Contact Us    Contact Us     |     Feedback
MOBILE VIEW  | 

APREPITANT AND RELATED AGENTS

Export To Excel

Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Aprepitant and rolapitant are neurokinin-1 (NK-1)-receptor antagonists. Fosaprepitant is a prodrug of aprepitant and is rapidly converted to aprepitant following intravenous administration.

Specific Substances

    A) APREPITANT
    1) MK-869
    2) L-754030
    3) CAS 170729-80-3
    FOSAPREPITANT
    1) Fosaprepitant dimeglumine
    2) MK-0517
    3) CAS 172673-20-0 (fosaprepitant)
    4) CAS 265121-04-8 (fosaprepitant dimeglumine)
    ROLAPITANT
    1) CAS 552292-08-7

    1.2.1) MOLECULAR FORMULA
    1) Aprepitant: C23-H21-F7-N4-O3
    2) Rolapitant hydrochloride: C25H26F6N2O2

Available Forms Sources

    A) FORMS
    1) APREPITANT is available as 40 mg, 80 mg, and 125 mg capsules(Prod Info EMEND(R) oral capsules, 2014).
    2) FOSAPREPITANT is available as 115 mg and 150 mg as sterile lyophilized powder in single dose vials for intravenous administration after reconstitution and dilution (Prod Info EMEND(R) intravenous injection, 2014).
    3) ROLAPITANT is available as 90 mg tablets (Prod Info VARUBI(TM) oral tablets, 2015).
    B) USES
    1) APREPITANT AND FOSAPREPITANT may be used in combination with other anti-emetic drugs to prevent acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy, including high-dose cisplatin, and moderately emetogenic cancer chemotherapy (Prod Info EMEND(R) intravenous injection, 2014; Prod Info EMEND(R) oral capsules, 2014).
    2) Aprepitant is also used to prevent postoperative nausea and vomiting (Prod Info EMEND(R) oral capsules, 2014).
    3) ROLAPITANT is used in combination with other anti-emetic agents to prevent delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including highly emetogenic chemotherapy (Prod Info VARUBI(TM) oral tablets, 2015).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Aprepitant and fosaprepitant may be used in combination with other anti-emetic drugs to prevent acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy, including high-dose cisplatin, and moderately emetogenic cancer chemotherapy. Aprepitant is also used to prevent postoperative nausea and vomiting. Rolapitant is used in combination with other anti-emetic agents to prevent delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including highly emetogenic chemotherapy.
    B) PHARMACOLOGY: Aprepitant and rolapitant are neurokinin-1 (NK-1)-receptor antagonists (substance P antagonists). Substance P is a tachykinin (neurokinin) located in neurons of the central and peripheral nervous system; it is associated with a variety of functions, including emesis, depression, pain after inflammation, and inflammatory/immune responses in asthma and other diseases. Fosaprepitant is a prodrug of aprepitant and is rapidly converted to aprepitant following intravenous administration.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most commonly reported adverse effects following therapeutic administration, at an incidence greater than 5% and at a greater incidence than standard therapy, are alopecia, hypotension, anorexia, nausea, diarrhea, dyspepsia, constipation, hiccups, dizziness, dehydration, asthenia/fatigue, and infusion site reactions (eg, swelling, extravasation, phlebitis).
    2) INFREQUENT: Adverse effects that have occurred less frequently include: bradycardia, neutropenia, elevated liver enzymes, abdominal pain, gastritis and epigastric discomfort, and stomatitis.
    3) RARE: Stevens-Johnson syndrome has been rarely reported. Isolated instances of acute hypersensitivity reactions (ie, flushing, erythema, dyspnea, and anaphylaxis) have occurred during IV infusion of fosaprepitant.
    E) WITH POISONING/EXPOSURE
    1) Overdose data are limited. Drowsiness and headache have been reported following an overdose ingestion of aprepitant. In general, overdose effects are anticipated to be an extension of adverse effects following therapeutic administration.
    0.2.20) REPRODUCTIVE
    A) Data are lacking regarding the use of aprepitant and related agents in pregnant women and nursing mothers. Accordingly, these drugs should be used cautiously during pregnancy and lactation. .

Laboratory Monitoring

    A) Monitor fluid and electrolyte status in patients with significant diarrhea.
    B) Monitor vital signs and hepatic enzymes in symptomatic patients. Rises in serum transaminases have been reported with therapeutic use.
    C) Plasma concentrations are not readily available or clinically useful in the management of overdose.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea. Manage mild hypotension with IV fluids.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Treat severe hypotension with IV 0.9% NaCl at 10 to 20 mL/kg. Add dopamine or norepinephrine if unresponsive to fluids. Atropine may be used when severe bradycardia is associated with hypotension. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required.
    C) DECONTAMINATION
    1) PREHOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    2) HOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with severe allergic reactions.
    E) ANTIDOTE
    1) None
    F) BRADYCARDIA
    1) Usually does not require treatment. Treat bradycardia with atropine; if unresponsive, use beta adrenergic agonists (eg, isoproterenol). Consider temporary pacemaker insertion.
    G) ENHANCED ELIMINATION PROCEDURE
    1) Hemodialysis is not expected to be of benefit because of the high degree of protein binding.
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be monitored until they are clearly improving and clinically stable.
    3) ADMISSION CRITERIA: Patients with severe symptoms despite treatment should be admitted.
    4) CONSULT CRITERIA: Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    I) PITFALLS
    1) When managing a suspected aprepitant or fosaprepitant overdose, the possibility of multidrug involvement should be considered. Patients may also be taking chemotherapeutic agents that have a similar adverse effect profile (eg, alopecia, neutropenia, stomatitis).
    J) PHARMACOKINETICS
    1) The mean absolute bioavailability is 60% to 65% following a dose range of 80 to 125 mg. Aprepitant is at least 95% protein-bound; volume of distribution is approximately 70 L (steady-state). Fosaprepitant is a prodrug of aprepitant and is rapidly converted to aprepitant following intravenous administration. Elimination half-life is 9 to 13 hours.
    K) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that cause hypotension or gastrointestinal effects (eg, diarrhea, nausea).

