Issue: 2018 > April > review

Drug-drug interactions with aprepitant in antiemetic prophylaxis for chemotherapy

R. Schoffelen, A.G. Lankheet, C.M.L. van Herpen, J.J.M. van der Hoeven, I.M.E. Desar, C. Kramers
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Antiemetic prophylaxis, chemotherapy, drug-drug interactions


Over the last years, great improvements have been achieved in the control of chemotherapy-induced nausea and vomiting (CINV). A new group of antiemetics, the neurokinin-1 (NK1 ) receptor antagonists, has been developed. In combination with 5-HT3 antagonists and dexamethasone, this treatment prevents 70-80% of CINV.1 In the last years the international guidelines of the American Society for Clinical Oncology (ASCO), Multinational Association of Supportive Care in Cancer (MASCC), the European Society of Medical Oncology (ESMO), and the National Comprehensive Cancer Network (NCCN) were updated.2,3
The antiemetic regimens implemented in the Netherlands, based on scientific evidence, availability and costs, are shown in table 1. Patients on highly emetogenic chemotherapy (> 90% of the patients experience CINV in the absence of antiemetic prophylaxis) receive a standard antiemetic regimen of three medications: ondansetron, aprepitant and dexamethasone. The addition of aprepitant to ondansetron and dexamethasone has significantly increased efficacy in controlling nausea and vomiting.4-6 With moderately emetogenic chemotherapy (30-90%), the prophylaxis involves a 5-HT3 -receptor antagonist (ondansetron) and dexamethasone. Low emetogenic chemotherapy (10-30%) only requires antiemetics on the day of administration, without specific preference for one class of drugs. When patients experience breakthrough or refractory symptoms another drug can be added, e.g. olanzapine or metoclopramide.2,3 Olanzapine might soon become part of the standard regimen for highly emetogenic chemotherapy.7 In patients who have anticipatory CINV or extreme anxiety, lorazepam or another anxiolytic drug can be administered, prior to and during the chemotherapy.8
In the international guidelines, several drugs are included in the standard regimens, which are not yet implemented in our national or local guidelines9 because they are not yet available or not reimbursed due to high costs, such as fosaprepitant, rolapitant, netupitant, palonosetron and NEPA, a combination of netupitant and palonosetron. Fosaprepitant is an intravenous prodrug of aprepitant, which showed non-inferiority of a single intravenous dose of fosaprepitant compared with oral administration of aprepitant for three days.10 Palonosetron is a newer 5-HT3-receptor antagonist with a longer half-life than ondansetron (40 vs 3 hours), with superior efficacy in moderately and highly emetogenic chemotherapy.11-13
Besides the better prevention of CINV, the concurrent use of several antiemetic drugs simultaneously, especially including aprepitant, may pose an increased risk of drug-drug interactions.14 Here, we will discuss the complexity and clinical significance of possible drug-drug interactions with aprepitant in anti-cancer treatment.

Pharmacokinetic drug-drug interactions due to aprepitant
Aprepitant is a moderate inhibitor of CYP3A4 during the chemotherapy treatment,15 while after a three-day treatment with aprepitant it induces CYP2C9, and to a lesser extent, CYP3A4.16 The induction effect is maximum at three to five days after the last dose of aprepitant, and thereafter gradually declines over two weeks.17 The most important interactions are due to the effect of aprepitant on other drugs, i.e. on the other antiemetics, mainly dexamethasone, on anticancer drugs, and other drugs that are frequently used in this population (painkillers, anticoagulants, and psychoactive drugs) (table 2). 

