Fosaprepitant administration schedule for adults (>18 years) for highly or moderately emetogenic chemotherapy

Fosaprepitant administration schedule for children receiving single-day highly or moderately emetogenic chemotherapy

Fosaprepitant administration schedule for children receiving multiday highly or moderately emetogenic chemotherapy

Fosaprepitant is administered in 150 ml normal saline (145 ml normal saline + 5 ml fosaprepitant). The final concentration before administration should be 1 mg/ml. Fosaprepitant is incompatible with any solutions containing divalent cations (e.g., Ca2+, Mg2+), including Lactated Ringer's Solution and Hartmann's Solution. The reconstituted final drug solution is stable for 24 h at ambient room temperature (at or below 25°C).[9],[10]

Drug Interactions

Fosaprepitant is an inhibitor of the CYP3A4 enzyme in the liver and increases the serum level of many drugs metabolized by CYP3A4.[11] It is recommended to reduce dexamethasone dose by 50% for the first 48 h after administration of fosaprepitant as it has been shown that the dexamethasone levels increase after administration of aprepitant or fosaprepitant.[12] The recent NCCN guidelines for adults have a reduced dexamethasone dose of 12 mg on day 1 and 8 mg once a day on day 2–4 of chemotherapy administration. Therefore, guidelines do not recommend further dose reduction of dexamethasone when administered with aprepitant or fosaprepitant.[4] Pediatric guidelines recommend a dexamethasone dose of 16–24 mg/m2, which is higher compared to doses recommended in adults, and therefore, pediatric patients receiving dexamethasone should have their dose reduced by 50% for the first 48 h after administration of fosaprepitant.[13]

There are concerns that aprepitant and fosaprepitant by inhibiting the CYP3A4 enzyme can increase the serum levels and thereby the adverse effects of chemotherapy drugs such as cyclophosphamide, ifosfamide, vinblastine, and vincristine that are CYP3A4 substrates.[11] However, randomized trials with aprepitant and fosaprepitant in children and adults included the above drugs and did not show any concerning adverse effects.[14],[15],[16],[17] The FDA recommends close monitoring for adverse effects when fosaprepitant is used concomitantly with chemotherapeutic agents that have significant interactions.

Coadministration of fosaprepitant with warfarin can decrease the prothrombin time, and therefore, frequent monitoring of international normalized ratio is required.[9],[10] Fosaprepitant reduces the efficacy of oral contraceptive pills (OCPs), and therefore, other methods of contraception should be advised to patients on OCPs receiving fosaprepitant.[9],[10]

Adverse Reactions

Fosaprepitant is a safe drug with minimal side effects reported in randomized trials.[14],[15],[16],[17] Infusion site reactions such as pain, irritation, and thrombophlebitis were more common with fosaprepitant when compared to standard therapy (2.2% vs. 0.6%).[15] These reactions were more common in patients receiving vesicant drugs such as anthracyclines. The FDA recommends that fosaprepitant should be given through a central line in children. However, a recent randomized trial in children showed that it is safe to administer fosaprepitant through a peripheral line without increased incidence of thrombophlebitis.[10],[17]

Use in Special Circumstances

The effect of fosaprepitant in pregnancy and lactation has not been studied. Although animal studies have shown that fosaprepitant is safe in pregnancy,[9],[10] no dosage adjustment is necessary for patients with mild to moderate hepatic impairment (Child–Pugh score 5–9) and renal impairment.[9],[10] There are no clinical or pharmacokinetic data in patients with severe hepatic impairment (Child–Pugh score >9), and therefore, close clinical monitoring is required in this group of patients.[9],[10]

Clinical Efficacy

In a Phase III, double-blind trial, adult cancer patients scheduled to receive MEC, a single-dose fosaprepitant 150 mg was compared to placebo. Both arms received ondansetron and dexamethasone on day 1. Complete response (CR) rate was defined as no vomiting or use of rescue medications. The fosaprepitant regimen improved the CR rate significantly in the delayed (78.9% vs. 68.5%; P < 0 class="i" xss=removed>P < 0 xss=removed href="https://www.thieme-connect.com/products/ejournals/html/10.4103/ijmpo.ijmpo_57_19#JR_14" xss=removed>14]

A randomized, double-blind, noninferiority clinical trial with 2322 patients receiving cisplatin ≥70 mg/m2 compared a 3-day oral aprepitant schedule to a regimen containing a single dose of intravenous fosaprepitant.[15] All patients received dexamethasone and ondansetron prophylaxis. The trial showed that fosaprepitant was noninferior to aprepitant with regard to CR rates.[15] The only increased adverse event noticed with fosaprepitant in comparison to aprepitant was thrombophlebitis.

Fosaprepitant has been found to be effective when administered weekly with palonosetron and dexamethasone in patients with cervical cancer receiving weekly cisplatin concurrent with radiotherapy. The proportion of patients with sustained no emesis at 5 weeks in the trial was 48·7% for the placebo group compared with 65·7% for patients in the fosaprepitant group.[16]

FDA approved the use of fosaprepitant in children above 6 months of age in May 2018. However, this approval was based on unpublished data submitted by Merck pharmaceuticals to FDA. The only randomized controlled trial till date on the use of fosaprepitant in children was published by Radhakrishnan et al. in November 2018.[17] The study randomized 163 pediatric patients between the age of 1 and 12 years receiving MEC or HEC to fosaprepitant and placebo. Both arms received dexamethasone and ondansetron. CR rates defined as no vomiting were significantly higher in the fosaprepitant arm compared to those in the placebo arm during the acute phase of vomiting (86% vs. 60%, P < 0 class="i" xss=removed>P < 0 class="i" xss=removed>P < 0 href="https://www.thieme-connect.com/products/ejournals/html/10.4103/ijmpo.ijmpo_57_19#OR_10" xss=removed>10],[17] FDA recommends a higher dose and longer duration of fosaprepitant administration in children compared to adults because pharmacokinetic data have shown that children <12 href="https://www.thieme-connect.com/products/ejournals/html/10.4103/ijmpo.ijmpo_57_19#OR_10" xss=removed>10] Despite using a reduced dose and shorter infusion time, no reduction in efficacy or increase in adverse events were noted in the study by Radhakrishnan et al.[17]

Conclusion

Fosaprepitant is a prodrug of aprepitant that is safe, easy to administer, and requires only a single-dose administration unlike a 3-day course of oral aprepitant, thereby, increasing patient compliance. It has been shown in randomized controlled trials to be effective and noninferior to aprepitant in preventing CINV due to MEC and HEC.

Conflict of Interest

There are no conflicts of interest.

• References

•