Range Of Toxicity

    A) APREPITANT: In healthy volunteers, single doses up to 600 mg were generally well tolerated. In cancer patients, single doses up to 375 mg were well tolerated. One patient developed drowsiness and headache after ingesting 1440 mg of aprepitant. FOSAPREPITANT: Single doses up to 200 mg administered intravenously were well tolerated in healthy volunteers, with 3 individuals experiencing only mild injection site thrombosis.
    B) THERAPEUTIC DOSES: APREPITANT: ADULTS: 125 mg orally 1 hour before chemotherapy treatment (Day 1) and 80 mg once daily in the morning on Days 2 and 3. FOSAPREPITANT: ADULTS: Single-dose regimen, 150 mg IV as an infusion over 20 to 30 minutes only on Day 1, 30 minutes before chemotherapy treatment; three-day dose regimen, 115 mg IV as an infusion over 15 minutes, 30 minutes before chemotherapy treatment (Day 1), then oral aprepitant at a dose of 80 mg once daily on Days 2 and 3.

Clinical Effects

Summary Of Exposure

    A) USES: Aprepitant and fosaprepitant may be used in combination with other anti-emetic drugs to prevent acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy, including high-dose cisplatin, and moderately emetogenic cancer chemotherapy. Aprepitant is also used to prevent postoperative nausea and vomiting. Rolapitant is used in combination with other anti-emetic agents to prevent delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including highly emetogenic chemotherapy.
    B) PHARMACOLOGY: Aprepitant and rolapitant are neurokinin-1 (NK-1)-receptor antagonists (substance P antagonists). Substance P is a tachykinin (neurokinin) located in neurons of the central and peripheral nervous system; it is associated with a variety of functions, including emesis, depression, pain after inflammation, and inflammatory/immune responses in asthma and other diseases. Fosaprepitant is a prodrug of aprepitant and is rapidly converted to aprepitant following intravenous administration.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most commonly reported adverse effects following therapeutic administration, at an incidence greater than 5% and at a greater incidence than standard therapy, are alopecia, hypotension, anorexia, nausea, diarrhea, dyspepsia, constipation, hiccups, dizziness, dehydration, asthenia/fatigue, and infusion site reactions (eg, swelling, extravasation, phlebitis).
    2) INFREQUENT: Adverse effects that have occurred less frequently include: bradycardia, neutropenia, elevated liver enzymes, abdominal pain, gastritis and epigastric discomfort, and stomatitis.
    3) RARE: Stevens-Johnson syndrome has been rarely reported. Isolated instances of acute hypersensitivity reactions (ie, flushing, erythema, dyspnea, and anaphylaxis) have occurred during IV infusion of fosaprepitant.
    E) WITH POISONING/EXPOSURE
    1) Overdose data are limited. Drowsiness and headache have been reported following an overdose ingestion of aprepitant. In general, overdose effects are anticipated to be an extension of adverse effects following therapeutic administration.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) LOW BLOOD PRESSURE
    1) WITH THERAPEUTIC USE
    a) During postoperative nausea and vomiting prevention studies, hypotension was reported in 5.7% of patients administered aprepitant 40 mg orally (n=564) compared with 4.6% of patients administered ondansetron 4 mg (n=538), (Prod Info EMEND(R) oral capsules, 2014).
    B) BRADYCARDIA
    1) WITH THERAPEUTIC USE
    a) During postoperative nausea and vomiting prevention studies, bradycardia was reported in 4.4% of patients administered aprepitant 40 mg orally (n=564) compared with 3.9% of patients administered IV ondansetron 4 mg (n=538) (Prod Info EMEND(R) oral capsules, 2014).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) HICCOUGHS
    1) WITH THERAPEUTIC USE
    a) In 2 well-controlled clinical studies involving nausea and vomiting prevention with highly-emetogenic chemotherapy, hiccups were reported in 10.8% (n=544) of patients receiving oral aprepitant plus standard therapy (dexamethasone/ondansetron) compared to 5.6% (n=550) treated with standard therapy alone (first cycle of chemotherapy)(Prod Info EMEND(R) oral capsules, 2014).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) ASTHENIA
    1) WITH THERAPEUTIC USE
    a) In 2 well-controlled clinical studies involving nausea and vomiting prevention with highly-emetogenic chemotherapy, asthenia/fatigue was reported in 17.8% of patients receiving oral aprepitant plus standard therapy (dexamethasone/ondansetron) (n=544) compared with 11.8% of patients treated with standard therapy alone (n=550) during the first cycle of chemotherapy (Prod Info EMEND(R) oral capsules, 2014).
    b) Asthenia/fatigue (14%) have been more frequent with oral aprepitant (300 mg daily) compared to placebo (4%) in patients with major depression; however, this difference did not reach statistical significance(Krishnan, 2002; De Vane, 2001).
    B) DROWSY
    1) WITH THERAPEUTIC USE
    a) Somnolence (20% of patients) has been more frequent with oral aprepitant (300 mg daily) compared to placebo (9%) in patients with major depression; however, this difference did not reach statistical significance(Krishnan, 2002; De Vane, 2001).
    2) WITH POISONING/EXPOSURE
    a) One patient developed drowsiness and headache after ingesting 1440 mg of aprepitant (Prod Info EMEND(R) oral capsules, 2014).
    C) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) In 2 well-controlled clinical studies involving nausea and vomiting prevention with highly-emetogenic chemotherapy, dizziness was reported in 6.6% of patients receiving oral aprepitant plus standard therapy (dexamethasone/ondansetron) (n=544) compared with 4.4% of patients treated with standard therapy alone (n=550) during the first cycle of chemotherapy (Prod Info EMEND(R) oral capsules, 2014).
    D) HEADACHE
    1) WITH POISONING/EXPOSURE
    a) One patient developed drowsiness and headache after ingesting 1440 mg of aprepitant (Prod Info EMEND(R) oral capsules, 2014).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA
    1) WITH THERAPEUTIC USE
    a) Nausea occurred in 18% of patients with major depression receiving oral aprepitant 300 mg daily in a phase II study; although this was slightly higher than the incidence with placebo (10%), the difference was not statistically significant(Krishnan, 2002; De Vane, 2001) . Other GI effects occurred with similar frequency as placebo. However, larger studies may be required to distinguish aprepitant adverse effects.
    b) In 2 well-controlled clinical studies involving nausea and vomiting prevention with highly-emetogenic chemotherapy, nausea was reported in 12.7% of patients receiving oral aprepitant plus standard therapy (dexamethasone/ondansetron) (n=544) compared with 11.8% of patients treated with standard therapy alone (n=550) during the first cycle of chemotherapy (Prod Info EMEND(R) oral capsules, 2014).
    B) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) In 2 well-controlled clinical studies involving nausea and vomiting prevention with highly-emetogenic chemotherapy, diarrhea was reported in 10.3% (n=544) of patients receiving oral aprepitant plus standard therapy (dexamethasone/ondansetron) compared to 7.5% (n=550) treated with standard therapy alone (first cycle of chemotherapy) (Prod Info EMEND(R) oral capsules, 2014).
    b) In studies investigating the efficacy of aprepitant in cisplatin-induced emesis, diarrhea occurred more frequently with the addition of aprepitant to standard antiemetic regimens (Prod Info Emend(R), aprepitant capsules, 2003; Van Belle et al, 2002; Campos et al, 2001; Sorbera et al, 2002). However, this often occurred in groups not given 5HT3-receptor antagonists, which are known to have a constipating effect and blunt diarrhea caused by cisplatin. When given alone to healthy subjects or patients with depression, diarrhea has not been a complication of oral aprepitant (Van Belle et al, 2002; De Vane, 2001).
    C) INDIGESTION
    1) WITH THERAPEUTIC USE
    a) In 2 clinical studies involving nausea and vomiting prevention with moderately-emetogenic chemotherapy, dyspepsia was reported in 5.8% of patients receiving oral aprepitant plus standard therapy (dexamethasone/ondansetron) (n=868) compared with 3.8% of patients treated with standard therapy alone (n=846) during the first cycle of chemotherapy (Prod Info EMEND(R) oral capsules, 2014).
    D) HEARTBURN
    1) WITH THERAPEUTIC USE
    a) In 2 well-controlled clinical studies involving nausea and vomiting prevention with highly-emetogenic chemotherapy, heartburn was reported in 5.3% of patients receiving oral aprepitant plus standard therapy (dexamethasone/ondansetron) (n=544) compared with 4.9% of patients treated with standard therapy alone (n=550) during the first cycle of chemotherapy (Prod Info EMEND(R) oral capsules, 2014).
    E) LOSS OF APPETITE
    1) WITH THERAPEUTIC USE
    a) In 2 well-controlled clinical studies involving nausea and vomiting prevention with highly-emetogenic chemotherapy, anorexia was reported in 10.1% of patients receiving oral aprepitant plus standard therapy (dexamethasone/ondansetron) (n=544) compared with 9.5% of patients treated with standard therapy alone (n=550) during the first cycle of chemotherapy (Prod Info EMEND(R) oral capsules, 2014).
    F) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) In well-controlled postoperative nausea and vomiting prevention studies, constipation was reported in 8.5% of patients administered aprepitant 40 mg orally (n=564) compared with 7.6% of patients administered IV ondansetron 4 mg (n=538), (Prod Info EMEND(R) oral capsules, 2014).
    G) DEHYDRATION
    1) WITH THERAPEUTIC USE
    a) In 2 well-controlled clinical studies involving nausea and vomiting prevention with highly-emetogenic chemotherapy, dehydration was reported in 5.9% of patients receiving oral aprepitant (n=544) plus standard therapy (dexamethasone and ondansetron) compared with 5.1% of patients receiving standard therapy alone (n=550) (Prod Info EMEND(R) oral capsules, 2014).
    H) STOMATITIS
    1) WITH THERAPEUTIC USE
    a) In 2 clinical studies involving nausea and vomiting prevention with moderately-emetogenic chemotherapy, stomatitis was reported in 3.1% of patients receiving oral aprepitant plus standard therapy (dexamethasone/ondansetron) (n=868) compared with 2.7% of patients treated with standard therapy alone (n=846) during the first cycle of chemotherapy (Prod Info EMEND(R) oral capsules, 2014).
    I) EPIGASTRIC DISCOMFORT
    1) WITH THERAPEUTIC USE
    a) In 2 well-controlled clinical studies involving nausea and vomiting prevention with highly-emetogenic chemotherapy, epigastric discomfort was reported in 4% of patients receiving oral aprepitant plus standard therapy (dexamethasone/ondansetron) (n=544) compared with 3.1% of patients treated with standard therapy alone (n=550) during the first cycle of chemotherapy (Prod Info EMEND(R) oral capsules, 2014).
    J) GASTRITIS
    1) WITH THERAPEUTIC USE
    a) In 2 well-controlled clinical studies involving nausea and vomiting prevention with highly-emetogenic chemotherapy, gastritis was reported in 4.2% of patients receiving oral aprepitant plus standard therapy (dexamethasone/ondansetron) (n=544) compared with 3.1% of patients treated with standard therapy alone (n=550) during the first cycle of chemotherapy (Prod Info EMEND(R) oral capsules, 2014).
    K) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) During Cycle 1 of a clinical trial including patients receiving highly emetogenic cancer chemotherapy, abdominal pain was reported in 4.6% of patients receiving oral aprepitant (n=544) plus standard therapy (dexamethasone and ondansetron) compared with 3.3% of patients receiving standard therapy alone (n=550) (Prod Info EMEND(R) oral capsules, 2014).
    L) ULCER
    1) WITH THERAPEUTIC USE
    a) Perforating duodenal ulcer has occurred rarely during aprepitant therapy (Prod Info EMEND(R) oral capsules, 2014). Causality is uncertain.

