TRIPASS XR تري باس

 Emetogenicity of Selected Antineoplastic Agents by Dose and Route of Administration

Chemotherapy Agent Injectable Administration Oral Administration

Aldesleukin (Proleukin) >12–15 million units/m2 = Moderate

≤12 million units/m2 = Low

Alemtuzumab (Campath) Minimal

Altretamine (Hexalen) High

Arsenic trioxide (Trisenox) Moderate

Asparaginase (Elspar) Minimal

Azacitdine (Vidaza) Moderate

Bendamustine (Treanda) Moderate

Bevacizumab (Avastin) Minimal

Bexarotene (Targretin) Low

Bleomycin (Blenoxane) Minimal

Bortezomib (Velcade) Low

Busulfan (Busulfex, Myleran) Moderate ≥4 mg = Moderate

<4 mg = Minimal

Cabazitaxel (Javtana) Moderate

Capecitabine (Xeloda) Low

Carboplatin (Paraplatin) Moderate with high risk of delayed CINV

Carmustine (BiCNU) >250 mg/m2 = High

≤250 mg/m2 = Moderate

Chlorambucil (Leukeran) Minimal

Cetuximab (Erbitux) Minimal

Cisplatin (Platinol) ≥50 mg/m2 = High

<50 mg/m2 = Moderate

High risk of delayed CINV

Cladribine (Leustatin) Minimal

Clofarabine (Clolar) Moderate

Cyclophosphamide (Cytoxan) >1,500 mg/m2 = High

≤1,500 mg/m2 = Moderate

High risk of delayed CINV

≥100 mg/m2

/d = Moderate

<100 mg/m2

/d = Low

Cytarabine (Ara-C, Cytosar-U) >200 mg/m2 = Moderate

100–200 mg/m2 = Low

<100 mg/m2 = Minimal

Dacarbazine (DTIC) High

Dactinomycin (Cosmegen) Moderate

Dasatinib (Sprycel) Minimal

Daunorubicin (Cerubidine) Moderate

Decitabine (Dacogen) Minimal

Docetaxel (Taxotere) Low

Doxorubicin (Adriamycin) Moderate

High risk of delayed CINV

Doxorubicin liposomal (Doxil) Moderate

Epirubicin (Ellence) Moderate

High risk of delayed CINV

Erlotinib (Tarceva) Minimal

Etoposide (VePeSid) Low Moderate

Everolimus (Afinitor) Minimal

Fludarabine (Fludara) Minimal Low

Fluorouracil (Adrucil) Low

Gefitinib (Iressa) Minimal

Gemcitabine (Gemzar) Low

Hydroxyurea (Hydrea) Minimal

Idarubicin (Idamycin) Moderate

High risk of delayed CINV

Ifosfamide (Ifex) Moderate

Imatinib (Gleevec) Moderate

Interferon α2B (Intron A) ≥10 million units/m2 = Moderate

<10 million units/m2 = Low

Irinotecan (Camptosar) Moderate

Some risk of delayed CINV

Ixabepilone (Ixempra) Low

Lapatinib (Tykerb) Low

Lenalidomide (Revlimid) Minimal

Lomustine (CeeNU) Moderate

Mechlorethamine (Mustargen) High

Melphalan (Alkeran) Moderate Minimal

Mercaptopurine (Purinethol) Minimal

(continued )

104 Section 1 General Care

TABLE 6-2

Emetogenicity of Selected Antineoplastic Agents by Dose and Route of Administration

(Continued)

