Evaluation of Sources of Drug Interaction Information for Nirmatrelvir/ritonavir

Summary

The Japanese package insert (J-PI) for nirmatrelvir/ritonavir (N/r) (specially approved pharmaceutical) includes numerous warnings about drug interactions. However, discrepancies in the information on drug interaction are reported between J-PI and foreign databases. This study aimed to evaluate various information sources on N/r drug interactions. We categorized and compared information on N/r drug interactions from the J-PI, prescribing information from foreign regulatory agencies, guidance from the National Institutes of Health and University Health Network, the Ontario coronavirus disease 2019 (COVID-19) Science Advisory Table, University of Liverpool, Lexicomp, and the Japanese Society of Pharmaceutical Health Care and Sciences (JSPHCS). We assessed information quantity, missing data in J-PI, predicted change of the area under the blood concentration–time curve (AUC) for nirmatrelvir or co-administered drugs, and the information source consistency. From these information sources, we compiled a dataset with 115 contraindications and 203 precautions for N/r co-administration, and 51 contraindications are missing in J-PI. Among them, at least 12 drugs have large predicted AUC changes with N/r (AUC ≥5-fold or <1/5 of the baseline value). Nine of these 12 drugs are included as contraindications in Lexicomp and the JSPHCS. The consistency among the information sources is low. Information in the J-PI alone may be insufficient and Lexicomp or the JSPHCS guidelines should be useful because of their large amounts of information and wide coverage of drugs with large AUC changes. Due to low source consistency, multiple sources are needed for clinical management.

INTRODUCTION

Nirmatrelvir/ritonavir (N/r), a specially approved pharmaceutical in Japan granted in February 2022, is a medication for coronavirus disease 2019 (COVID-19) in which nirmatrelvir inhibits the main protease of severe acute respiratory syndrome coronavirus 2 and prevents viral replication by inhibiting polyprotein cleavage.^1,2) In the EPIC-HR trial (evaluation of protease inhibition for COVID-19 in high-risk patients), which included nonhospitalized patients at a high risk of progression to severe COVID-19, N/r reduced the risk of hospitalization and all-cause mortality (absolute risk 6.3%, relative risk 89.1%).³⁾ Furthermore, the U.S. National Institutes of Health (NIH) strongly recommends the use of N/r for nonhospitalized patients at a high risk of disease progression.⁴⁾ Nirmatrelvir is used in combination with ritonavir to maintain the blood concentration of nirmatrelvir at effective levels.¹⁾ Ritonavir has a potent inhibitory effect on drug metabolizing enzymes including cytochrome P450 (CYP) 3A, CYP2D6, and drug transporters of P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP), and is also an inducer of CYP1A2, CYP2B6, CYP2C9, CYP2C19, uridine diphosphate glucuronosyltransferase, and is known to have many drug–drug interactions.^2,5) In addition, nirmatrelvir itself is a substrate of CYP3A, P-gp^1,2) and is also affected by the inhibition and induction of CYP3A activity and inhibition of P-gp, Organic Anion Transporting Polypeptide 1B1. Therefore, the Japanese package insert (J-PI) for N/r, Paxlovid PACK (2nd ed., 2022) lists many contraindications and precautions for co-administration related to potential interactions with some of these metabolizing enzymes and transporters.

However, a difference exists in the list of drug combinations that should be avoided or used with caution between the J-PI and Lexicomp Drug Interactions, a database from Wolters Kluwer.⁶⁾ J-PI may not fully cover information on drugs that are considered contraindicated for concomitant use.⁷⁾ Differences in drug interaction information among different databases and drug labels from five countries have also been reported.^8,9) In fact, although tacrolimus is classified as a precaution in J-PI, a case had been reported in which concomitant use of N/r led to a significant increase in blood concentration of tacrolimus, causing serious problems.^10,11) Therefore, the drug interactions of N/r may not be adequately managed based on information from the J-PI alone. However, no studies have compared these sources of information.

In this study, we investigated and compared the descriptions of prescribing information from foreign regulatory agencies and domestic and foreign databases on N/r drug interaction, and clarified missing information in the J-PI.

