COG Chemo Admin Guidelines

Version Date: 01/25/10
Version Number: 5
PARENTERAL AND ORAL CHEMOTHERAPY ADMINISTRATION GUIDELINES USED BY

THE CHILDREN’S ONCOLOGY GROUP
Investigators and their staff are reminded that this information is likely proprietary to the drug company,
is likely subject to an IND or other regulatory filing, is to be kept strictly confidential except to authorized
COG researchers and personnel who have appropriate confidentiality agreements and procedures in place,
and is to be used in conformance with the investigator’s brochure or other drug information provided by
the pharmaceutical company (as well as the COG protocol). Investigators and their staff are also asked to
inform patients, their parents and representatives that:
 The information contained herein concerns drugs, biologics, medical devices, and other
biotechnology products that are being used or being contemplated for use in a research setting,
that is in an experimental setting possibly using unproven therapies.
 The products referenced herein may be unapproved or uncleared in formulation or method of use
for commercial use either in the United States, Canada and/or other countries. For example, the
agents, while approved by the FDA under other conditions of use, may not be approved for use in
children or for the indications or dosages stipulated in the protocols.
 Safe use of the products referenced herein requires adherence to the relevant COG protocol or
study document and the directions of the COG investigator, physician or other study personnel.
For example, COG may use certain agents for “off label” use (in compliance with FDA
regulations); and this would likely require strict compliance to provisions found in the COG
protocol (and not in generally available product brochures or practice guidelines).
 The Children’s Oncology Group conducts research through a cooperative group of member
institutions. The member institutions are responsible for the medical care of the patients in
accordance with state and local guidelines.
Prepared by the COG Pharmacy Committee.

The special contributions of Julia Cartwright, Claudia Deffenbaugh, Dave Henry, Dean Jorstad, Michael
Kellick, John Murphy, Betsy Bickert Poon, Diane Sinsabaugh, Mark Sorenson and Rivka Siden (COG
pharmacist) are acknowledged.
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TABLE OF CONTENTS
TITLE PAGE
COG PARENTERAL AND ORAL CHEMOTHERAPY ADMINISTRATION GUIDELINES 4
Aldesleukin 6
Alemtuzumab 6
Amifostine 7
Arsenic trioxide 7
Asparaginase (E. Coli) 8
Azacitidine 8
Bevacizumab 9
Bleomycin 9
Bortezomib 10
Busulfan 10
CARBOplatin 10
Carmustine 11
Cetuximab 11
CISplatin 12
Cladribine 13
Clofarabine 13
Cyclophosphamide 13
Cytarabine 14
Dacarbazine 15
Dactinomycin 15
Dasatinib 16
DAUNOrubicin 16
Dexrazoxane 16
DOCEtaxel 17
DOXOrubicin 17
Etoposide 18
Etoposide phosphate 19
Fludarabine 19
Fluorouracil 19
Gemcitabine 20
Gemtuzumab ozogamicin 20
IDArubicin 20
Ifosfamide 21
Imatinib 21
Irinotecan 22
Isotretinoin 22
Leucovorin 23
Lomustine 23
Mechlorethamine 24
Melphalan 24
Mercaptopurine 24
Mesna 25
Methotrexate 27
MitoMYCIN 31
Mitotane 31
MitoXANTRONE 31
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Oxaliplatin 32
PACLItaxel 32
Pegaspargase 33
Rituximab 33
Streptozocin 34
Temozolomide 35
Thioguanine 35
Thiotepa 36
Topotecan 36
Trastuzumab 36
Tretinoin 36
VinBLAStine 37
VinCRIStine 38
VinORELBine 38
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COG PARENTERAL AND ORAL CHEMOTHERAPY ADMINISTRATION GUIDELINES
Abbreviations
0.9% NaCl-0.9% sodium chloride injection
BP-blood pressure
BMT-bone marrow transplant
BUN-blood urea nitrogen
CBC-complete blood count
CYP-cytochrome P450 enzyme
D5W-5% dextrose in water injection
D5W1/4NS-5% dextrose in water with 0.225% sodium chloride injection
ECG-electrocardiogram
IM-intramuscular
IT-intrathecal
IV-intravenous
KCl-potassium chloride
LDH-lactate dehydrogenase
NSAIDs-non-steroidal anti-inflammatory drugs
PCP-Pneumocystis carinii pneumonia (also called Pneumocystis jiroveci pneumonia)
PO-by mouth
PVC-polyvinylchloride
SIADH-syndrome of inappropriate antidiuretic hormone
TMP/SMX-trimethoprim/sulfamethoxazole
ULN-upper limit of normal
Interaction with live vaccines