Chemotherapy Agent Injectable Administration Oral Administration

Methotrexate (Trexall) ≥250 mg/m2 = Moderate

50–249 mg/m2 = Low

<50 mg/m2 = Minimal

Some risk of delayed CINV

Minimal

Mitomycin (Mutamycin) Low

Mitoxantrone (Novantrone) Low

Nelarabine (Arranon) Minimal

Nilotinib (Tasigna) Low

Oxaliplatin (Eloxatin) Moderate

Paclitaxel (Taxol) Low

Paclitaxel Protein Bound (Abraxane) Low

Panitumumab (Vectibix) Minimal

Pazopanib (Votrient) Low

Pegasparaginase (Oncaspar) Minimal

Pemetrexed (Alimta) Low

Pentostatin (Nipent) Low

Pralatrexate (Folotyn) Moderate

Procarbazine (Matulane) High

Rituximab (Rituxan) Minimal

Romidepsin (Istodax) Low

Sorafenib (Nexavar) Minimal

Streptozocin (Zanosar) High

Sunitinib (Sutent) Minimal

Temozolamide (Temodar) Moderate >75 mg/m2

/d = Moderate

≤75 mg/m2

/d = Low

Temsirolimus (Torisel) Minimal

Teniposide (Vumon) Low

Thalidomide (Thalomid) Minimal

Thioguanine (Tabloid) Minimal

Thiotepa (Thiotepa) Low

Topotecan (Hycamptin) Moderate Low

Trastuzumab (Herceptin) Minimal

Tretinoin (Vesanoid) Low

Vinblastine (Velban) Minimal

Vincristine (Oncovin) Minimal

Vinorelbine (Navelbine) Minimal

Vorinostat (Zolinza) Low

High = >90% (of patients would experience chemotherapy-induced nausea and vomiting [CINV] without antiemetic

premedication); Moderate = 30%–90%; Low = 10%–30%; Minimal = <10%.

Source: Ettinger DS et al. Antiemesis: clinical practice guidelines in oncology. V2.2010. http://www.nccn.org/professionals/

physician gls/pdf/antiemesis.pdf. Accessed September 30, 2010; Grunberg SM et al. Evaluation of new antiemetic agents and

definition of antineoplastic agent emetogenicity—an update. Support Care Cancer. 2005;13:80; American Society of Clinical Oncology

et al. American Society of Clinical Oncology guideline for antiemetics in oncology: update 2006 [published correction appears

in J Clin Oncol. 2006;24:5341]. J Clin Oncol. 2006;24:2932; Roila F et al. Guideline update for MASCC and ESMO in the prevention

of chemotherapy- and radiotherapy-induced nausea and vomiting: results of the Perugia consensus conference. Ann Oncol.

2010;21(Suppl 5):v232.

effective for at least a few days, but little data are published using

repeated doses in fewer than 7 days. Palonosetron has been studied in a three-dose regimen (administration on days 1, 3, 5) for

multiday chemotherapy in an uncontrolled trial.26 This regimen

appeared to be safe and effective, but was not compared with any

other regimen. It is not clear that palonosetron would have superior activity compared with repeated doses of the other 5-HT3

antagonists.

It is difficult to identify the 5-HT3 antagonist with the highest overall cost-effectiveness because drug acquisition costs vary

between the inpatient and outpatient clinics and from institution

to institution. Costs of the different agents should be compared

at each practice site to determine the preferred agent.

CORTICOSTEROIDS

The mechanism of action of corticosteroids as antiemetics has not

been fully determined. Some suggest that corticosteroids may

decrease serotonin release, antagonize 5-HT3, or activate corticosteroid receptors in the NTS of the medulla in the CNS.20 Many

studies validate the effectiveness of corticosteroids in the prophylaxis of CINV symptoms. Efficacy with both dexamethasone and

methylprednisolone has been described, but dexamethasone is

much more widely studied and almost exclusively used. Dexamethasone improves the antiemetic control of 5-HT3 antagonists

by about 15% to 20%.20 In addition to its use in the acute phase

of CINV, dexamethasone is one of the cornerstone agents used

to prevent delayed CINV. It is inexpensive and available in both

IV and oral formulations.

The optimal dose of dexamethasone with different emetic

stimuli has been studied in controlled trials.27 For moderately

emetogenic chemotherapy in the acute phase, a single 8-mg

dose was as effective as larger 24-mg doses or prolonged administration. In the setting of highly emetogenic cisplatin-based

chemotherapy, higher doses of 12 or 20 mg were superior to

doses of 4 and 8 mg. If dexamethasone is used with aprepitant

in the acute phase, the lower 12-mg prechemotherapy dose is

105Nausea and Vomiting Chapter 6

recommended because of inhibition of steroid metabolism by

aprepitant (see the NK1 receptor antagonist section).12 For prevention of delayed CINV symptoms, the most commonly used

dose of dexamethasone is 8 mg twice daily on days 2 and 3 after

chemotherapy without aprepitant. The dose for delayed CINV

should be reduced to 8 mg daily when used with aprepitant.