MATERIALS AND METHODS

Information Sources on N/r Drug Interactions and Definitions of Contraindications and Precautions for Co-administration

The following were used as sources of information on N/r drug interactions: J-PI, prescribing information from foreign regulatory agencies [U.K. Medicines and Healthcare Products Regulatory Agency (MHRA) (Paxlovid 150 mg/100 mg summary of product characteristics; 2022), European Medicines Agency (EMA) (Paxlovid 150 mg/100 mg summary of product characteristics; 2022), U.S. Food and Drug Administration (FDA)¹⁾], and domestic and foreign databases [NIH database,¹²⁾ University Health Network (UHN) database,¹³⁾ Ontario COVID-19 Science Advisory Table (now superseded by the Ontario Public Health Emergencies Science Advisory Committee) guidelines,¹⁴⁾ University of Liverpool COVID-19 drug interaction checker,¹⁵⁾ Lexicomp,¹⁶⁾ and drug interaction management guidelines for Paxlovid PACK published by the Japanese Society of Pharmaceutical Health Care and Sciences (JSPHCS)¹⁷⁾]. As the NIH refers to the UHN for information on anticancer drugs, this study treated the NIH and UHN as a single source of information. Table 1 defines the alert categories in each information source, divided into contraindications and precautions for concomitant use with N/r. Although the JSPHCS does not categorize the drugs as contraindications or precautions, in this study, area under the blood concentration–time curve (AUC) changes of ≥5-fold were treated as contraindication equivalent and other changes were treated as precaution equivalent. Information was collected as of July 2022, and only active ingredients available as pharmaceutical products in Japan at the time of information collection were included.

Table 1. Information Sources and Their Definitions of Contraindications/precautions for Concomitant Use

Source	Country	Contraindications		Precautions
MHRA	U.K.	Contraindication		Precaution
EMA	EU	Contraindication		Precaution
FDA	U.S.	Contraindication		Precaution
NIH	U.S.	Alternative therapy	Temporarily withhold	Adjust dose	Monitor therapy
UHN	Canada	Contraindication		Adjust dose	Monitor therapy
Ontario	Canada	Contraindication	Temporarily withhold	Precaution
Liverpool	U.K.	Do not co-administer		Potential interaction	Potential weak interaction
Lexicomp	Netherlands	Avoid combination		Therapy modification	Monitor therapy
JSPHCS	Japan	≥5-fold AUC change		Precaution

MHRA, Medicines and Healthcare Products Regulatory Agency; EMA, European Medicines Agency; FDA, U.S. Food and Drug Administration; NIH, National Institutes of Health; UHN, University Health Network; Ontario, Ontario COVID-19 Science Advisory Table; Liverpool, University of Liverpool COVID-19 drug interaction checker; JSPHCS, drug interaction management guidelines for Paxlovid PACK published by the Japanese Society of Pharmaceutical Health Care and Sciences; U.K., United Kingdom; EU, European Union; U.S., United States; AUC, area under the blood concentration–time curve.

Quantity of Information from Each Data Source

We compiled a dataset of drugs for which contraindications or precautions for co-administration with N/r are indicated in the investigated sources. Within this dataset, drugs classified as contraindications in at least one source were categorized as “contraindications,” whereas the remaining drugs were categorized as “precautions.” Subsequently, we compared the number of drugs that are classified as contraindications or precautions between each source and across the dataset, as well as the number of drugs that are not listed in the J-PI.

Relationship between Alert Category and Changes in the AUC

We investigated the relationship between the predicted AUC changes of potential concomitant drugs and nirmatrelvir under N/r co-administration and the alert category in the J-PI and other sources. The “Guideline on drug interaction for drug development and appropriate provision of information”¹⁸⁾ defines substrates whose AUC increases by ≥5-fold or decreases to <1/5 when co-administered with strong inhibitors or inducers as “sensitive substrates”; thus, we classified the AUC changes of drugs into two groups: “a ≥5-fold increase or a decrease to ≤1/5 of the baseline” (i.e., a large predicted AUC change) and “a <5-fold increase or a decrease to >1/5 of the baseline.” Table 2 lists strong CYP3A inhibitors and strong CYP3A inducers as defined by either the FDA¹⁹⁾; the Ministry of Health, Labour, and Welfare²⁰⁾; or Maeda et al.²¹⁾