Interactions between aprepitant and anticancer drugs
Aprepitant could potentially inf luence the pharmacokinetics of anticancer drugs that are CYP3A4 or CYP29C substrates. Known substrates of CYP3A4 include cyclophosphamide, docetaxel, erlotinib, etoposide, gefitinib, ifosfamide, irinotecan, imatinib, paclitaxel, tamoxifen and vinca alkaloids. Some of the anticancer drugs are metabolised by multiple CYP enzymes, such as CYP3A4, CYP2B6 and CYP2C9 for cyclophosphamide, and CYP3A4 and CYP2D6 for tamoxifen.18 Several of these compounds are pro-drugs, e.g. irinotecan, cyclophosphamide and ifosfamide, of these, cyclophosphamide and ifosfamide need the CYP3A4-enzyme to be activated.19-21 No chemotherapeutic drugs are predominantly metabolised by CYP2D9.18 Here we will give an overview of the most important current data on potential drug-drug interactions with anticancer drugs.
Several studies have investigated the metabolism of cyclophosphamide during co-administration of aprepitant. Although one of the studies found a greater exposure to cyclophosphamide,22 no important difference in the exposure of the active (4-OH) metabolite was found, only lower exposure to its neurotoxic metabolite.22-24
Aprepitant is suspected to increase the risk of encephalopathy when co-administered with ifosfamide, but just a few case reports and retrospective studies are available.25-30 Only one case report showed pharmacokinetic data, but these are difficult to interpret.25 Further studies are needed to confirm this effect on the pharmacokinetics of ifosfamide and a causal relation with an induced risk of encephalopathy. However, if encephalopathy develops during a course containing ifosfamide, a different antiemetic regimen should be considered in subsequent treatment.
The effect of aprepitant on the pharmacokinetics of irinotecan and its active metabolite SN-38 was studied in a pilot study. The maximum concentration and the area under the concentration time curve (AUC) of SN-38 were slightly higher when co-administered with aprepitant (23.5 vs 18.8, and 18 vs 15, respectively), but this difference does not seem to be clinically relevant.31
Pharmacokinetic studies of vinorelbine combined with aprepitant showed no difference in AUC on day 1 compared with day 8, excluding a clinically relevant inhibiting effect.32 Likewise, aprepitant did not influence the pharmacokinetics of docetaxel.33
Among the anticancer drugs, not only chemotherapeutic agents are CYP substrates, but also many of the oral kinase inhibitors. However, most of them will not often be used concomitantly with aprepitant, due to their lower emetogenic impact. One of these compounds, erlotinib, was shown to have a relevant drug interaction with aprepitant when it was used off-label for pruritus. Erlotinib had a two-fold higher serum level, which could increase toxicity as well as efficacy.34
For many other chemotherapeutic agents which are CYP3A4 substrates, there is a theoretical interaction with aprepitant, but no clinical studies have been performed to investigate this effect, for example for doxorubicin, etoposide, gefitinib, imatinib, paclitaxel, vinblastine or vincristine.35

Interactions between aprepitant and other antiemetic agents
Due to the moderate inhibition of CYP3A4 by aprepitant, the metabolism of dexamethasone is decreased, leading to a 2.2-fold increase of the AUC of dexamethasone.36 High-dose dexamethasone gives a high risk of serious adverse effects, such as infections and mental disturbances.37 In the guidelines, it is recommended that the dose of dexamethasone is decreased by 50% when combined with aprepitant. Pharmacokinetic studies with aprepitant did not reveal a different effect for oral versus intravenous dosing of dexamethasone.38
Ondansetron, the other compound of the three-drug combination to prevent CINV with highly emetogenic agents, is also a substrate of CYP3A4, as well as CYP1A2 and CYP2D6.39 In contrast to dexamethasone no clinically relevant pharmacokinetic interaction was observed when co-administered with aprepitant.40 This can be explained by the fact that the other CYP enzymes are alternative routes for ondansetron when CYP3A4 is blocked.