This statement will be added to the treatment plan of protocols:
Caution: Live virus vaccines (e.g., measles, mumps, rubella, varicella, intranasal influenza
[LAIV], oral polio, yellow fever, vaccinia) and live bacterial vaccines (e.g., BCG) may be
contraindicated during therapy with antineoplastic agents and/or in patients who are
immunosuppressed. Clinical judgment is indicated to determine risk vs. benefit.
Interactions: selected drugs

The list of drug interactions is not comprehensive. It only includes the most common or significant
interactions. Drug information references should be consulted for further information. The list of
selected drug interactions will be added to the drug monographs.
Monitoring
Statements for patient monitoring contained within this document should be considered as
suggested monitoring and may not necessarily represent sufficient monitoring for individual
patients.
Patient education on oral chemotherapy administration at home

Each institution needs to educate patients and families on chemotherapy agents precautions,
handling, and disposal and give patients the appropriate supplies to administer the drug and
manage a spill.
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Patient drugs returns

Patients and families should be instructed to bring used and unused drug container(s) and diary (if
applicable) to the clinic or hospital at each visit.
Containers of used and unused drugs provided by a sponsor (eg, the NCI or a drug company) that
are returned by patients/caregivers to the clinic or hospital should be returned to the pharmacy for
logging on the drug accountability logs.
Pre-and Post-Chemotherapy Hydration

Instructions regarding hydration volumes and additives are suggested guidelines and not
requirements and will be included in the protocol for consideration; institutional guidelines for
hydration that are consistent with current standard of care are acceptable.
Premedications, supportive care and antiemetics

Information regarding premedications including supportive care and antiemetics are suggested
guidelines and not requirements and will be included in the protocol for consideration;
institutional guidelines that are consistent with current standard of care and the drug package
insert are acceptable. Grading of emetogenicity and suggested guidelines for prevention of nausea
and vomiting can be found in the COG Supportive Care Guidelines.
Preparation and administration checks

When chemotherapeutic drugs are used, two pharmacist and two nurses should independently
check the preparation and administration, respectively. TALLman lettering and brand names
should be used to avoid confusion between sound-alike/look-alike medications.
Preparation and stability information

Refer to the drug monograph for drug preparation and stability information.
Re-dosing
Oral absorption of drugs depends on several factors, and can be difficult to judge in the event that
a patient vomits within 30-60 minutes after taking a dose. If intact capsules or tablets, or large
pieces of tablets are observed in the vomit, there is a good chance that very little of the drug was
absorbed. If vomiting occurs greater than 60 minutes after the dose, it is generally prudent to
assume a significant amount of absorption may have occurred.
Time to absorption depends on the drug properties such as chemical characteristics of the drug
itself, and the formulation taken by the patient (solid, liquid, or sustained release). Additionally,
patient factors such as gastric emptying time can be important: on an empty stomach gastric
emptying time is usually 30-60 minutes; when the stomach is full, gastric emptying is more likely
to be 1-3 hours. If the dose is vomited shortly after administration, these elements should be
considered before re-dosing.
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Drug Administration Guidelines