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) INCREASED LIVER ENZYMES
    1) WITH THERAPEUTIC USE
    a) In 2 well-controlled clinical studies involving nausea and vomiting prevention with highly-emetogenic chemotherapy, increased ALT and AST were reported in 6% and 3%, respectively, of patients receiving oral aprepitant plus standard therapy (dexamethasone/ondansetron) (n=544) compared with 4.3% and 1.3%, respectively, of patients treated with standard therapy alone (n=550) during the first cycle of chemotherapy (Prod Info EMEND(R) oral capsules, 2014).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) NEUTROPENIA
    1) WITH THERAPEUTIC USE
    a) In 2 well-controlled clinical studies involving nausea and vomiting prevention with highly-emetogenic chemotherapy, neutropenia was reported in 3.1% of patients receiving oral aprepitant plus standard therapy (dexamethasone/ondansetron) (n=544) compared with 2.9% of patients treated with standard therapy alone (n=550) during the first cycle of chemotherapy (Prod Info EMEND(R) oral capsules, 2014).
    b) In 2 clinical studies involving nausea and vomiting prevention with moderately-emetogenic chemotherapy, neutropenia was reported in 5.8% of patients receiving oral aprepitant plus standard therapy (dexamethasone/ondansetron) (n=868) compared with 5.6% of patients treated with standard therapy alone (n=846) during the first cycle of chemotherapy (Prod Info EMEND(R) oral capsules, 2014).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ALOPECIA
    1) WITH THERAPEUTIC USE
    a) In 2 clinical studies involving nausea and vomiting prevention with moderately-emetogenic chemotherapy, alopecia was reported in 12.4% of patients receiving oral aprepitant plus standard therapy (dexamethasone/ondansetron) (n=868) compared with 11.9% of patients treated with standard therapy alone (n=846) during the first cycle of chemotherapy (Prod Info EMEND(R) oral capsules, 2014).
    B) STEVENS-JOHNSON SYNDROME
    1) WITH THERAPEUTIC USE
    a) In a chemotherapy-induced nausea and vomiting study, Stevens-Johnson syndrome was reported in 1 patient receiving aprepitant with cancer chemotherapy (Prod Info EMEND(R) oral capsules, 2014).
    C) INJECTION SITE REACTION
    1) WITH THERAPEUTIC USE
    a) A retrospective analysis of patients receiving fosaprepitant for management of highly emetogenic chemotherapy, was conducted to determine the incidence of infusion site adverse events (ISAE) associated with fosaprepitant administration. The study included 81 patients who were receiving platinum-based chemotherapy without inclusion of an anthracycline agent. Six patients (7.4%) experienced ISAEs. The most commonly reported signs and symptoms were mild to moderate in intensity and included swelling (3%), extravasation (3%), and phlebitis (3%). Of the 81 patients, 64 initially had peripheral IV access and 17 had central venous access, with one patient transitioning to peripheral IV access. All of the ISAEs were associated with peripheral IV access, thereby increasing the incidence to 9.4% in patients with peripheral IV access (Hegerova et al, 2015).
    1) Comparing the risk of ISAEs in fosaprepitant patients, with peripheral IV access, receiving anthracycline-based chemotherapy compared to platinum-based chemotherapy, the risk significantly increased, with an ISAE rate of 37.9% in the anthracycline group (n=99) compared to 9.4% in the platinum group (n=81). The ISAEs occurred at an average of 22 days (range 0 to 61 days) from initial exposure to fosaprepitant in the anthracycline group compared to an average of 52 days from initial exposure to fosaprepitant in the platinum group. Eleven of 33 anthracycline patients experienced ISAEs after the first fosaprepitant dose compared to one patient in the platinum group (Hegerova et al, 2015).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    1) Isolated events of immediate hypersensitivity reactions, including flushing, erythema, dyspnea, and anaphylaxis, have been reported during IV infusion of fosaprepitant (Prod Info EMEND(R) intravenous injection, 2014).

