Keywords
Chemotherapy - fosaprepitant and NK1 antagonist - vomiting
Introduction
Chemotherapy-induced nausea and vomiting (CINV) is the most common debilitating side
effect of chemotherapy administration.[1],[2],[3] It affects 50%–80% of adult and pediatric patients receiving moderate to highly
emetogenic chemotherapy (MEC or HEC).[1],[2],[3] The National Comprehensive Cancer Network (NCCN) 4-point scale and the 4-point pediatric
scale proposed by Dupuis et al. are used for classifying the emetogenicity of chemotherapy drugs without the use
of prophylactic antiemetics.[4],[5] According to the scales, agents with a predicted incidence of CINV <10% are graded
as minimal-risk emetogenic potential, 10%–30% as low-risk, 30%–90% as moderate-risk,
and >90% as high-risk emetogenic potential.[4],[5]
Acute CINV is defined as CINV occurring within 24 h of administration of the last
dose of chemotherapy and delayed as CINV occurring 24 h after and till 5 days from
the last dose of chemotherapy. Chemotherapeutic agents cause nausea and vomiting by
acting on peripheral and central receptors. Acute CINV is mediated by 5-hydroxytryptamine
(5-HT3) receptors located in the enterochromaffin cells of the gut.[6] Delayed CINV is predominantly driven by a central pathway involving the neurokinin-1
(NK-1) receptor; therefore, the addition of an NK-1 receptor antagonist like fosaprepitant
to antiemetic prophylactic regimens involving a 5-HT3 receptor antagonist and a corticosteroid
has been found to be most useful in preventing delayed CINV.[7] Substance-P is the most important activator of the NK-1 receptor.[7]
Fosaprepitant was approved by the United States of America Food and Drug Administration
(FDA) in 2008 for use as a prophylactic antiemetic for preventing CINV in patients
receiving MEC or HEC in combination with a 5-HT3 antagonist and dexamethasone. The
current drug update will focus on the pharmacology and clinical aspects of the use
of fosaprepitant in oncology.
Mechanism of Action
Fosaprepitant is a prodrug of aprepitant, and its actions are attributable to aprepitant.
Aprepitant is a highly selective antagonist of substance-P/NK-1 receptor. After administration,
fosaprepitant is rapidly converted in the blood, liver, kidney, and ileum to aprepitant.[8] Plasma levels of fosaprepitant are below the level of detection (10 ng/mL) within
30 min after its infusion.[8] Aprepitant is primarily metabolized CYP3A4 enzyme in the liver and other tissues.[8] It is excreted in the urine and stools and has a half-life of 9–13 h.[8] Aprepitant is 95% protein bound.
Indication for Use
The FDA has approved the use of fosaprepitant for the prevention of acute and delayed
nausea and vomiting associated with initial and repeat courses of HEC and delayed
nausea and vomiting associated with initial and repeat courses of MEC in adults and
children above 6 months of age.[9],[10] The Central Drugs Standard Control Organization of India has approved the use of
fosaprepitant for the above indications in adults.
Dosage form and strength
150 mg, lyophilized powder in a single-dose vial for reconstitution.
Dose and administration
The dose and schedule for administration of fosaprepitant in adults have been given
in [Table 1] and for children in [Table 2] and [Table 3].[9],[10]
Table 1
Fosaprepitant administration schedule for adults (>18 years) for highly or moderately
emetogenic chemotherapy
|
Day 1
|
Day 2
|
Day 3
|
Day 4
|
|
*Dexamethasone only on day 2 and 3 for MEC. MEC – Moderate to highly emetogenic chemotherapy;
5HT – 5-hydroxytryptamine
|
|
Fosaprepitant
|
150 mg intravenously over 20-30 min approximately 30 min before chemotherapy None
|
None
|
None
|
|
Dexamethasone
|
12 mg orally 8 mg orally
|
8 mg orally
|
8 mg orally*
|
|
5HT3 antagonist
|
Dose and duration according to the drug used -
|
-
|
-
|
Table 2
Fosaprepitant administration schedule for children receiving single-day highly or
moderately emetogenic chemotherapy
|
Age
|
Regimen
|
|
5HT – 5-hydroxytryptamine
|
|
Fosaprepitant
|
>12 years
|
150 mg intravenously over 30 min
|
|
2 years-<12
|
4 mg/kg (maximum dose 150 mg) intravenously over 60 min
|
|
6 months-<2 years
|
5 mg/kg (maximum dose 150 mg) intravenously over 60 min
|
|
Dexamethasone
|
6 months-17 years
|
If a corticosteroid, such as dexamethasone, is coadministered, administer 50% of the
recommended corticosteroid dose on days 1 and 2
|
|
5HT3 antagonist
|
6 months-17 years
|
Dose according to the drug used
|
Table 3
Fosaprepitant administration schedule for children receiving multiday highly or moderately
emetogenic chemotherapy
|
Age group
|
Drug
|
Day 1
|
Day 2
|
Day 3
|
|
*Dexamethasone should be continued for 48 h after the last dose of chemotherapy. +Aprepitant
pediatric formulations are currently not available in India, and the adult dose capsules
are approved for use in children above the age of 12 years. 5HT – 5-hydroxytryptamine
|
|
12-17 years
|
Fosaprepitant
|
115 mg intravenously over 30 min
|
-
|
-
|
|
Aprepitant
|
|
80 mg orally
|
80 mg orally
|
|
6 months-<12 years
|
Fosaprepitant
|
3 mg/kg (maximum dose 115 mg) intravenously over 60 min
|
-
|
-
|
|
Aprepitant oral suspension+
|
|
2 mg/kg orally (maximum 80 mg)
|
2 mg/kg orally (maximum 80 mg)
|
|
6 months-17 years
|
Dexamethasone
|
If a corticosteroid, such as dexamethasone, is coadministered, administer 50% of the
recommended corticosteroid dose on days 1 through 4
|
|
|
|
6 months-17 years
|
5HT3 antagonist
|
Dose and duration according to the drug used
|
|
|
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
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 < 0.001) and overall (77.1% vs. 66.9%; P < 0.001) phases, but not in the acute phase (93.2% vs. 91.0%; P = 0.184), versus
placebo.[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 < 0.001), delayed phase (79% vs. 51%, P < 0.001), and overall phase (70% vs. 41%, P < 0.001). This trial used a fosaprepitant dose of 3 mg/kg (maximum 150 mg) administered
over 30 min like the adult schedule rather than the FDA recommended dose of 4 mg/kg
in children between 2 and 12 years and 5 mg/kg in children between 6 months and 2
years administered over 60 min.[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 years convert fosaprepitant to aprepitant in the blood slowly compared to adults
and achieve a lower mean area under the curve.[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.