Interactions between aprepitant and other medications
Other CYP3A4 or CYP2C9 substrates that are frequently used by cancer patients and therefore could potentially have an interaction with aprepitant include oxycodone (CYP3A4), coumarin derivatives (CYP2C9), and hormonal contraceptives (CYP3A4).14,35
In pharmacokinetic studies with oxycodone, its active metabolite oxymorphone had a significantly higher AUC (+34%), but this did not result in more adverse effects (e.g. respiratory depression, sedation, constipation, nausea or vomiting).41 It seems reasonable not to make preventive dose adjustments, but to monitor patients more closely during combined therapy.17
All studies on coumarin derivatives were done with warfarin instead of acenocoumarol or phenprocoumon. From five days after the first administration of aprepitant (three-day schedule), the S-warfarin plasma levels were decreased, with a maximum difference at day 8 (-34%), resulting in a lower international normalised ratio (INR) of -14%.42 A point of discussion is whether this is a clinically relevant effect, taking into account the normal variation in INR. In daily practice, extra INR monitoring for two or three weeks after aprepitant administration is recommended. 
There is also an effect of aprepitant on hormonal contraceptives due to CYP3A4 induction. A pharmacokinetic study showed a long-lasting (three to four weeks) decrease in the AUC of ethinyl oestradiol and norethindrone (> 60%). Patients should be advised to use an alternative or back-up method of contraception for up to one month after the last dose.17
Psychoactive agents are often used by patients with cancer, but most of these drugs are metabolised by CYP2D6, so are not susceptible for CYP inhibition or induction due to aprepitant. Quetiapine is an exception of a psychoactive drug that has been demonstrated to have a clinically relevant drug-drug interaction with aprepitant. This drug is a CYP3A4 substrate and has showed higher plasma levels when co-administered with aprepitant.43


In this review, we give an overview of the potential risk of clinically relevant drug-drug interactions with aprepitant, an NK1 -receptor antagonist. In particular, it can influence the pharmacokinetics of other drugs, including oncolytic drugs, as it is initially an inhibitor and later on an inducer of CYP3A4. When CYP-enzyme induction leads to lower exposure of its substrate, this could theoretically result in loss of effectiveness. The same holds true for enzyme inhibition when a pro-drug needs CYP enzymes to form the active drug. So far, it is not known if this will result in clinically relevant changes during chemotherapy combined with aprepitant. Because it takes several days before enzyme induction reaches its effect, the effect depends on the timing of the different drugs. However, when a serious interaction occurs, this might be unrecognised since pharmacokinetic results are not usually available. In curative regimens, such as bleomycin-etoposide-cisplatin for carcinoma of the testis, this potential risk should be avoided. So far, only a few pharmacokinetic studies have investigated these serious potential interactions. In our hospital, when we suspect an interaction between a chemotherapeutic drug in a therapy with curative intent, we have decided not to use aprepitant until studies have demonstrated that the anti-tumour effects are not decreased. 
Apart from the need for more data on the effects of aprepitant, newer NK1 -receptor antagonists, such as netupitant and rolapitant, which interfere less with CYP enzymes compared with aprepitant, might be safer options. Several phase III studies have shown good responses of rolapitant compared with placebo.44,45
However, no studies were powered to compare the efficacy and safety of aprepitant, netupitant (in the combination with palonosetron as NEPA) and rolapitant.46 Moreover, for the two newer agents very few studies have been conducted to prove that they might have less impact on the pharmacokinetics, and thus the effect and toxicity, of chemotherapeutic agents. Besides, these agents are not yet available in the Netherlands.
In conclusion, it is crucial that more studies on drug-drug interactions with aprepitant and their influence on pharmacokinetics are performed. Therapeutic drug monitoring of oncolytic drugs could be useful to assess the clinical relevance of the interactions. However, it is crucial that more research is done to define the concentration-effect relationships. This knowledge should then put into perspective the clinical consequences and recommendations for each drug, such as dose adjustments (for example for dexamethasone when co-administered with aprepitant), avoidance or extra monitoring. In the meantime, physicians should be aware of the potential risk of drug-drug interactions with aprepitant, especially in regimens with curative intent. Close collaboration between oncologists and pharmacists is essential for safe drug administrations during chemotherapy. 