Reproductive

    3.20.1) SUMMARY
    A) Data are lacking regarding the use of aprepitant and related agents in pregnant women and nursing mothers. Accordingly, these drugs should be used cautiously during pregnancy and lactation. .
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) FOSAPREPITANT
    a) LACK OF EFFECT: Animal studies showed no embryofetal lethality or malformations after exposure to the recommended human dose of aprepitant during organogenesis. Aprepitant crosses the placenta in rabbits and rats (Prod Info EMEND(R) intravenous injection, 2016).
    2) ROLAPITANT
    a) LACK OF EFFECT: There were no reports of teratogenicity or embryofetal effects in animals administered oral rolapitant at doses up to 2.9 times the maximum recommended human dose (MRHD) during organogenesis (Prod Info VARUBI(TM) oral tablets, 2015).
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) FOSAPREPITANT
    a) There are no adequate and well-controlled studies of fosaprepitant in pregnant women, and its effects, if any, on the developing fetus are unknown (Prod Info EMEND(R) intravenous injection, 2016).
    B) RISK SUMMARY
    1) APREPITANT
    a) Exercise caution when administering aprepitant to a pregnant woman (Prod Info EMEND(R) oral capsules, 2015).
    2) FOSAPREPITANT
    a) Administer fosaprepitant to a pregnant woman only if the potential benefit outweighs the potential risk to the fetus (Prod Info EMEND(R) intravenous injection, 2016).
    3) ROLAPITANT
    a) Exercise caution when administering this drug to a pregnant woman (Prod Info VARUBI(TM) oral tablets, 2015).
    C) ANIMAL STUDIES
    1) APREPITANT
    a) Aprepitant crosses the placenta in animals. During animal studies, there were no reports of embryofetal lethality or malformations with aprepitant doses approximately 1.5 times the adult human exposure (Prod Info EMEND(R) oral capsules, 2015).
    2) ROLAPITANT
    a) There were no reports of teratogenicity or embryofetal effects in animals administered oral rolapitant at doses up to 2.9 times the maximum recommended human dose (MRHD) during organogenesis. Evidence of maternal toxicity (eg, decreased weight gain, decreased food consumption, total litter loss, prolonged parturition, decreased length of gestation) was noted with rolapitant doses approximately 1.2 times the MRHD. Decreased postnatal survival, decreased body weight, and decreased body weight gain were observed at doses approximately 1.2 times the MRHD and may have been related to the maternal toxicity (Prod Info VARUBI(TM) oral tablets, 2015).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) APREPITANT
    a) Lactation studies have not yet been conducted and it is unknown if aprepitant is excreted into human breast milk (Prod Info EMEND(R) oral capsules, 2015).
    2) FOSAPREPITANT
    a) Lactation studies with fosaprepitant have not been conducted in humans, and it is not known whether the drug is excreted into human milk (Prod Info EMEND(R) intravenous injection, 2016).
    B) BREAST MILK
    1) APREPITANT
    a) Administer to a lactating woman only if the potential maternal benefit outweighs the potential infant risk (Prod Info EMEND(R) oral capsules, 2015).
    2) FOSAPREPITANT
    a) Advise women to consider the developmental and health benefits of breastfeeding as well as the mother's need for fosaprepitant treatment against the potential adverse effects on the breastfed infant (Prod Info EMEND(R) intravenous injection, 2016).
    3) ROLAPITANT
    a) It is unknown whether rolapitant is excreted in human milk. Due to potential adverse effects in the nursing infant, administer to a lactating woman only if the potential benefit outweighs the potential risk (Prod Info VARUBI(TM) oral tablets, 2015).
    C) ANIMAL STUDIES
    1) FOSAPREPITANT
    a) Animal studies have shown that fosaprepitant is excreted into rat milk (Prod Info EMEND(R) intravenous injection, 2016).
    2) ROLAPITANT
    a) Radioactivity from rolapitant was observed in the milk of lactating animals following administration of rolapitant at doses equivalent to 22.5 mg/kg of rolapitant free base. Maximum radioactivity was observed at 12 hours post-dose and the mean milk/plasma radioactivity concentration ratios in dams at 1 and 48 hours post-dose were 1.24 to 3.25. Based on the determined maximum milk radioactivity and the average daily consumption of milk (2 mL/day), offspring exposure is expected to be 0.32% of the oral dose (Prod Info VARUBI(TM) oral tablets, 2015).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) APREPITANT
    a) No effects on fertility or general reproductive performance were reported with aprepitant administration in male and female animals at doses up to about 1.6 times the adult human exposure (Prod Info EMEND(R) oral capsules, 2015).
    2) ROLAPITANT
    a) Rolapitant administration at doses approximately 4.9 times the recommended human dose had no effect on the fertility or general reproductive performance of male animals. Transient decreases in maternal weight gain, increases in pre- and postimplantation loss, decreased numbers of corpora lutea, and decreased numbers of implantation sites were observed in female animals administered rolapitant at doses up to 0.5 times the recommended human dose (Prod Info VARUBI(TM) oral tablets, 2015).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor fluid and electrolyte status in patients with significant diarrhea.
    B) Monitor vital signs and hepatic enzymes in symptomatic patients. Rises in serum transaminases have been reported with therapeutic use.
    C) Plasma concentrations are not readily available or clinically useful in the management of overdose.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with severe symptoms despite treatment should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic, need to be monitored until they are clearly improving and clinically stable.