Corticosteroids are sometimes underused because of the

potential risk of side effects. The adverse effects of corticosteroids include insomnia, jitteriness, increased appetite, GI distress, and perineal irritation if the IV dexamethasone is infused

too quickly.18,27,28 For most patients, however, dexamethasone

is well tolerated, especially because the therapy is typically short

term at lower doses. Steroid-related hyperglycemia may occur,

especially in patients with pre-existing diabetes.20 These patients

should be advised to monitor their glucose levels more frequently

and contact their practitioner if the levels remain elevated. In

the nondiabetic patient, hyperglycemia is uncommon. Tapering

the corticosteroid dose after the end of treatment for CINV is

usually unnecessary because the duration of therapy is short.

Rare patients who have steroid withdrawal-like symptoms may,

however, benefit from a short taper on repeated corticosteroid

courses.

Corticosteroids also have antitumor properties and are a part

of the antineoplastic regimen for some malignancies, such as

lymphoma, lymphoid leukemia, and myeloma, and additional

dexamethasone for the antiemetic protection is not necessary. In

these cases, the corticosteroid should be administered just before

the rest of the chemotherapy to provide antiemetic activity. If

aprepitant is part of an antiemetic regimen in a situation where

the corticosteroid is given for antitumor reasons, the dose of the

corticosteroid should not be reduced.12

NEUROKININ 1 RECEPTOR ANTAGONISTS

The potential use of NK1 receptor antagonists as antiemetics

became apparent when the role of substance P in the peripheral

nervous system and CNS was recognized in the emetic stimulus

pathway. Aprepitant, the first NK1 receptor antagonist available,

is active in both the acute and delayed phases of CINV caused by

moderately and highly emetogenic chemotherapy. Aprepitant is

usually given as a 3-day oral regimen, 125 mg on day 1 and 80 mg

on days 2 and 3. Early trials determined that aprepitant could

not replace a 5-HT3 antagonist, but that it would be used best

in conjunction with corticosteroids and a 5-HT3 antagonist.29

Studies have shown that aprepitant-containing regimens were

TABLE 6-3

Antiemetic Agents for Chemotherapy-Induced Nausea and Vomiting (CINV)

Medication (Trade Name) Class Indication

Dose in Adults (Doses Should be Given

30–60 Minutes Before Chemotherapy)

Aprepitant (Emend) NK1 antagonist Acute and delayed PO: 125 mg on day 1, 80 mg on days 2 and 3

Dexamethasone (Decadron) Corticosteroid Acute (high emetogenicity) PO/IV: 12 mg (with aprepitant) or 20 mg

(without aprepitant)

Acute (moderate emetogenicity) PO/IV: 8–12 mg

Acute (low emetogenicity) PO/IV: 4–8 mg

Delayed PO/IV: 8 mg daily days 2–4 or days 2 and 3 or

PO: 4 mg BID days 2–4

Dolasetron (Anzemet) 5-HT3 antagonist Acute PO: 100–200 mg

Dronabinol (Marinol) Cannabinoid Breakthrough PO: 2.5–10 mg PO TID to QID

Droperidol (Inapsine) Butyrophenone Breakthrough IV: 0.625–1.25 mg every 4–6 hours PRN

Fosaprepitant (Emend) NK1 antagonist Acute IV: 150 mg ×1 dose or 115 mg initial dose

(followed by aprepitant 80 mg PO on days 2

and 3

Granisetron (Kytril) 5-HT3 antagonist Acute IV: 1 mg or 0.01 mg/kg

PO: 2 mg

TOP: 3.1 mg/24-h patch applied 24–48 hours

before chemotherapy and kept on until

24 hours after chemotherapy or up to 7 days

Haloperidol (Haldol) Butyrophenone Breakthrough PO/IV/IM: 0.5–1 mg every 6 hours PRN

Metoclopramide (Reglan) Dopamine antagonist Breakthrough PO/IV: 10–40 mg every 6 hours PRN

Lorazepam (Ativan) Benzodiazepine Breakthrough PO/IV/IM/SL: 0.5–2 mg every 6 hours PRN

Nabilone (Cesamet) Cannabinoid Refractory symptoms PO: 1–2 mg BID (max 2 mg TID)