Table 2. Strong CYP3A Inhibitors and CYP3A Inducers

Strong CYP3A inhibitors	Strong CYP3A inducers
Ceritinib19–21)	Apalutamide19,21)
Clarithromycin19,21)	Carbamazepine19–21)
Cobicistat19–21)	Enzalutamide19,21)
Grapefruit juice20,21)	Mitotane19,21)
Indinavir20)	Phenytoin19–21)
Itraconazole19–21)	Phenobarbital20,21)
Ketoconazole19)	Rifampin19–21)
Nefazodone19,20)	St. John’s wort19–21)
Nelfinavir19,20)
Posaconazole19–21)
Ritonavir19–21)
Saquinavir20)
Telithromycin19)
Voriconazole19–21)

CYP: Cytochrome P450.

Information on AUC changes that can be induced by drug combinations was obtained from Lexicomp. In this study, “AUC change of approximately 5-fold” in the Lexicomp was treated as “AUC changes of ≥5-fold.” When no information on the relevant combination is available in Lexicomp, the largest AUC change value obtained from other sources investigated in this study was used. For the AUC changes of concomitant drugs, we used the values reported when they were co-administered with N/r or ritonavir. In the absence of this information, we used the largest AUC change value reported when the drugs were concomitantly used with any strong CYP3A inhibitor (Table 2) that is rated to be equivalent in strength to ritonavir. The dose of ritonavir varies from report to report, and although the inhibitory effect of ritonavir is generally considered to be dose-dependent, there are reports of maximum inhibition at 100 to 200 mg,²²⁾ even if dose-dependent, it is not linear, and the effect on the increase in AUC decreases as the dose increases,²³⁾ and since the ritonavir dose for N/r is 200 mg/d, the effect of different ritonavir doses is considered small. For the AUC changes of nirmatrelvir due to concomitant drugs, available information on nirmatrelvir AUC reduction was used. Carbamazepine, a strong CYP3A inducer, has been shown to reduce the AUC of nirmatrelvir by 55% (data in combination with ritonavir).¹⁾ Ohno et al. introduced a formula [AUC decrease=1/(1+CR·IC)] and [AUC increase=1/(1-CR·IR)] to assess each the impact of CYP3A induction and CYP3A inhibition. This formula considers the contribution rate (CR) of the substrate to oral clearance and a parameter IC and IR representing the increase in clearance due to CYP3A induction and inhibition rate of CYP3A, respectively.^24,25) The AUC of nirmatrelvir was reported to increase 1.39 fold when combined with itraconazole, a selective CYP 3A inhibitor with an IR of 0.95 (data from J-PI), the CR for nirmatrelvir is estimated at around 0.3. In the absence of specific data on nirmatrelvir AUC reduction, we anticipate a 50 to 70% reduction when combined with the inducers listed in Table 2 (each IC, rifampin: 7.7, phenytoin: 4.7, carbamazepine: 3).²⁴⁾ When the AUC change values are reported as a range, the largest values were adopted.

Comprehensiveness of Information from Each Data Source

We compared the indicated contraindications and precautions for concomitant use with N/r across the dataset to investigate the amount of missing information in each source. We also evaluated the predicted AUC changes for contraindications not listed in the respective sources.

Consistency of Information

The consistency of information (contraindications, precautions, or no data) among the sources was evaluated using the kappa coefficient and categorized as follows: 0.81–1.0, almost consistent; 0.61–0.8, substantially consistent; 0.41–0.6, moderately consistent; 0.21–0.4, fairly consistent; and 0–0.2, slightly consistent.²⁶⁾ The kappa coefficient was calculated using JMP Pro 16 (SAS Institute Inc., Cary).

RESULTS

Quantity of Information from Each Data Source

Figure 1 shows the number of drugs listed as a contraindication or precaution in the entire dataset and in each investigated source, as well as the number of drugs not listed as a contraindication or precaution in the J-PI for N/r. The number of contraindications and precautions is 39 and 62, respectively, in the J-PI, and 115 and 203, respectively, in the entire dataset. Within the dataset, the number of contraindications and precautions not listed in the J-PI is 51 and 166, respectively. Among the drugs listed as precautions in the J-PI, 25 are listed as contraindications in some of the other information sources. The 25 drugs included atorvastatin, rosuvastatin, simvastatin and drugs requiring blood concentration monitoring such as cyclosporine, tacrolimus, and everolimus. Of the sources examined, Lexicomp contains the greatest number of contraindications and precautions and covers the highest amount of information that is missing from the J-PI.