Monitoring

    A) Monitor fluid and electrolyte status in patients with significant diarrhea.
    B) Monitor vital signs and hepatic enzymes in symptomatic patients. Rises in serum transaminases have been reported with therapeutic use.
    C) Plasma concentrations are not readily available or clinically useful in the management of overdose.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea. Manage mild hypotension with IV fluids.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. Treat severe hypotension with IV 0.9% NaCl at 10 to 20 mL/kg. Add dopamine or norepinephrine if unresponsive to fluids. Atropine may be used when severe bradycardia is associated with hypotension.
    B) MONITORING OF PATIENT
    1) Monitor fluid and electrolyte status in patients with significant diarrhea.
    2) Monitor vital signs and hepatic enzymes in symptomatic patients. Rises in serum transaminases have been reported with therapeutic use.
    3) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    C) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    D) BRADYCARDIA
    1) ATROPINE/DOSE
    a) ADULT BRADYCARDIA: BOLUS: Give 0.5 milligram IV, repeat every 3 to 5 minutes, if bradycardia persists. Maximum: 3 milligrams (0.04 milligram/kilogram) intravenously is a fully vagolytic dose in most adults. Doses less than 0.5 milligram may cause paradoxical bradycardia in adults (Neumar et al, 2010).
    b) PEDIATRIC DOSE: As premedication for emergency intubation in specific situations (eg, giving succinylchoine to facilitate intubation), give 0.02 milligram/kilogram intravenously or intraosseously (0.04 to 0.06 mg/kg via endotracheal tube followed by several positive pressure breaths) repeat once, if needed (de Caen et al, 2015; Kleinman et al, 2010). MAXIMUM SINGLE DOSE: Children: 0.5 milligram; adolescent: 1 mg.
    1) There is no minimum dose (de Caen et al, 2015).
    2) MAXIMUM TOTAL DOSE: Children: 1 milligram; adolescents: 2 milligrams (Kleinman et al, 2010).
    2) ISOPROTERENOL INDICATIONS
    a) Used for temporary control of hemodynamically significant bradycardia in a patient with a pulse; generally other modalities (atropine, dopamine, epinephrine, dobutamine, pacing) should be used first because of the tendency to develop ischemia and dysrhythmias with isoproterenol (Neumar et al, 2010).
    b) ADULT DOSE: Infuse 2 micrograms per minute, gradually titrating to 10 micrograms per minute as needed to desired response (Neumar et al, 2010).
    c) CAUTION: Decrease infusion rate or discontinue infusion if ventricular dysrhythmias develop(Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    d) PEDIATRIC DOSE: Not well studied. Initial infusion of 0.1 mcg/kg/min titrated as needed, usual range is 0.1 mcg/kg/min to 1 mcg/kg/min (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    E) ACUTE ALLERGIC REACTION
    1) SUMMARY
    a) Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta adrenergic agonists, corticosteroids or epinephrine. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids.
    2) BRONCHOSPASM
    a) ALBUTEROL
    1) ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007). CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 mg/kg (up to 10 mg) every 1 to 4 hours as needed, or 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    3) CORTICOSTEROIDS
    a) Consider systemic corticosteroids in patients with significant bronchospasm.
    b) PREDNISONE: ADULT: 40 to 80 milligrams/day. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 to 2 divided doses divided twice daily (National Heart,Lung,and Blood Institute, 2007).
    4) MILD CASES
    a) DIPHENHYDRAMINE
    1) SUMMARY: Oral diphenhydramine, as well as other H1 antihistamines can be used as indicated (Lieberman et al, 2010).
    2) ADULT: 50 milligrams orally, or 10 to 50 mg intravenously at a rate not to exceed 25 mg/min or may be given by deep intramuscular injection. A total of 100 mg may be administered if needed. Maximum daily dosage is 400 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    3) CHILD: 5 mg/kg/24 hours or 150 mg/m(2)/24 hours. Divided into 4 doses, administered intravenously at a rate not exceeding 25 mg/min or by deep intramuscular injection. Maximum daily dosage is 300 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    5) MODERATE CASES
    a) EPINEPHRINE: INJECTABLE SOLUTION: It should be administered early in patients by IM injection. Using a 1:1000 (1 mg/mL) solution of epinephrine. Initial Dose: 0.01 mg/kg intramuscularly with a maximum dose of 0.5 mg in adults and 0.3 mg in children. The dose may be repeated every 5 to 15 minutes, if no clinical improvement. Most patients respond to 1 or 2 doses (Nowak & Macias, 2014).
    6) SEVERE CASES
    a) EPINEPHRINE
    1) INTRAVENOUS BOLUS: ADULT: 1 mg intravenously as a 1:10,000 (0.1 mg/mL) solution; CHILD: 0.01 mL/kg intravenously to a maximum single dose of 1 mg given as a 1:10,000 (0.1 mg/mL) solution. It can be repeated every 3 to 5 minutes as needed. The dose can also be given by the intraosseous route if IV access cannot be established (Lieberman et al, 2015). ALTERNATIVE ROUTE: ENDOTRACHEAL ADMINISTRATION: If IV/IO access is unavailable. DOSE: ADULT: Administer 2 to 2.5 mg of 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube. CHILD: DOSE: 0.1 mg/kg to a maximum of 2.5 mg administered as a 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube (Lieberman et al, 2015).
    2) INTRAVENOUS INFUSION: Intravenous administration may be considered in patients poorly responsive to IM or SubQ epinephrine. An epinephrine infusion may be prepared by adding 1 mg (1 mL of 1:1000 (1 mg/mL) solution) to 250 mL D5W, yielding a concentration of 4 mcg/mL, and infuse this solution IV at a rate of 1 mcg/min to 10 mcg/min (maximum rate). CHILD: A dosage of 0.01 mg/kg (0.1 mL/kg of a 1:10,000 (0.1 mg/mL) solution up to 10 mcg/min (maximum dose 0.3 mg) is recommended for children (Lieberman et al, 2010). Careful titration of a continuous infusion of IV epinephrine, based on the severity of the reaction, along with a crystalloid infusion can be considered in the treatment of anaphylactic shock. It appears to be a reasonable alternative to IV boluses, if the patient is not in cardiac arrest (Vanden Hoek,TL,et al).
    7) AIRWAY MANAGEMENT
    a) OXYGEN: 5 to 10 liters/minute via high flow mask.
    b) INTUBATION: Perform early if any stridor or signs of airway obstruction.
    c) CRICOTHYROTOMY: Use if unable to intubate with complete airway obstruction (Vanden Hoek,TL,et al).
    d) BRONCHODILATORS are recommended for mild to severe bronchospasm.
    e) ALBUTEROL: ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007).
    f) ALBUTEROL: CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    8) MONITORING
    a) CARDIAC MONITOR: All complicated cases.
    b) IV ACCESS: Routine in all complicated cases.
    9) HYPOTENSION
    a) If hypotensive give 500 to 2000 milliliters crystalloid initially (20 milliliters/kilogram in children) and titrate to desired effect (stabilization of vital signs, mentation, urine output); adults may require up to 6 to 10 L/24 hours. Central venous or pulmonary artery pressure monitoring is recommended in patients with persistent hypotension.
    1) VASOPRESSORS: Should be used in refractory cases unresponsive to repeated doses of epinephrine and after vigorous intravenous crystalloid rehydration (Lieberman et al, 2010).
    2) DOPAMINE: Initial Dose: 2 to 20 micrograms/kilogram/minute intravenously; titrate to maintain systolic blood pressure greater than 90 mm Hg (Lieberman et al, 2010).
    10) H1 and H2 ANTIHISTAMINES
    a) SUMMARY: Antihistamines are second-line therapy and are used as supportive therapy and should not be used in place of epinephrine (Lieberman et al, 2010).
    1) DIPHENHYDRAMINE: ADULT: 25 to 50 milligrams via a slow intravenous infusion or IM. PEDIATRIC: 1 milligram/kilogram via slow intravenous infusion or IM up to 50 mg in children (Lieberman et al, 2010).
    b) RANITIDINE: ADULT: 1 mg/kg parenterally; CHILD: 12.5 to 50 mg parenterally. If the intravenous route is used, ranitidine should be infused over 10 to 15 minutes or diluted in 5% dextrose to a volume of 20 mL and injected over 5 minutes (Lieberman et al, 2010).
    c) Oral diphenhydramine, as well as other H1 antihistamines, can also be used as indicated (Lieberman et al, 2010).
    11) DYSRHYTHMIAS
    a) Dysrhythmias and cardiac dysfunction may occur primarily or iatrogenically as a result of pharmacologic treatment (epinephrine) (Vanden Hoek,TL,et al). Monitor and correct serum electrolytes, oxygenation and tissue perfusion. Treat with antiarrhythmic agents as indicated.
    12) OTHER THERAPIES
    a) There have been a few reports of patients with anaphylaxis, with or without cardiac arrest, that have responded to vasopressin therapy that did not respond to standard therapy. Although there are no randomized controlled trials, other alternative vasoactive therapies (ie, vasopressin, norepinephrine, methoxamine, and metaraminol) may be considered in patients in cardiac arrest secondary to anaphylaxis that do not respond to epinephrine (Vanden Hoek,TL,et al).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis is not expected to be of benefit because of the high degree of protein binding (greater than 95%) (Prod Info EMEND(R) oral capsules, 2014).

Range Of Toxicity

Summary

    A) APREPITANT: In healthy volunteers, single doses up to 600 mg were generally well tolerated. In cancer patients, single doses up to 375 mg were well tolerated. One patient developed drowsiness and headache after ingesting 1440 mg of aprepitant. FOSAPREPITANT: Single doses up to 200 mg administered intravenously were well tolerated in healthy volunteers, with 3 individuals experiencing only mild injection site thrombosis.
    B) THERAPEUTIC DOSES: APREPITANT: ADULTS: 125 mg orally 1 hour before chemotherapy treatment (Day 1) and 80 mg once daily in the morning on Days 2 and 3. FOSAPREPITANT: ADULTS: Single-dose regimen, 150 mg IV as an infusion over 20 to 30 minutes only on Day 1, 30 minutes before chemotherapy treatment; three-day dose regimen, 115 mg IV as an infusion over 15 minutes, 30 minutes before chemotherapy treatment (Day 1), then oral aprepitant at a dose of 80 mg once daily on Days 2 and 3.