Aldesleukin IV: Aldesleukin is diluted in D5W and infused over 15 minutes. Flush line with
D5W before and after drug administration.
The drug
administration is IV continuous infusion: Dilute in D5W and administer via pump as directed in
optimal and protocol the COG commercial drug monograph. Do not use in-line filter when
specific dose administering. Flush line with D5W before and after drug administration.
modifications must
be considered in the Subcutaneous: Reconstituted solution may be administered subcutaneously
face of toxicities. without further dilution. Aspirate prior to injection to avoid injection into a blood
vessel.
Emetogenicity: ≤ 12 million units/m2-mild risk; > 12 million units/m2-high risk
Suggested monitoring during administration: Vital signs (temperature, pulse,

blood pressure and respiration rate), pulse oximetry, arterial, blood gases (if
pulmonary symptoms). During and after the infusion, monitor for capillary leak
syndrome.
Possible monitoring could include: Baseline chest x-ray, pulmonary function

tests, CBC with differential and platelets, electrolytes, BUN, serum creatinine,
hepatic enzymes, weight, fluid intake and output.
Alemtuzumab IV: Infuse the diluted solution over 2 hours. Do not give as IV push.
The drug Subcutaneous: The undiluted solution (30 mg/mL) can be used for
administration is subcutaneous administration. Aspirate prior to injection to avoid injection into a
optimal and protocol blood vessel. Premedication and anti-infective prophylaxis regimens should be
specific dose considered with IV administration.
modifications must
be considered in the Special precautions: Consider gradually escalating the IV dose to the maximum
face of toxicities. recommended dose at the start of treatment and if the dose is held for ≥ 7 days.
For the subcutaneous route, most clinical trials use a dose escalation regimen.
Suggested premedications: Administer H1-receptor antagonist (eg,

diphenhydramine), acetaminophen and hydrocortisone or equivalent to start
30 minutes before infusion prior to the first dose, at dose escalations, and as
clinically indicated. Consider giving anti-infectives including PCP and herpes
viral infection prophylaxis from the initiation of treatment until 2 months after
completion of therapy or until the CD4+ lymphocyte count reaches or exceeds
200/μL.
Emetogenicity: Low risk
Suggested monitoring during administration: Vital signs including blood

pressure, infusion reactions (including hypotension, rigors, fever, shortness of
breath, bronchospasm, chills, and/or rash).
Possible monitoring could include: CBC with differential and platelets, signs
and symptoms of infection, CD4+ lymphocyte counts (after treatment and until
recovery).
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Amifostine IV (Dose = 200 mg/m²): The diluted solution should be infused over
≤ 3 minutes. Begin chemotherapy or radiation 15-30 minutes after completion of
The drug amifostine.
administration is
optimal and protocol IV (Dose ≥ 740 mg/m²): The diluted solution should be infused over
specific dose ≤ 15 minutes. Begin chemotherapy or radiation 15-30 minutes after completion
modifications must of amifostine.
be considered in the
face of toxicities. Subcutaneous: For subcutaneous injection, amifostine is reconstituted with
0.9% NaCl. For doses > 300 mg: give 2 separate injections in 2 different sites,
with the total amount of amifostine split equally. Aspirate prior to injection to
avoid injection into a blood vessel.
Special precautions: To prevent nausea, vomiting and hypotension, patients

should be well hydrated and kept in a supine or reclining position during the
infusion and for 15 minutes after the infusion.
Suggested hydration: For higher doses (≥ 70 mg/m²), prehydrate with 0.9%

NaCl 125-250 mL/m² IV one hour before amifostine administration.
Emetogenicity: ≤ 300 mg/m2-mild risk; > 300 mg/m2-high risk
Suggested monitoring during administration: Baseline blood pressure

followed by a blood pressure reading every 3-5 minutes during the 15 minute IV
infusion and 10 minutes after the subcutaneous injection. Amifostine IV should
be interrupted if the blood pressure decreases significantly from baseline or if the
patient develops symptoms related to decreased cerebral or cardiovascular
perfusion. Amifostine can be restarted if the blood pressure returns to the
baseline level.
Possible monitoring could include: Electrolytes, urinalysis, serum calcium,