Fig. 1. Numbers of Drugs Listed in Each Information Source and Drugs not Listed in J-PI

J-PI, Japanese package insert; Dataset, dataset of drugs that are identified as either contraindications or precautions for co-administration with nirmatrelvir/ritonavir in the investigated sources; MHRA, Medicines and Healthcare Products Regulatory Agency; EMA, European Medicines Agency; FDA, U.S. Food and Drug Administration; NIH, National Institutes of Health; UHN, University Health Network; Ontario, Ontario COVID-19 Science Advisory Table; Liverpool, University of Liverpool COVID-19 drug interaction checker; JSPHCS, drug interaction management guidelines for Paxlovid PACK published by the Japanese Society of Pharmaceutical Health Care and Science.

Relationship between Alert Category and AUC Changes

Based on available data on AUC changes in combination use, 10 of the 39 contraindications and 9 of the 62 precautions in the J-PI of N/r are associated with large predicted AUC changes for the concomitant drugs or nirmatrelvir. Table 3 shows the nine drugs indicated as precautions in the J-PI of N/r with large predicted AUC changes. In addition, among the contraindications not listed in the J-PI of N/r, 12 drugs have large predicted AUC changes (Table 4), with Lexicomp and the JSPHCS guidelines covering most of these drugs as contraindications (9/12 drugs), followed by NIH+UHN and Liverpool (6/12 drugs each) (Fig. 2). Other than the 12 drugs with large AUC changes, high-risk drugs such as anticancer drugs, arrhythmic drugs, immunosuppressants, antiepileptic drugs, and antipsychotics were classified as contraindicated.

Table 3. Drugs with Large Predicted AUC Changes with Nirmatrelvir/ritonavir and Listed as Precautions in the Japanese Package Insert

	MHRA	EMA	FDA	NIH+UHN	Ontario	Liverpool	Lexicomp	JSPHCS
Bosentan	P	P	P	C	C	C	P	P
Budesonide	P	P	P	—	—	P	C	C
Everolimus	P	P	—	C	C	C	C	C
Felodipine	—	—	P	P	P	P	P	C
Glecaprevir/pibrentasvir	P	P	P	C	C	C	C	P
Ibrutinib	P	P	P	C	C	C	C	C
Quetiapine	C	C	P	P	P	C	P	C
Salmeterol	P	P	P	C	C	C	C	P
Simvastatin	C	C	C	C	C	C	C	C

C, Contraindication; P, precaution; —, not listed; MHRA, Medicines and Healthcare Products Regulatory Agency; EMA, European Medicines Agency; FDA, U.S. Food and Drug Administration; NIH, National Institutes of Health; UHN, University Health Network; Ontario, Ontario COVID-19 Science Advisory Table; Liverpool, University of Liverpool COVID-19 drug interaction checker; JSPHCS, drug interaction management guidelines for Paxlovid PACK published by the Japanese Society of Pharmaceutical Health Care and Science. In JSPHCS, AUC changes of ≥5-fold are treated as contraindication equivalent and other changes are treated as precaution equivalent.

Table 4. Drugs with Large Predicted AUC Changes with Nirmatrelvir/ritonavir and not Listed in the Japanese Package Insert

	MHRA	EMA	FDA	NIH+UHN	Ontario	Liverpool	Lexicomp	JSPHCS
Acalabrutinib	—	—	—	C	—	C	C	P
Aprepitant	—	—	—	—	—	P	C	P
Bosutinib	—	—	—	C	C	C	C	C
Brotizolam	—	—	—	—	—	—	P	C
Ebastine	—	—	—	—	—	—	P	C
Entrectinib	—	—	—	—	—	—	P	C
Eplerenone	—	—	—	C	—	C	C	C
Fosaprepitant	—	—	—	—	—	—	C	P
Ivabradine	—	—	—	C	—	C	C	C
Rupatadine	—	—	—	—	—	—	C	C
Sirolimus	—	—	P	C	C	C	C	C
Ticagrelor	—	—	—	C	C	C	C	C