Therapeutic Dose

    7.2.1) ADULT
    A) APREPITANT
    1) ORAL CAPSULES
    a) CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING
    1) The recommended dose of aprepitant is 125 mg orally 1 hour before chemotherapy treatment (Day 1) and 80 mg once daily 1 hour prior to chemotherapy on Days 2 and 3 (Prod Info EMEND(R) oral capsules, suspension, 2015).
    b) POSTOPERATIVE NAUSEA AND VOMITING PROPHYLAXIS
    1) The recommended oral dose of aprepitant is 40 mg within 3 hours before anesthesia induction (Prod Info EMEND(R) oral capsules, 2015).
    2) ORAL SUSPENSION
    a) CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING
    1) Day 1: 3 mg/kg (MAX, 125 mg) orally 1 hour prior to chemotherapy. Days 2 and 3: 2 mg/kg (MAX, 80 mg) orally once daily 1 hour prior to chemotherapy (Prod Info EMEND(R) oral capsules, suspension, 2015).
    3) INTRAVENOUS
    a) NAUSEA AND VOMITING INDUCED BY HIGHLY OR MODERATELY EMETOGENIC CANCER CHEMOTHERAPY
    1) Day 1: Fosaprepitant dimeglumine 150 mg IV over 20 to 30 minutes administered approximately 30 minutes prior to chemotherapy (Prod Info EMEND(R) intravenous injection, 2016).
    B) ROLAPITANT
    1) Recommended dose is 180 mg orally 1 to 2 hours prior to start of each cisplatin-based chemotherapy cycle, at intervals of at least 2 weeks. Administer in combination with a 5-HT3 receptor antagonist and dexamethasone (Prod Info VARUBI(TM) oral tablets, 2015).
    7.2.2) PEDIATRIC
    A) APREPITANT
    1) ORAL CAPSULES
    a) CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING
    1) 12 YEARS OR OLDER, OR LESS THAN 12 YEARS WITH BODY WEIGHT 30 KG OR GREATER AND ABLE TO SWALLOW CAPSULES: The recommended dose of aprepitant is 125 mg orally 1 hour before chemotherapy treatment (Day 1) and 80 mg once daily 1 hour prior to chemotherapy on Days 2 and 3 (Prod Info EMEND(R) oral capsules, suspension, 2015).
    b) POSTOPERATIVE NAUSEA AND VOMITING PROPHYLAXIS
    1) Safety and effectiveness have not been established in pediatric patients (Prod Info EMEND(R) oral capsules, 2015).
    2) ORAL SUSPENSION
    a) CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING
    1) 6 MONTHS OR OLDER AND WEIGHING AT LEAST 6 KG: Day 1: 3 mg/kg (MAX, 125 mg) orally 1 hour prior to chemotherapy. Days 2 and 3: 2 mg/kg orally once daily (MAX, 80 mg) 1 hour before chemotherapy (Prod Info EMEND(R) oral capsules, suspension, 2015).
    3) INTRAVENOUS
    a) Safety and effectiveness have not been established in pediatric patients (Prod Info EMEND(R) intravenous injection, 2016).
    B) ROLAPITANT
    1) Safety and effectiveness have not been established in pediatric patients (Prod Info VARUBI(TM) oral tablets, 2015).

Maximum Tolerated Exposure

    A) ADULT
    1) APREPITANT: In healthy volunteers, single doses up to 600 mg were generally well tolerated. In cancer patients, single doses up to 375 mg were well tolerated. One patient developed drowsiness and headache after ingesting 1440 mg of aprepitant (Prod Info EMEND(R) oral capsules, 2014; Prod Info EMEND(R) oral capsules, 2009)
    2) FOSAPREPITANT: Single doses up to 200 mg administered intravenously were well tolerated in healthy volunteers, with 3 individuals experiencing only mild injection site thrombosis (Prod Info EMEND(R) intravenous injection, 2010).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Aprepitant is a neurokinin-1 (NK-1)-receptor antagonist (substance P antagonist) is indicated primarily for use in chemotherapy-induced nausea and vomiting, as well as prophylaxis for postoperative nausea and vomiting (Prod Info EMEND(R) oral capsules, 2014; Sorbera et al, 2002; Campos et al, 2001). Fosaprepitant is a prodrug of aprepitant and is rapidly converted to aprepitant following intravenous administration (Prod Info EMEND(R) intravenous injection, 2014).
    B) Substance P is a tachykinin (neurokinin) located in neurons of the central and peripheral nervous system; it is associated with a variety of functions, including emesis, depression, pain after inflammation, and inflammatory/immune responses in asthma and other diseases (Diemunsch & Grelot, 2000; Lieb et al, 2002; De Vane, 2001). Effects of substance P are mediated via the NK-1 receptor, a G-protein receptor coupled to the inositol phosphate signal pathway (Campos et al, 2001); antagonism of this receptor has thus been investigated as mechanism to treat conditions considered to be mediated at least in part by substance P.
    C) ROLAPITANT is a selective and competitive P/neurokinin 1 (NK1) receptor antagonist with antiemetic activity. Rolapitant crosses the blood brain barrier and occupies brain NK1 receptors (Prod Info VARUBI(TM) oral tablets, 2015).

Physicochemical

Physical Characteristics

    A) Aprepitant is a white to off-white crystalline solid; practically insoluble in water, sparingly soluble in ethanol and isopropyl acetate(Prod Info Emend(R), aprepitant capsules, 2003).
    B) Rolapitant hydrochloride is a white to off-white powder, with good solubility in common pharmaceutical solvents (eg, ethanol, propylene glycol, and 40% hydroxypropyl beta cyclodextrin); solubility in aqueous solution is pH dependant and is more soluble at lower pH (Prod Info VARUBI(TM) oral tablets, 2015).

