Nirmatrelvir and Ritonavir interacts in the following cases:
Nirmatrelvir and ritonavir are CYP3A substrates; Initiation of medicinal products that inhibit or induce CYP3A may increase or decrease concentrations of combination of nirmatrelvir with ritonavir, respectively.
These interactions may lead to:
Nirmatrelvir in combination with ritonavir is an inhibitor of CYP3A and may increase plasma concentrations of medicinal products that are primarily metabolised by CYP3A. Medicinal products that are extensively metabolised by CYP3A and have high first pass metabolism appear to be the most susceptible to large increases in exposure when coadministered with nirmatrelvir/ritonavir. Thus, coadministration of nirmatrelvir/ritonavir 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.
Initiation of combination of nirmatrelvir with ritonavir, a CYP3A inhibitor, in patients receiving medicinal products metabolised by CYP3A or initiation of medicinal products metabolised by CYP3A in patients already receiving the combination of nirmatrelvir with ritonavir, may increase plasma concentrations of medicinal products metabolised by CYP3A.
In patients with moderate renal impairment (eGFR ≥30 to <60 mL/min), the dose should be reduced to nirmatrelvir/ritonavir 150 mg/100 mg every 12 hours for 5 days to avoid over-exposure (this dose adjustment has not been clinically tested).
No clinical data are available in patients with severe renal impairment (including patients with ESRD). Based on pharmacokinetic data, the use of nirmatrelvir/ritonavir in patients with severe renal impairment could lead to over-exposure with potential toxicity. No recommendation in terms of dose adjustment could be elaborated at this stage pending dedicated investigation. Therefore, nirmatrelvir/ritonavir should not be used in patients with severe renal impairment (eGFR <30 mL/min, including patients with ESRD under haemodialysis).
No pharmacokinetic and clinical data are available in patients with severe hepatic impairment. Therefore, nirmatrelvir/ritonavir should not be used in patients with severe hepatic impairment.
Interaction – AUC change, Cmax change: ↑ Apalutamide
Clinical comments: Apalutamide is a moderate to strong CYP3A4 inducer and this may lead to a decreased exposure of nirmatrelvir/ritonavir and potential loss of virologic response. In addition, serum concentrations of apalutamide may be increased when coadministered with ritonavir resulting in the potential for serious adverse events including seizure. Concomitant use of nirmatrelvir/ritonavir with apalutamide is not recommended.
Hepatic transaminase elevations, clinical hepatitis and jaundice have occurred in patients receiving ritonavir. Therefore, caution should be exercised when administering nirmatrelvir/ritonavir to patients with pre-existing liver diseases, liver enzyme abnormalities or hepatitis.
Because nirmatrelvir is coadministered with ritonavir, there may be a risk of HIV-1 developing resistance to HIV protease inhibitors in individuals with uncontrolled or undiagnosed HIV-1 infection.
There are no data from the use of nirmatrelvir/ritonavir in pregnant women.
There was no nirmatrelvir-related effect on foetal morphology or embryo-foetal viability at any dose tested in rat or rabbit embryo-foetal developmental toxicity studies although lower foetal body weights were observed in rabbit.
A large number of women exposed to ritonavir during pregnancy indicate no increase in the rate of birth defects compared to rates observed in population-based birth defect surveillance systems.
Animal data with ritonavir have shown reproductive toxicity.
Nirmatrelvir/ritonavir is not recommended during pregnancy and in women of childbearing potential not using contraception unless the clinical condition requires treatment with nirmatrelvir/ritonavir.
There are no data on the use of nirmatrelvir/ritonavir in breast-feeding women.
It is unknown whether nirmatrelvir is present in human or animal milk, and the effects of it on the breast-fed newborn/infant, or the effects on milk production. Limited published data reports that ritonavir is present in human milk. There is no information on the effects of ritonavir on the breast-fed newborn/infant or on milk production. A risk to the newborn/infant cannot be excluded. Breast-feeding should be discontinued during treatment and as a precautionary measure for 7 days after completing nirmatrelvir/ritonavir.
There are no data on the use of nirmatrelvir/ritonavir in pregnant women to inform the drug-associated risk of adverse developmental outcomes; women of childbearing potential should avoid becoming pregnant during treatment with nirmatrelvir/ritonavir and as a precautionary measure for 7 days after completing nirmatrelvir/ritonavir.
Use of ritonavir may reduce the efficacy of combined hormonal contraceptives. Patients using combined hormonal contraceptives should be advised to use an effective alternative contraceptive method or an additional barrier method of contraception during treatment with nirmatrelvir/ritonavir, and until one menstrual cycle after stopping nirmatrelvir/ritonavir.
There are no human data on the effect of nirmatrelvir/ritonavir or ritonavir alone on fertility. Both nirmatrelvir and ritonavir, tested separately, produced no effects on fertility in rats.
Nirmatrelvir/ritonavir is expected to have no influence on the ability to drive and use machines.
The most common adverse reactions reported during treatment with nirmatrelvir 300 mg / ritonavir 100 mg every 12 hours for 5 days and during 34 days after the last dose were dysgeusia (5.6%), diarrhoea (3.1%), headache (1.4%) and vomiting (1.1%).
The adverse reactions are listed below 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).
| System organ class | Frequency category | Adverse reactions |
|---|---|---|
| Nervous system disorders | Common | Dysgeusia, headache |
| Gastrointestinal disorders | Common | Diarrhoea, vomiting |
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