Olanzapine (Zyprexa) Serotonin/dopamine

antagonist

Acute/delayed/breakthrough PO: 2.5–10 mg QHS or 2.5 mg BID or 2.5 mg

TID plus 5 mg QHS

Ondansetron (Zofran) 5-HT3 antagonist Acute (moderate or high

emetogenicity)

Delayed

IV: 8–12 mg or 0.15 mg/kg

PO: 16–24 mg

8 mg PO BID or 8 mg IV daily

Palonosetron (Aloxi) 5-HT3 antagonist Acute/delayed IV: 0.25 mg

PO: 0.5 mg

Prochlorperazine

(Compazine)

Dopamine antagonist Breakthrough

Acute

PO/IV/IM: 5–10 mg (up to 20 mg) every

4–6 hours PRN or

PR: 25 mg every 12 hours PRN

PO/IV: 10 mg

Promethazine (Phenergan) Dopamine antagonist Breakthrough PO/IV/IM/PR: 12.5–25 mg every 4–6 hours

PRN

BID, twice daily; IM, intramuscular; IV, intravenous; NK1, neurokinin 1; PO, oral; PR, rectal; PRN, as needed; QHS, at bedtime; QID, four times daily; TID, three times daily.

Source: Ettinger DS et al. Antiemesis: clinical practice guidelines in oncology. V2.2010. http://www.nccn.org/professionals/physician gls/pdf/antiemesis.pdf.

Accessed September 30, 2010; American Society of Clinical Oncology et al. American Society of Clinical Oncology guideline for antiemetics in oncology: update 2006

[published correction appears in J Clin Oncol. 2006;24:5341]. J Clin Oncol. 2006;24:2932; Roila F et al. Guideline update for MASCC and ESMO in the prevention of

chemotherapy- and radiotherapy-induced nausea and vomiting: results of the Perugia consensus conference. Ann Oncol. 2010;21(Suppl 5):v232.

106 Section 1 General Care

more effective in women than in men, which is fortunate because

women have more acute and delayed symptoms than men.29

Aprepitant has been studied in the prevention of CINV with

highly and moderately emetogenic chemotherapy.17,29 These

studies showed improved response rates when aprepitant was

added to antiemetic regimens containing a 5-HT3 antagonist

plus dexamethasone.

Although CINV symptoms tend to worsen from cycle to cycle,

the effects of aprepitant seem to be maintained during four cycles

of chemotherapy in patients receiving moderately emetogenic

chemotherapy.30 The addition of aprepitant to the antiemetic

regimen on cycle 2 (even when omitted from cycle 1) also seems

to improve control of CINV symptoms.31,32 For patients who

have had inadequate response to an antiemetic regimen that did

not include aprepitant, it may be useful to add it in later cycles.

The efficacy of aprepitant for the control of delayed CINV

symptoms was confirmed in a trial of 489 patients comparing

a standard aprepitant regimen (aprepitant, ondansetron, and

dexamethasone on day 1, followed by aprepitant and dexamethasone on days 2 and 3, and dexamethasone on day 4)

with a regimen without aprepitant (ondansetron and dexamethasone on days 1 through 4) in patients receiving highly

emetogenic chemotherapy.33 The aprepitant-containing regimen offered superior control of CINV in the acute, delayed, and

overall periods. The study confirmed that aprepitant is superior

to a 5-HT3 antagonist during the delayed phase of CINV.

There is growing evidence that the prechemotherapy dose of

aprepitant (or fosaprepitant) provides the majority of the benefit compared with the postchemotherapy doses.17,34 This first

dose of aprepitant blocks about 80% of the NK1 receptors in

the CNS.17,34 One study compared a single 150-mg IV dose of

fosaprepitant to the standard three-day oral regimen (along with

ondansetron and dexamethasone) in patients receiving highly

emetogenic chemotherapy. There was no difference found in the

antiemetic efficacy between the two groups.35 Ongoing research

is needed to further clarify the optimal dosing regimen.