Molecular Weight

    A) Aprepitant, 534.43 (Prod Info Emend(R), aprepitant capsules, 2003)
    B) Rolapitant hydrochloride, 554.95 (Prod Info VARUBI(TM) oral tablets, 2015)

References

General Bibliography

    1) Alaspaa AO, Kuisma MJ, Hoppu K, et al: Out-of-hospital administration of activated charcoal by emergency medical services. Ann Emerg Med 2005; 45:207-12.
    2) Campos D, Pereira JR, Reinhardt RR, et al: Prevention of cisplatin-induced emesis by the oral neurokinin-1 antagonist, MK-869, in combination with granisetron and dexamethasone or with dexamethasone alone.. J Clin Oncol 2001; 19:1759-1767.
    3) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    4) Dagnone D, Matsui D, & Rieder MJ: Assessment of the palatability of vehicles for activated charcoal in pediatric volunteers. Pediatr Emerg Care 2002; 18:19-21.
    5) De Vane CL: Substance P: a new era, a new role.. Pharmacotherapy 2001; 21(9):1061-1069.
    6) Diemunsch P & Grelot L: Potential of substance P antagonists as antiemetics.. Drugs 2000; 60(3):533-546.
    7) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    8) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    9) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    10) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    11) Guenther Skokan E, Junkins EP, & Corneli HM: Taste test: children rate flavoring agents used with activated charcoal. Arch Pediatr Adolesc Med 2001; 155:683-686.
    12) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    13) Hegerova LT, Leal AD, Grendahl DC, et al: An analysis of fosaprepitant-induced venous toxicity in patients receiving highly emetogenic chemotherapy. Support Care Cancer 2015; 23(1):55-59.
    14) Kleinman ME, Chameides L, Schexnayder SM, et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Part 14: pediatric advanced life support. Circulation 2010; 122(18 Suppl.3):S876-S908.
    15) Krishnan KR: Clinical experience with substance P receptor (NK1) antagonists in depression.. J Clin Psychiatry 2002; 63(Suppl 11):25-29.
    16) Lieb K, Treffurth Y, Berger M, et al: Substance P and affective disorders: new treatment opportunities by neurokinin 1 receptor antagonists?. Neuropsychobiology 2002; 45(Suppl 1):2-6.
    17) Lieberman P, Nicklas R, Randolph C, et al: Anaphylaxis-a practice parameter update 2015. Ann Allergy Asthma Immunol 2015; 115(5):341-384.
    18) Lieberman P, Nicklas RA, Oppenheimer J, et al: The diagnosis and management of anaphylaxis practice parameter: 2010 update. J Allergy Clin Immunol 2010; 126(3):477-480.
    19) National Heart,Lung,and Blood Institute: Expert panel report 3: guidelines for the diagnosis and management of asthma. National Heart,Lung,and Blood Institute. Bethesda, MD. 2007. Available from URL: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf.
    20) Neumar RW , Otto CW , Link MS , et al: Part 8: adult advanced cardiovascular life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010; 122(18 Suppl 3):S729-S767.
    21) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    22) Nowak RM & Macias CG : Anaphylaxis on the other front line: perspectives from the emergency department. Am J Med 2014; 127(1 Suppl):S34-S44.
    23) Peberdy MA , Callaway CW , Neumar RW , et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care science. Part 9: post–cardiac arrest care. Circulation 2010; 122(18 Suppl 3):S768-S786.
    24) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    25) Product Information: EMEND(R) intravenous injection, fosaprepitant dimeglumine intravenous injection. Merck & Co., Whitehouse Station, NJ, 2010.
    26) Product Information: EMEND(R) intravenous injection, fosaprepitant dimeglumine intravenous injection. Merck Sharp & Dohme Corp. (per FDA), Whitehouse Station, NJ, 2014.
    27) Product Information: EMEND(R) intravenous injection, fosaprepitant dimeglumine intravenous injection. Merck Sharp & Dohme Corp. (per FDA), Whitehouse Station, NJ, 2016.
    28) Product Information: EMEND(R) oral capsules, aprepitant oral capsules. MERCK & Co. Inc., Whitehouse Station, NJ, 2009.
    29) Product Information: EMEND(R) oral capsules, aprepitant oral capsules. Merck Sharp & Dohme Corp. (per FDA), Whitehouse Station, NJ, 2014.
    30) Product Information: EMEND(R) oral capsules, aprepitant oral capsules. Merck Sharp & Dohme Corp. (per manufacturer), Whitehouse Station, NJ, 2015.
    31) Product Information: EMEND(R) oral capsules, suspension, aprepitant oral capsules, suspension. Merck Sharp & Dohme Corp. (per FDA), Whitehouse Station, NJ, 2015.
    32) Product Information: Emend(R), aprepitant capsules. Merck & Co, Inc, Whitehouse Station, NJ, USA, 2003.
    33) Product Information: Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, isoproterenol HCl intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection. Hospira, Inc. (per FDA), Lake Forest, IL, 2013.
    34) Product Information: VARUBI(TM) oral tablets, rolapitant oral tablets. Tesaro Inc. (per manufacturer), Waltham, MA, 2015.
    35) Product Information: diphenhydramine HCl intravenous injection solution, intramuscular injection solution, diphenhydramine HCl intravenous injection solution, intramuscular injection solution. Hospira, Inc. (per DailyMed), Lake Forest, IL, 2013.
    36) Product Information: dopamine hcl, 5% dextrose IV injection, dopamine hcl, 5% dextrose IV injection. Hospira,Inc, Lake Forest, IL, 2004.
    37) Product Information: norepinephrine bitartrate injection, norepinephrine bitartrate injection. Sicor Pharmaceuticals,Inc, Irvine, CA, 2005.
    38) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    39) Sorbera LA, Castaner J, Bayes M, et al: Aprepitant and L-758298.. Drugs Future 2002; 27(3):211-222.
    40) Spiller HA & Rogers GC: Evaluation of administration of activated charcoal in the home. Pediatrics 2002; 108:E100.
    41) Tattersall FD, Rycroft W, Cumberbatch M, et al: The novel NK1 receptor antagonist MK-0869 (L-754,030) and its water soluble phosphoryl prodrug, L-758,298, inhibit acute and delayed cisplatin-induced emesis in ferrets.. Neuropharmacology 2000; 39:652-663.
    42) Thakore S & Murphy N: The potential role of prehospital administration of activated charcoal. Emerg Med J 2002; 19:63-65.
    43) Van Belle S, Lichinitser MR, Navari RM, et al: Prevention of cisplatin-induced acute and delayed emesis by the selective neurokinin-1 antagonists, L-758,298 and MK-869: a randomized controlled trial.. Cancer 2002; 94:3032-3041.
    44) Vanden Hoek,TL; Morrison LJ; Shuster M; et al: Part 12: Cardiac Arrest in Special Situations 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. American Heart Association. Dallas, TX. 2010. Available from URL: http://circ.ahajournals.org/cgi/reprint/122/18_suppl_3/S829. As accessed 2010-10-21.
    45) de Caen AR, Berg MD, Chameides L, et al: Part 12: Pediatric Advanced Life Support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2015; 132(18 Suppl 2):S526-S542.