Table 3.
Summary of reports of drug-drug interaction (excluding immunosuppressant) with nirmatrelvir/ritonavir (Paxlovid®) recorded in the French Pharmacovigilance database over the period from 01/20/2022 to 12/03/2022.
| Sex | Age group (years) | Seriousness (Y/N) | Drug | DDI description | Dose adjustment before Paxlovid® initiation? | ADRs related to the DDI | Time of occurrence from the beginning of Paxlovid® (D) | Comment |
|---|---|---|---|---|---|---|---|---|
| F | 80–90 | Y | Digoxine | Proven plasma overdose of digoxin (via probable inhibition of P-gP by ritonavir) | None | None | 5 | Evolution: favorable after stopping Paxlovid® and suspension of digoxin |
| M | 90–100 | Y | Apalutamide | Probable elevated plasma concentrations of apalutamide (NB: risk of reduction of nirmatrelvir by apalutamide) | None | Prolonged QT interval (506 ms versus 475 ms) Movement disorder (without précision) |
5 | Contraindicated combination Evolution: death (on possible cerebral hemorrhage) at D5 of the discovery of the effect |
| F | 70–80 | N | Verapamil | Probable increase in plasma verapamil concentrations | None | Bradycardia | 1 | Not recommended combination |
| M | 70–80 | Y | Atenolol (switch from bisoprolol) amlodipine (switch from lercanidipine) | Not expected with β-blockers or amlodipine | None | Bradycardia Hypotension Palpitations |
2 | Pharmacodynamic interaction between antihypertensives due to slowing down lercanidipin removal? + Problem with dose equivalency during therapeutic switchs? |
| F | 80–90 | N | Rifampicin/clindamycin | Double DDI (on CYP3A4): – between clindamycin and rifampicin (risk of ineffectiveness of clindamycin and nirmatrelvir by induction) – between ritonavir and clindamycin (likely elevated plasma concentrations of clindamycin by inhibition) |
None | Hepatic cytolysis | 7 | Contraindicated combination (rifampicine & Paxlovid®) Unexpected adverse effect (i.e., hepatic cytolysis) in this context |
| F | 50–60 | Y | Dapsone | Probable increase in formation of methemogloucizing metabolite of dapsone (by enzymatic induction of CYP2C9 and 2C19) | None | Methaemoglobinaemia (6% vs. 0.3%) | 3 | Evolution: favorable after stopping Paxlovid® and suspension of dapsone |
| M | 50–60 | Y | Fentanyl (+ mirtazapine & sertraline) | Probable increase in plasma concentrations of fentanyl, mirtazapine and sertraline | None | Bradycardia | 2 | Association with fentanyl not recommended in FSPT recommendations + Association contraindicated not taken into account with simvastatin |
| F | 70–80 | N | Atorvastatine | Probable increase in plasma concentrations of atorvastatin | ND | Muscle cramps | 3 | Association not recommended |
| M | 70–80 | N | Atorvastatine/amiodarone | Probable increase in plasma concentrations of atorvastatin and amiodarone | None | Acute hepatitis Rhabdomyolysis |
2 | Association not recommended with atorvastatin Contraindicated combination with amiodarone |
| Fluindione | Not expected (via enzyme induction?) | INR increase | Increase in INR at distance from stopping Paxlovid® = paradoxical with respect to expected DDI | |||||
| M | 70–80 | N | Fluindione | Not expected (via enzyme induction?) | None | INR reduction | 11 | – |
| F | 70–80 | N | Acenocoumarol | Possible decrease in plasma VKA concentrations (via enzyme induction) | None | INR reduction and then increase | 18 | Increase in INR at distance from stopping Paxlovid® = paradoxical with respect to expected DDI Hypothesis of a rebound effect due to the lifting of enzymatic induction = unlikely (no change in AVK dosage |
| M | 70–80 | Y | Rivaroxaban | Plasma overdose proven in rivaroxaban | None | Melena | 4 | Not recommended combination Evolution: favorable after stopping Paxlovid® and suspension of oral anticoagulant |
| M | 70–80 | Y | Enoxaparin | Not expected with heparins (pharmacodynamic interaction between anticoagulants due to slower elimination of rivaroxaban?) | Yes (relay of oral anticoagulant by heparin) | Muscle hematoma Acute post-hemorrhagic anemia |
9 | Incidental discovery of bleeding away from stopping Paxlovid® (already present before Paxlovid®?) |
| M | 80–90 | Y | Calcium heparin | Muscle hematoma | 9 | Off label use (Oxygen Patient Requiring Prior to Paxlovid®) Incidental discovery of bleeding away from stopping Paxlovid® (already present before Paxlovid®?) |
ADR: adverse drug reaction; D: day; DDI: drug-drug interaction; F: female; FSPT: French Society of Pharmacology and Therapeutics; INR: international normalized ratio; M: male; Y: yes.