C, Contraindication; P, precaution; —, not listed; MHRA, Medicines and Healthcare Products Regulatory Agency; EMA, European Medicines Agency; FDA, U.S. Food and Drug Administration; NIH, National Institutes of Health; UHN, University Health Network; Ontario, Ontario COVID-19 Science Advisory Table; Liverpool, University of Liverpool COVID-19 drug interaction checker; JSPHCS, drug interaction management guidelines for Paxlovid PACK published by the Japanese Society of Pharmaceutical Health Care and Science. In JSPHCS, AUC changes of ≥5-fold are treated as contraindication equivalent and other changes are treated as precaution equivalent.

Fig. 2. Predicted AUC Changes of Drugs Classified as Contraindications in Other Sources not Listed in J-PI

Dataset, dataset of drugs that are identified as either contraindications or precautions for co-administration with nirmatrelvir/ritonavir in the investigated sources; MHRA, Medicines and Healthcare Products Regulatory Agency; EMA, European Medicines Agency; FDA, U.S. Food and Drug Administration; NIH, National Institutes of Health; UHN, University Health Network; Ontario, Ontario COVID-19 Science Advisory Table; Liverpool, University of Liverpool COVID-19 drug interaction checker; JSPHCS, drug interaction management guidelines for Paxlovid PACK published by the Japanese Society of Pharmaceutical Health Care and Science.

Comprehensiveness of Information from Each Data Source

The amount of missing information in each source compared with the entire dataset and the predicted AUC changes for missing contraindications are shown in Fig. 3. Lexicomp has the lowest number of missing information (6 missing contraindications and 66 missing precautions). In contrast, the JSPHCS guidelines have relatively more missing information (25 missing contraindications and 145 missing precautions). Both of these sources covered many contraindications with large predicted AUC changes, at least based on the available information.

Fig. 3. Number of Drugs not Listed in Each Data Source and Predicted AUC Changes for Missing Contraindications

(A) Number of drugs not listed in each data source, (B) Predicted AUC changes for missing contraindications. J-PI, Japanese package insert; MHRA, Medicines and Healthcare Products Regulatory Agency; EMA, European Medicines Agency; FDA, U.S. Food and Drug Administration; NIH, National Institutes of Health; UHN, University Health Network; Ontario, Ontario COVID-19 Science Advisory Table; Liverpool, University of Liverpool COVID-19 drug interaction checker; JSPHCS, drug interaction management guidelines for Paxlovid PACK published by the Japanese Society of Pharmaceutical Health Care and Science.

Consistency of Information

The consistency between sources was analyzed and is presented in Fig. 4. Moderate or better consistency was found between the sources provided by regulatory agencies, including the J-PI. The information from the Ontario COVID-19 Science Advisory Table is moderately consistent with that from foreign regulatory agencies and the NIH+UHN. The consistency among other sources is low; particularly, Lexicomp tends to have low consistency with the other sources.

Fig. 4. Consistency between Information Sources

Values represent the kappa coefficient. J-PI, Japanese package insert; MHRA, Medicines and Healthcare Products Regulatory Agency; EMA, European Medicines Agency; FDA, U.S. Food and Drug Administration; NIH, National Institutes of Health; UHN, University Health Network; Ontario, Ontario COVID-19 Science Advisory Table; Liverpool, University of Liverpool COVID-19 drug interaction checker; JSPHCS, drug interaction management guidelines for Paxlovid PACK published by the Japanese Society of Pharmaceutical Health Care and Science.

DISCUSSION

Our evaluation of various information sources revealed that >200 drugs with potential interactions with N/r are not indicated as contraindications or precautions for co-administration in the J-PI for N/r. In addition, nine of the drugs listed as precautions in the J-PI are expected to have a >5-fold increased AUC when used in combination with N/r (Table 3). Among these, simvastatin is widely used in the treatment of lifestyle-related diseases, and increased exposure to simvastatin can lead to an increased risk of side effects. Therefore, it is important to recognize and evaluate high-risk drugs among those listed as precautions. In addition, 12 drugs that are classified as contraindications in the dataset (consisting of all investigated sources) and have large predicted AUC changes when used in combination with N/r are not listed in the J-PI; these include the frequently used hypnotic brotizolam and cardiovascular drugs such as ivabradine and eplerenone (Table 4). Co-administration of these drugs would be difficult to avoid when only the J-PI is used in concomitant drug management, and this can be a serious problem.