Aprepitant, an NK1 -receptor antagonist, is now standard treatment in patients receiving highly emetogenic chemotherapy, combined with ondansetron and dexamethasone. Aprepitant is an inhibitor and inducer of CYP3A4, so it could influence the pharmacokinetics of CYP3A4 substrates, including chemotherapeutic drugs. The new NK1 -receptor antagonists netupitant (in the combination with palonosetron as NEPA) and rolapitant might be safer options, as they interfere less with CYP enzymes compared with aprepitant. However, they do not have EMA approval at this moment. More studies should investigate these potential drug-drug interactions to provide data on their clinical relevance. High awareness of these risks among oncologists and close collaboration with pharmacists could increase the safety of cancer patients receiving highly emetogenic chemotherapy. This is especially true in regimens with curative intention.


All authors declare no conflict of interest. No funding or financial support was received.


  1. Jordan K, Gralla R, Jahn F, Molassiotis A. International antiemetic guidelines on chemotherapy induced nausea and vomiting (CINV): content and implementation in daily routine practice. Eur J Pharmacol. 2014;722:197-202.
  2. Hesketh PJ, Bohlke K, Lyman GH, et al. Antiemetics: American Society of Clinical Oncology Focused Guideline Update. J Clin Oncol. 2016;34:381-6. 
  3. Roila F, Molassiotis A, Herrstedt J, et al. 2016 MASCC and ESMO guideline update for the prevention of chemotherapy- and radiotherapyinduced nausea and vomiting and of nausea and vomiting in advanced cancer patients. Ann Oncol. 2016;27:v119-v33. 
  4. Schmoll HJ, Aapro MS, Poli-Bigelli S, et al. Comparison of an aprepitant regimen with a multiple-day ondansetron regimen, both with dexamethasone, for antiemetic efficacy in high-dose cisplatin treatment. Ann Oncol. 2006;17:1000-6. 
  5. Hesketh PJ, Grunberg SM, Gralla RJ, et al. The oral neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a multinational, randomized, double-blind, placebocontrolled trial in patients receiving high-dose cisplatin--the Aprepitant Protocol 052 Study Group. J Clin Oncol. 2003;21:4112-9. 
  6. Poli-Bigelli S, Rodrigues-Pereira J, Carides AD, et al. Addition of the neurokinin 1 receptor antagonist aprepitant to standard antiemetic therapy improves control of chemotherapy-induced nausea and vomiting. Results from a randomized, double-blind, placebo-controlled trial in Latin America. Cancer. 2003;97:3090-8. 
  7. Navari RM, Qin R, Ruddy KJ, et al. Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting. N Engl J Med. 2016;375:134-42. 
  8. Malik IA, Khan WA, Qazilbash M, Ata E, Butt A, Khan MA. Clinical efficacy of lorazepam in prophylaxis of anticipatory, acute, and delayed nausea and vomiting induced by high doses of cisplatin. A prospective randomized trial. Am J Clin Oncol. 1995;18:170-5. 
  9. De Graeff A, Kuyper MB, Hesselmann GM. Guideline Comprehensive Cancer Centre Middle Netherlands: Nausea and vomiting. Last revision: October 2013. Available at: (last accessed 29 June 2017). 
  10. Grunberg S, Chua D, Maru A, et al. Single-dose fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with cisplatin therapy: randomized, double-blind study protocol--EASE. J Clin Oncol. 2011;29:1495-501.
  11. Aapro MS, Grunberg SM, Manikhas GM, et al. A phase III, double-blind, randomized trial of palonosetron compared with ondansetron in preventing chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy. Ann Oncol. 2006;17:1441-9. 
