Liverpool COVID-19 Interactions

Potential Interaction

Nirmatrelvir/ritonavir (5 days)

Nifedipine

Quality of Evidence: Very Low

Summary:

Coadministration has not been assessed in clinical studies. Nifedipine is metabolised mainly by CYP3A4. Nirmatrelvir/ritonavir is a strong inhibitor of CYP3A4 and coadministration may substantially increase plasma concentrations of nifedipine as nifedipine is a sensitive CYP3A4 substrate. Results from a PBPK/PD modelling study predict that coadministration of nifedipine and ritonavir (100 mg twice daily) could profoundly increase nifedipine Cmax and AUC which may lead to hypotension. A probable interaction with nirmatrelvir/ritonavir and nifedipine has been reported in a 79-year old woman whose concomitant medications included extended release nifedipine (60 mg daily) and who developed acute exacerbation of chronic heart failure and kidney injury after 3 days of nirmatrelvir/ritonavir. Coadministration should be avoided where possible or, if clinically necessary, use with caution and a dose reduction of 50% or taking the dose every other day should be considered. If coadministered, patients should be advised to monitor for side effects such as hypotension, flushing, and oedema, and, if necessary, to temporarily pause the antihypertensive drug if needed. If the dose is adjusted, the usual dose of nifedipine should be resumed 3 days after the last dose of nirmatrelvir/ritonavir as the inhibitory effect of ritonavir is expected to last up to 3 days after completing nirmatrelvir/ritonavir.

Description:

Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent inhibits CYP3A4 and as a result is expected to increase the plasma concentrations of calcium channel antagonists. Careful monitoring of therapeutic and adverse effects is recommended when this medicine is concomitantly administered with ritonavir.

Paxlovid GB Summary of Product Characteristics, Pfizer Ltd, December 2024.

Paxlovid EU Summary of Product Characteristics, Pfizer, February 2025.

Co-administration may increase concentrations of the calcium channel blocker. Caution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co-administered with Paxlovid. If co-administered, refer to individual product label for the calcium channel blocker for further information.

Paxlovid US Prescribing Information, Pfizer Inc, February 2025.

A probable interaction with nirmatrelvir/ritonavir and nifedipine was observed in a 79-year old woman whose concomitant medications included nifedipine extended-release 60 mg daily. After 3 days of nirmatrelvir/ritonavir, she presented with new swelling in extremities, a feeling of abdominal fullness, malaise, and decreased urine output, which were not resolved with self-administered furosemide. Significant laboratories upon hospital admission included increased serum creatinine (2.68 mg/dL versus baseline of 1.6-2.1 mg/dL) and N-terminal pro-brain natriuretic peptide (NT-proBNP) of 3688 pg/mL (reference range: 0-450 pg/mL). An electrocardiogram (ECG) report showed left anterior fascicular block. Physical exam was notable for 2+ lower extremity edema to the knees and trace edema in the hands, blood pressure of 120/54 mm Hg, and heart rate of 60 bpm. Her nirmatrelvir/ritonavir and nifedipine medications were discontinued upon admission due to suspicion of a drug-drug interaction, which presented as acute exacerbation of CHF and kidney injury. Edema and renal function normalized with minimal medical intervention over the next 2 days until the patient was discharged home. Her nifedipine and other medications were restarted upon discharge; nirmatrelvir/ritonavir was permanently discontinued. Subsequent outpatient clinic visits demonstrated continued tolerance of nifedipine.

A CYP3A4 drug-drug interaction between nirmatrelvir/ritonavir and nifedipine leading to edema, oliguria, and acute kidney injury: a case report. Rauser MS, McGrane IR. Ann Pharmacother. 2023, 57(8):991-992.

PBPK/PD models for 3 formations of nifedipine were developed based on the Simcyp nifedipine model and the models were verified using published data. The effects of ritonavir on nifedipine exposure and systolic blood pressure (SBP) were assessed for instant-release, sustained-release and controlled-release formulations in patients. The predicted maximum concentration (Cmax), area under plasma concentration-time curve (AUC), maximum reduction in SBP and area under effect-time curve were all within 0.5-2.0-fold of the observed data. Model simulations showed that the inhibitory effect of ritonavir on CYP3A4 increased the Cmax of nifedipine 17.92-48.85-fold and the AUC 63.30-84.01-fold at steady state and decreased the SBP by >40 mmHg. Thus, the combination of nifedipine and ritonavir could lead to severe hypotension. It is not recommended for patients to take nifedipine- and ritonavir-containing regimens simultaneously.

Investigating the interaction between nifedipine- and ritonavir-containing antiviral regimens: A physiologically based pharmacokinetic/pharmacodynamic analysis. Niu W, Li S, Jin S, et al. Br J Clin Pharmacol. 2021; 87(7):2790-2806.