We found that the information on concomitant medications in the J-PI is not considerably different from and is moderately consistent with that provided by foreign regulatory agencies. Other databases tend to have more information, with Lexicomp having the highest amount of information and the lowest consistency with the other sources. Hisaka et al. reported that even combinations that are expected to cause a ≥5-fold change in AUC are often not warned about in prescribing information in various countries; they considered that one of the reasons for this is that drug information documents from regulatory agencies, such as package inserts, include only information that has been proven at the time of approval.²⁷⁾ This study suggests that Lexicomp is a superior information source for N/r drug interaction management, as it contains a large amount of information that the J-PI may lack and has the least amount of missing information among the investigated sources. Also, there is a large amount of information in NIH+UHN, Liverpool, and JSPHCS, and JSPHCS is able to cover information on drugs with large AUC changes. JSPHCS and NIH have summarized drugs according to their efficacy. And Lexicomp employs categories of “No action needed” and “No known interaction,” while Liverpool also provides a category of “No interaction expected.” This information may be helpful when considering alternative drugs.

One reason for such discrepancies in information is the lack of a common standard for providing co-administration alerts that indicate the risk of drug interactions. In Japan, no specific standard exists for describing contraindications and precautions for co-administration in package inserts. Regulatory authorities have issued guidelines for evaluating interactions in drug development¹⁸⁾; however, each pharmaceutical company makes its own decisions considering risks and benefits. In addition, each database has its own criteria and risk assessment, and previous reports have indicated that the consistency among databases is low.^7,28,29) Therefore, in the management of N/r interactions, it is considered necessary to obtain information from multiple sources and evaluate the risk of interaction individually, taking into account the contribution rate of CYP3A and other factors. Essentially, not only to raise awareness by comprehensive lists, but it may also be necessary to alert in categories like ‘CYP3A substrates’, prompting healthcare professionals to verify whether the concomitant drug is ‘CYP3A substrates’, or for pharmacists to make predictions and evaluations. In addition, the effect of CYP3A inhibition may remain for about 3 d after discontinuation of ritonavir, and since the effect varies widely among individuals, it is recommended to avoid concomitant use for 5 d if possible.^2,13) The first limitation of this study was the use of predicted AUC changes alone to assess the risk of drug interactions. In general, changes in AUC values and drug exposure are assumed to be the major factors leading to decreased efficacy and increased risk of adverse events. Although awareness of this issue is important when deciding whether to co-administer drugs, some drugs differ in efficacy and safety ranges, and the risk of co-administration cannot be quantitatively evaluated based on AUC changes alone. Second, we mainly used Lexicomp as a source of information for the predicted AUC changes in this study; however, potential bias exists in the underlying information. Third, in the absence of information on concomitant use with N/r or ritonavir, we used data on concomitant use with other strong CYP3A inhibitors; however, the effects on P-gp or BCRP were not considered. Fourth, we hypothesized that a strong CYP3A inducer with no information on nirmatrelvir AUC change would cause changes similar to those produced by CYP3A strong inducer; however, the estimated nirmatrelvir AUC reduction with strong inducer is 50–70%, which does not fall within the criterion for a large decrease (i.e., AUC <1/5 of the baseline value), and also some CYP3A strong inducer itself is also enzyme inhibited by ritonavir, but there are no data on the effect. A strong CYP3A inducer such a carbamazepine, is designated as a contraindication to co-administration with N/r in many sources. Therefore, the concomitant use of other drugs known to induce CYP3A activity should also be avoided.

CONCLUSION

When managing N/r drug interactions, information in the J-PI alone may be insufficient to avoid high-risk drugs with large AUC changes. Other sources such as Lexicomp contain more information on drug interactions than the J-PI and prescribing information from foreign regulatory agencies. In particular, Lexicomp and the JSPHCS guidelines are useful because they have a wide coverage of information on drugs with large AUC changes when co-administered with N/r. However, the differences in coverage among the investigated sources suggest that multiple sources of information should be used in the clinical management of N/r interactions.

Conflict of Interest

The authors declare no conflict of interest.

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