Medicinal product interactions of Paxlovid (nirmatrelvir/ritonavir) with certain immunosuppressants
Medicinal product interactions of Paxlovid (nirmatrelvir/ritonavir) with certain immunosuppressants
Paxlovid is used to treat coronavirus disease 2019 (COVID-19) in adults who do not require oxygen therapy or hospitalisation due to COVID-19 and who are at increased risk of developing a severe form of COVID-19. Paxlovid (nirmatrelvir, ritonavir) is a strong CYP3A inhibitor.
Particular attention should be paid to this mechanism of action when other medicinal products are used concomitantly. Medicinal products with strongly CPY3A-dependent clearance – including oncologicals such as venetoclax, immunosuppressants such as tacrolimus, statins such as simvastatin and antipsychotics such as clozapine – are contraindicated with Paxlovid.
Paxlovid, CYP3A4, inhibitors, tacrolimus, narrow therapeutic range, trazodone, ritonavir, nirmatrelvir, COVID-19
Incident data |
Description |
Case: 2022 Age group: 25-55 years Sex: Female Medicinal products: Paxlovid®, Advagraf™ Active substances: Nirmatrelvir/ritonavir, tacrolimus Indication: COVID-19 infection (Paxlovid®); prevention of transplant rejection (Advagraf™) ADRs: Pharmacokinetic interaction, hypertension, headache Outcome: Recovering |
Following a heart transplant 10 years ago, the patient was being treated with tacrolimus and azathioprine, among others. Due to a positive SARS-CoV-2 test, outpatient treatment with Paxlovid was started on the same day. The tacrolimus dosage was left unchanged. The patient developed severe headaches and presented at the emergency department. On admission, her blood pressure values were substantially elevated. Other clinical findings were normal. Her tacrolimus level was 10 times higher than the previous levels. Tacrolimus was therefore paused and Paxlovid was stopped. While the patient was in hospital, her tacrolimus level fell but was still elevated four days after being discontinued. The patient's clinical picture subsequently improved. |
Case: 2022 Age group: >65 years Sex: Male Medicinal products: Paxlovid®, Prograf™, Trittico® Active substances: Nirmatrelvir/ritonavir, tacrolimus, trazodone. Indication: COVID-19 infection (Paxlovid®); prevention of transplant rejection (Prograf™); depression (Trittico®) ADRs: Acute on chronic renal failure, hyperkalaemia, prolonged QTc interval, metabolic acidosis, pharmacokinetic interaction Outcome: Recovered |
During hospitalisation due to urosepsis, COVID-19 infection was detected in the patient and treatment with Paxlovid was started. Two days after starting this treatment, an elevated tacrolimus level was determined. The patient developed increasing acute on chronic renal failure with severe hyperkalaemia, metabolic acidosis and incipient ECG changes; emergency dialysis was necessary. Paxlovid was stopped and treatment with tacrolimus and trazodone was paused. Acute tacrolimus and trazodone toxicity in the context of a pharmacokinetic interaction with Paxlovid was assumed to be the cause of the symptoms. |
Summary and recommendation
As a strong CYP3A inhibitor, Paxlovid can significantly inhibit the clearance of CYP3A substrates. The resulting elevated level can lead to severe, in some cases life-threatening reactions, particularly for medications with a narrow therapeutic range. Caution is therefore advised in the case of concomitant administration of immunosuppressants such as calcineurin inhibitors (ciclosporin, tacrolimus) and mTOR inhibitors (everolimus and sirolimus), among others.
Cases with a very rapid, sharp rise in the tacrolimus level within just 1–3 days following concomitant use of a strong CYP3A inhibitor and despite an immediate reduction in the tacrolimus dose have been reported for tacrolimus. It is therefore strongly recommended that, in the first few days of concomitant use, the tacrolimus level in the blood and renal function be monitored and that the patient be observed for a prolongation of the QT interval on an electrocardiogram, as well as for the occurrence of other side effects.
CYP3A4 inhibitors can also lead to significant increases in the plasma concentrations of trazodone. Studies in healthy patients found that the plasma concentration of trazodone more than doubled with administration of 200 mg ritonavir twice daily, resulting in nausea, syncope and hypotension. If trazodone is administered with a strong CYP3A4 inhibitor, a lower dose of trazodone should be considered. In more severe cases, this can result in coma, tachycardia, hypotension, hyponatraemia, seizures and respiratory arrest. Possible cardiac symptoms include bradycardia, a prolonged QT interval and Torsade de Pointes tachycardia. Symptoms can occur within 24 hours of the overdose or later.
Statutory duty of healthcare professionals to report adverse drug reactions (ADRs)
In Switzerland, healthcare professionals who are authorised to dispense or administer medicinal products are obligated to report severe and/or previously unknown side effects. Reports to Swissmedic can be entered and sent in the Electronic Vigilance Reporting Portal “ElViS” (ElViS login).
Supplementary information
www.swissmedicinfo.ch
Medicinal product information Paxlovid®, Advagraf™, Prograf™, Trittico® Information for healthcare professionals
