that the close and regular monitoring is performed not only during the co-administration with ensitrelvir but is also pursued after the treatment with ensitrelvir.

Ensitrelvir inhibits CYP3A and as a result is expected to increase the plasma concentrations of cinacalcet. Dose adjustments may be needed.

The effect of ensitrelvir (750 mg on Day 1 and 250 mg on Days 2 to 5) on the pharmacokinetics of dexamethasone and prednisolone (both CYP3A4 substrates) were investigated. Dexamethasone exposure increased with co-administration of ensitrelvir and this effect decreased over time following the last dose of ensitrelvir. The C_max and AUC_0-inf of dexamethasone on Day 5 increased 1.47-fold and 3.47-fold, those on day 9 increased 1.24-fold and 2.38-fold and those on Day 14 (10th day after the last ensitrelvir dose) increased 1.17-fold and 1.58-fold, compared to those following single-dose administration of dexamethasone alone. Caution is recommended in case of concomitant treatment with dexamethasone. Administration of ensitrelvir did not have any clinically meaningful effect on the pharmacokinetics of prednisolone.

Ensitrelvir may increase plasma concentrations of disopyramide which could result in an increased risk of adverse events such as cardiac arrhythmias. Caution is warranted and therapeutic concentration monitoring is recommended for disopyramide if available.

Ensitrelvir inhibits CYP3A and as a result is expected to increase the plasma concentrations of eletriptan. Ensitrelvir should not be used with eletriptan.

Ensitrelvir inhibits CYP3A and as a result is expected to increase the plasma concentrations of everolimus and sirolimus. This co-administration should only be considered with close and regular monitoring of immunosuppressant blood concentrations, to reduce the dose of the immunosuppressant in accordance with the latest guidelines and to avoid over-exposure and subsequent increase of serious adverse reactions of the immunosuppressant. It is important that the close and regular monitoring is performed not only during the co-administration with ensitrelvir but is also pursued after the treatment with ensitrelvir.

Ensitrelvir inhibits CYP3A and as a result is expected to increase the plasma concentrations of guanfacine. Dose adjustment is recommended, refer to guanfacine SmPC.

Plasma concentrations of ibrutinib may be increased due to CYP3A inhibition by ensitrelvir, resulting in increased risk for toxicity including risk of tumour lysis syndrome. Co-administration of ibrutinib and ensitrelvir should be avoided. If the benefit is considered to outweigh the risk and ensitrelvir must be used, reduce the ibrutinib dose to 140 mg and monitor patient closely for toxicity.

Ensitrelvir may increase plasma concentrations of ivosidenib, which may increase the risk of toxicity, including the risk of serious adverse events such as QT interval prolongation. Ivosidenib is also a CYP3A inducer and this may lead to a decreased exposure of ensitrelvir and potential loss of virologic response. Co-administration should be avoided (refer to the ivosidenib SmPC for more information).

Ensitrelvir is expected to increase the plasma levels of maraviroc as a result of CYP3A inhibition. For further information, refer to the SmPC for maraviroc.

Ensitrelvir may increase plasma concentrations of neratinib. Therefore, the co-administration of neratinib with ensitrelvir is not recommended. Refer to the neratinib SmPC for more information.

Ensitrelvir inhibits CYP3A and as a result is expected to increase the plasma concentrations of oxybutynin.

An increase in rifabutin exposure is expected due to the inhibition of CYP3A by ensitrelvir.

Plasma concentrations may be increased due to CYP3A and P-gp inhibition by ensitrelvir. The co-administration of riociguat with ensitrelvir is not recommended.

Ensitrelvir inhibits BCRP and as a result increases the plasma concentrations of rosuvastatin (refer to rosuvastatin SmPC).

Concomitant use with ensitrelvir is not recommended since silodosin blood levels may be increased.

Ensitrelvir inhibits CYP3A and as a result is expected to increase the plasma concentrations of tofacitinib. Dose adjustment of tofacitinib is recommended. Refer to the tofacitinib SmPC for more information.

Ensitrelvir inhibits CYP3A and as a result is expected to increase the plasma concentrations of tolvaptan. Dose reduction of tolvaptan is recommended for patients. Refer to the tolvaptan SmPC for more information.

Ensitrelvir inhibits CYP3A and as a result is expected to increase the plasma concentrations of zopiclone. Dose adjustments may be needed.

There is a limited amount of data from the use of ensitrelvir in pregnant women. Studies in animals have shown reproductive toxicity. Ensitrelvir is contraindicated during pregnancy.

It is unknown whether ensitrelvir is excreted in human milk. A non-clinical study in rats has shown that ensitrelvir is excreted in milk. A risk to the suckling child cannot be excluded. Therefore, breast-feeding is not recommended during treatment and for 2 weeks after the last dose of ensitrelvir.

Women of childbearing potential/contraception in males and females

Women of childbearing potential have to use effective contraception during treatment with ensitrelvir and for 2 weeks after the last dose of ensitrelvir. Pregnancy must be excluded before starting treatment.

Fertility

The effect of ensitrelvir on fertility in humans has not been studied. Based on animal study data, there is no evidence that ensitrelvir has an effect on male or female fertility.

Ensitrelvir has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

The most common adverse reactions are hypertriglyceridaemia (5.4%), headache (2.7%), diarrhoea (1.9%) and nausea (1.1%).

The most serious adverse reactions are anaphylaxis and anaphylactic shock (frequency not known).

Tabulated list of adverse reactions

The safety profile of the product is based on adverse reactions reported in clinical trials and spontaneous reporting. The adverse reactions in Table 2 below are listed by system organ class and frequency. Frequencies are defined as follows: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); not known (frequency cannot be estimated from the available data).

Table 2. Adverse reactions:

^* Post-marketing data

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.