  12. Gralla R, Lichinitser M, Van Der Vegt S, et al. Palonosetron improves prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: results of a double-blind randomized phase III trial comparing single doses of palonosetron with ondansetron. Ann Oncol. 2003;14:1570-7. 
  13. Botrel TE, Clark OA, Clark L, Paladini L, Faleiros E, Pegoretti B. Efficacy of palonosetron (PAL) compared with other serotonin inhibitors (5-HT3R) in preventing chemotherapy-induced nausea and vomiting (CINV) in patients receiving moderately or highly emetogenic (MoHE) treatment: systematic review and meta-analysis. Support Care Cancer. 2011;19:823-32. 
  14. Patel P, Leeder SL, Piquette-Miller M, Dupuis LL. Aprepitant and fosaprepitant drug interactions: a systematic review. Br J Clin Pharmacol. 2017;83:2148-62. 
  15. Majumdar AK, McCrea JB, Panebianco DL, et al. Effects of aprepitant on cytochrome P450 3A4 activity using midazolam as a probe. Clin Pharmacol Ther. 2003;74:150-6. 
  16. Shadle CR, Lee Y, Majumdar AK, et al. Evaluation of potential inductive effects of aprepitant on cytochrome P450 3A4 and 2C9 activity. J Clin Pharmacol. 2004;44:215-23. 
  17. Product Information: EMEND(R) oral capsules, aprepitant oral capsules. Merck Sharp & Dohme Corp. (per manufacturer), Whitehouse Station, NJ, 2015. 
  18. Fujita K. Cytochrome P450 and anticancer drugs. Curr Drug Metab. 2006;7:23-37. 
  19. Product Information: CAMPTOSAR(R) intravenous injection, irinotecan intravenous injection. Pharmacia & Upjohn Co (per Manufacturer), New York, NY, 2014. 
  20. Product Information: ifosfamide intravenous injection, ifosfamide intravenous injection. Teva Pharmaceuticals USA, Inc. (per DailyMed), North Wales, PA, 2015.
  21. Product Information: CYCLOPHOSPHAMIDE intravenous injection, oral tablets, cyclophosphamide intravenous injection, oral tablets. Baxter Healthcare Corporation (per FDA), Deerfield, IL, 2013. 
  22. Walko CM, Combest AJ, Spasojevic I, et al. The effect of aprepitant and race on the pharmacokinetics of cyclophosphamide in breast cancer patients. Cancer Chemother Pharmacol. 2012;69:1189-96. 
  23. De Jonge ME, Huitema AD, Holtkamp MJ, van Dam SM, Beijnen JH, Rodenhuis S. Aprepitant inhibits cyclophosphamide bioactivation and thiotepa metabolism. Cancer Chemother Pharmacol. 2005;56:370-8. 
  24. Bubalo JS, Cherala G, McCune JS, Munar MY, Tse S, Maziarz R. Aprepitant pharmacokinetics and assessing the impact of aprepitant on cyclophosphamide metabolism in cancer patients undergoing hematopoietic stem cell transplantation. J Clin Pharmacol. 2012;52:586-94. 
  25. Durand JP, Gourmel B, Mir O, Goldwasser F. Antiemetic neurokinin-1 antagonist aprepitant and ifosfamide-induced encephalopathy. Ann Oncol. 2007;18:808-9. 
  26. Jarkowski A, 3rd. Possible contribution of aprepitant to ifosfamideinduced neurotoxicity. Am J Health Syst Pharm. 2008;65:2229-31. 
  27. Shindorf ML, Manahan KJ, Geisler JP. The interaction of ifosfamide and aprepitant in gynecologic malignancies. Gynecol Oncol. 2013;6:34-5. 
  28. Séjourné A, Noal S, Boone M, et al. Two cases of fatal encephalopathy related to Ifosfamide: an adverse role of aprepitant? Case Rep Oncol. 2014;7:669-72. 
  29. Howell JE, Szabatura AH, Hatfield Seung A, Nesbit SA. Characterization of the occurrence of ifosfamide-induced neurotoxicity with concomitant aprepitant. J Oncol Pharm Pract. 2008;14:157-62. 
  30. Szabatura AH, Cirrone F, Harris C, et al. An assessment of risk factors associated with ifosfamide-induced encephalopathy in a large academic cancer center. J Oncol Pharm Pract. 2015;21:188-93. 