serum magnesium, fluid intake and output.
Arsenic trioxide IV: Infuse over 1-2 hours. If acute vasomotor reaction occurs, slow rate and
infuse over a maximum of 4 hours. Does not require administration through a
The drug central line.
administration is
optimal and protocol Emetogenicity: High risk
specific dose
modifications must Suggested monitoring during administration: Vasomotor reaction,
be considered in the hypersensitivity, injection site reaction.
face of toxicities.
Possible monitoring could include: Baseline and then twice weekly 12-lead
ECG, baseline and then twice weekly serum electrolytes (especially magnesium
and potassium), hematologic and coagulation profiles at least twice weekly
during induction and at least once weekly during consolidation.
Selected drug interactions: Concomitant use with drugs that prolong QTc
interval may increase risk of potentially fatal arrhythmias. A list of drugs can be
found at http://www.azcert.org. Consult drug information references for further
information.
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Asparaginase (E. IM: (preferred secondary to lower incidence of severe hypersensitivity reaction):
Coli) Administer at a final concentration of 5,000 or 10,000 units/mL. Consider dose
volume and size of patient; total dose may need to be administered at more than
The drug one injection site. It is suggested not to administer more than 2 mL at each
administration is injection site. Aspirate prior to injection to avoid injection into a blood vessel.
optimal and protocol
specific dose IV: Infused into the tubing of freely running IV solution of 0.9% NaCl or D5W
modifications must over at least 30 minutes.
face of toxicities. Special precautions:
1. Asparaginase is contraindicated with a history of severe pancreatitis with
prior asparaginase therapy, serious thrombosis with prior asparaginase
therapy, or serious hemorrhagic events with prior asparaginase therapy.
2. Asparaginase may affect coagulation factors and predispose to bleeding
and/or thrombosis. Caution should be used when administering any
concurrent anticoagulant therapy.
Emetogenicity: Mild risk
Suggested monitoring during administration: Vital signs, fever, chills, or

acute allergic reactions including anaphylaxis. Monitor patient for signs and
symptoms of hypersensitivity reactions. Have medications to treat
hypersensitivity reactions readily available at each administration (eg,
epinephrine, IV corticosteroids, antihistamines). Consider prescribing an
EpiPen® for home use.
Possible monitoring could include: CBC, urinalysis, amylase, liver enzymes,

bilirubin, BUN, serum creatinine, urine glucose, blood glucose, uric acid.
Monitor for onset of abdominal pain and mental status changes.
Azacitidine Subcutaneous: Azacitidine is formulated as a suspension and the dose in the
syringe must be inverted several times and rolled between the palms for
The drug approximately 30 seconds immediately prior to administration. The
administration is manufacturer recommends dividing a dose greater than 4 mL into 2 equal
optimal and protocol injections. Patient size and subcutaneous tissue amount should be considered for
specific dose determining the injection volume per site for children. The manufacturer
modifications must recommends an expiration time of 1 hour at room temperature and 8 hours if
be considered in the refrigerated. Aspirate prior to injection to avoid injection into a blood vessel.
face of toxicities.
IV: Infuse the diluted solution over 10-40 minutes. Infusion must be completed
within 1 hour of vial reconstitution.
Emetogenicity: High risk
Suggested monitoring during administration: Injection site for erythema and

pain (more common with IV administration). Rotate injection sites. Erythema
may last for 72 hours (may use topical steroids 24 hours after injection).
Possible monitoring could include: Liver function tests, renal function tests
(BUN and serum creatinine), CBC with differential and platelets (the agent is
indicated for use with myelodysplasia, thus these lab values are likely to be
abnormal).
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Bevacizumab IV: Infuse first dose over 90 minutes. If tolerated without infusion related side
effects, second dose may be given over 60 minutes. Again, if tolerated, third
The drug dose and all subsequent doses may be given over 30 minutes. Bevacizumab is
administration is incompatible with D5W (the drug is inactivated).
optimal and protocol A safe administration of a 5 mg/kg dose over 10 minutes (0.5 mg/kg/min) was
specific dose described by Reidy DL, et al. (J Clin Oncol 2007; 25:2691-5).
modifications must
be considered in the Special precautions: Black box warning includes risk of gastrointestinal
face of toxicities. perforation and wound healing complications (fatal results have occurred).
Suspend dosing at least 28 days prior to elective surgery. Do not initiate
bevacizumab for at least 28 days after a major surgery (eg, organ resection,
exploratory laparotomy, thoracotomy) or 14 days after intermediate surgical
procedure (eg, paracentesis or thoracocentesis) and until the surgical wound is
fully healed. Minor surgical procedures (eg, biopsies, infusaport or Broviac line
placement) need to have fully healed and occurred > 7 days prior to initiation of
bevacizumab.
Suggested monitoring during administration: Depending on the length of the