Aprepitant is generally well tolerated with mild side effects,

including fatigue, hiccups, headache, and diarrhea.29,33 The overall adverse effects in standard aprepitant-containing regimens are

not appreciably different from regimens without aprepitant. An

intravenous prodrug, fosaprepitant, is now available, and an IV

dose of 115 mg can replace the first prechemotherapy 125-mg

PO dose of aprepitant.34

Aprepitant is metabolized by the CYP3A4 enzyme system. It

is a moderate inhibitor and inducer of CYP3A4, and an inducer

of CYP2C9.1,29 Consequently, several drugs potentially interact

with aprepitant. The most commonly encountered interaction

is with the corticosteroids. Aprepitant increases the AUC of dexamethasone such that the dexamethasone dose (when used as

an antiemetic) should be reduced by about one-half of the usual

dose when these drugs are used together.1,17,29 The interaction is

greatest when the corticosteroid is administered orally. However,

when the corticosteroid is also given as part of the antitumor regimen, the corticosteroid dose should not be reduced because of

concern that the antineoplastic activity might be compromised.12

Aprepitant may also enhance warfarin metabolism by inducing

CYP2C9. International normalized ratio (INR) values in patients

treated with warfarin and the standard aprepitant regimen are

significantly reduced, especially on day 8 of the chemotherapy

cycle.17,29,36,37 The patient’s coagulation status after aprepitant

administration should be monitored, especially during the 7- to

10-day period after aprepitant. The dosage of warfarin should

be adjusted if the INR is out of range. Several chemotherapy

agents (paclitaxel, etoposide, ifosfamide, irinotecan, imatinib,

vinca alkaloids, and others) are metabolized by the CYP3A4

enzyme system, and the metabolism of these agents may be

altered by aprepitant. Aprepitant was used in clinical trials with

some of these agents. Caution is warranted because the clinical

relevance of this potential interaction is not known.29,38 Other

drugs that may interact with aprepitant include oral contraceptives, itraconazole, terfenadine, and phenytoin.29

OTHER ANTIEMETICS

Medications from other drug classes have also been used

as antiemetics for CINV. These include dopamine antagonists (prochlorperazine, promethazine), benzodiazepines

(lorazepam), butyrophenones (droperidol, haloperidol), benzamides (metoclopramide), and cannabinoids. Many of these

agents were used widely until more effective antiemetic agents

became available. These agents remain useful for breakthrough

symptoms or for patients who are refractory to standard therapy.

The dosages and indications for these agents are shown in Table

6-3. Many of these agents have more side effects than contemporary agents, especially sedation and extrapyramidal side effects,

such as dystonia and akathisia. Lorazepam is commonly used as

a rescue antiemetic. Its mechanism of action as an antiemetic is

not completely understood, but it may involve disruption of the

cortical impulses to the VC, as well as anxiolytic activity.

Olanzapine is an atypical antipsychotic agent that antagonizes

several serotonin and dopamine receptors as well as other neurotransmitter receptors.39 Its antiemetic action was first described

in patients with refractory nausea or vomiting and advanced cancer. Olanzapine has activity both in the prevention of CINV in

patients at high risk, as well as rescue treatment for patients with

refractory nausea and vomiting. Studies have demonstrated its

efficacy in preventing CINV in the setting of highly and moderately emetogenic chemotherapy. Newer, controlled trials show

improved response rates when added to an antiemetic regimen

of a 5-HT3 antagonist plus dexamethasone, as well as comparable activity to aprepitant.23,36,39,40 The usual dose of olanzapine

used in these trials was 10 mg PO daily on days 1 through 5.

Olanzapine is also active as a rescue agent for patients with

refractory CINV. In this setting, the usual dose of olanzapine

is 2.5 to 10 mg daily in one to four divided doses. The common side effects of olanzapine include sleepiness, dry mouth,

and dizziness, although these were not significant in the preliminary reports.23,36,39,40 Olanzapine is a good choice for control

of highly refractory CINV symptoms, but further study is warranted before it should be routinely recommended for prophylaxis of acute and delayed CINV.

Cannabinoids have long been used for refractory nausea and

vomiting. This is based on the effect of the CNS cannabinoid

receptors on the CTZ, the NTS, and the VC.41 Small trials have

shown conflicting effectiveness in the prevention of CINV.42,43 A

new oral cannabinoid, nabilone, was approved for the treatment

of CINV in patients who do not respond adequately to other

antiemetics.41 Cannabinoids are associated with side effects, such

as drowsiness, dry mouth, dysphoria, vertigo, and euphoria.41,42

Although some patients have a clear preference for, and good