  31. Nieva J WWaSG. Pharmacokinetic effect of aprepitant on irinotecan in patients with colorectal cancer. ASCO Annual Meeting Proceedings (Post-Meeting Edition). J Clin Oncol. 2007;25(18S). 
  32. Loos WJ, de Wit R, Freedman SJ, et al. Aprepitant when added to a standard antiemetic regimen consisting of ondansetron and dexamethasone does not affect vinorelbine pharmacokinetics in cancer patients. Cancer Chemother Pharmacol. 2007;59:407-12. 
  33. Kaneta T, Fujita K, Akiyama Y, et al. No pharmacokinetic alteration of docetaxel following coadministration of aprepitant 3 h before docetaxel infusion. Cancer Chemother Pharmacol. 2014;74:539-47. 
  34. Mir O, Blanchet B, Goldwasser F. More on aprepitant for erlotinib-induced pruritus. N Engl J Med. 2011;364:487.
  35. Dushenkov A, Kalabalik J, Carbone A, Jungsuwadee P. Drug interactions with aprepitant or fosaprepitant: Review of literature and implications for clinical practice. J Oncol Pharm Pract. 2017;23:296-308. 
  36. McCrea JB, Majumdar AK, Goldberg MR, et al. Effects of the neurokinin1 receptor antagonist aprepitant on the pharmacokinetics of dexamethasone and methylprednisolone. Clin Pharmacol Ther. 2003;74:17-24.
  37. Product Information: dexamethasone sodium phosphate intravenous injection, intramuscular injection, dexamethasone sodium phosphate intravenous injection, intramuscular injection. West-ward Pharmaceutical Corp. (per DailyMed), Eatontown, NJ, 2011. 
  38. Nakade S, Ohno T, Kitagawa J, et al. Population pharmacokinetics of aprepitant and dexamethasone in the prevention of chemotherapyinduced nausea and vomiting. Cancer Chemother Pharmacol. 2008;63:75-83.
  39. Product Information: ZOFRAN(R) oral tablets, oral solution, ZOFRAN ODT(R) orally disintegrating tablets, ondansetron hcl oral tablets, oral solution, orally disintegrating solution. GlaxoSmithKline, Research Triangle Park, NC, 2006. 
  40. Blum RA, Majumdar A, McCrea J, et al. Effects of aprepitant on the pharmacokinetics of ondansetron and granisetron in healthy subjects. Clin Ther. 2003;25:1407-19. 
  41. Fujiwara Y, Toyoda M, Chayahara N, et al. Effects of aprepitant on the pharmacokinetics of controlled-release oral oxycodone in cancer patients. PloS One. 2014;9:e104215.
  42. Depre M, Van Hecken A, Oeyen M, et al. Effect of aprepitant on the pharmacokinetics and pharmacodynamics of warfarin. Eur J Clinical Pharmacol. 2005;61:341-6. 
  43. Verwimp-Hoeks MP, van Herpen CM, Burger DM. Aprepitant quetiapine: a clinically significant drug interaction in a patient treated for head and neck cancer. Ann Oncol. 2012;23:801-2. 
  44. Schwartzberg LS, Modiano MR, Rapoport BL, et al. Safety and efficacy of rolapitant for prevention of chemotherapy-induced nausea and vomiting after administration of moderately emetogenic chemotherapy or anthracycline and cyclophosphamide regimens in patients with cancer: a randomised, active-controlled, double-blind, phase 3 trial. Lancet Oncol. 2015;16:1071-8. 
  45. Rapoport BL, Chasen MR, Gridelli C, et al. Safety and efficacy of rolapitant for prevention of chemotherapy-induced nausea and vomiting after administration of cisplatin-based highly emetogenic chemotherapy in patients with cancer: two randomised, active-controlled, double-blind, phase 3 trials. Lancet Oncol. 2015;16:1079-89. 
  46. Navari R. Rolapitant hydrochloride: prophylactic treatment for chemotherapy-induced nausea and vomiting. Drugs Today (Barc). 2016;52:431-8.