infusion, check vital signs and monitor for infusion related reactions prior to
infusion, every 30 minutes and at the end of the infusion. Monitor every
15 minutes while the infusion rate is being adjusted.
Possible monitoring could include: Urinalysis (hold for moderate to severe

proteinuria), BP (hold for uncontrolled hypertension), CBC with differential and
platelets (monitor platelet count due to bleeding risk), signs and symptoms or
bleeding.
Bleomycin IV: Infuse over a minimum of 10 minutes (no greater than 1 unit/minute) and at
a concentration not to exceed 3 units/mL. Bleomycin can also be given by
The drug continuous infusion.
administration is
optimal and protocol IM or subcutaneous: A concentration of 3-15 units/mL can be used for
specific dose IM/subcutaneous administration. Aspirate prior to injection to avoid injection
modifications must into a blood vessel. IM-Inject into a large muscle.
face of toxicities. Special precautions: Test dose: it is recommended by the manufacturer because
of the possibility of an anaphylactic reaction, that lymphoma patients receive a
test dose of 2 units or less IV, IM or subcutaneously for the first 2 doses.
Following administration of the test dose, consider monitoring of vital signs
every 15 minutes for at least 1 hour and if no acute reaction occurs, the full dose
may be given. Note: test doses may produce a false negative result.
Suggested monitoring during administration: Vital signs including

temperature and hypersensitivity reactions.
Possible monitoring could include: Pulmonary function tests, BUN, serum

creatinine, chest x-ray, CBC with differential and platelets, skin changes.
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Bortezomib IV: Administer the reconstituted solution (1 mg/mL) by IV bolus over 3-

5 seconds. Consecutive doses must be separated by at least 72 hours.
The drug
administration is Suggested premedications: Fever and chills may occur 2-6 hours following IV
optimal and protocol administration. Premedication with acetaminophen, H1 antagonist
specific dose (antihistamine), and hydrocortisone may decrease the severity of fever and chills.
modifications must
be considered in the Emetogenicity: Low risk
face of toxicities.
Possible monitoring could include: CBC with differential and platelets,
evaluate peripheral neuropathy and asthenia symptoms, BP, dehydration, cardiac
function, liver function tests, renal function and pulmonary function.
Selected drug interactions: No drug interaction studies have been performed

but the drug is a substrate for CYP3A4 (major), CYP2C19 (major), CYP1A2,
CYP2C6, and CYP2D9 (minor) and an inhibitor of CYP2C19 (moderate). The
manufacturer recommends that patients on inhibitors or inducers of CYP450
agents be monitored closely for toxicity or reduced efficacy. Consult drug
information references for further information.
Busulfan IV: Administer at a final concentration of approximately 0.5 mg/mL in D5W or
0.9% NaCl over 2 hours via central line. Flush line with D5W or 0.9% NaCl
The drug before and after busulfan administration. Do not use polycarbonate syringes or
administration is filters.
specific dose Oral: Administer with or without food as a tablet or in suspension. Administer
modifications must all tablets at once (eg, within 15 minutes). If large numbers of tablets must be
be considered in the swallowed, they may first be placed in empty oral gelatin capsules for ease of
face of toxicities. swallowing. If the tablets (or tablet-filled capsules) cannot be swallowed, the
tablets may also be formulated into a suspension (see drug monograph).
Suggested premedications: The manufacturer recommends starting

prophylactic phenytoin therapy prior to treatment with high dose busulfan.
Emetogenicity: ≤ 4 mg/kg/day-low risk; > 4 mg/kg/day-high risk
Possible monitoring could include: CBC with differential and platelets, liver
function tests including alkaline phosphatase and bilirubin, seizures. Busulfan
plasma concentration with high dose (BMT).
Selected drug interactions: Busulfan is a substrate to cytochrome P450 3A4

(major); inhibitors may increase level/effects and inducers may decrease
level/effects. Consult drug information references for further information.
Concurrent long-term continuous therapy with busulfan and thioguanine may
cause hepatotoxicity, portal hypertension and esophageal varices.
CARBOplatin Study committee to choose between short and continuous infusion.
The drug IV: Infuse the diluted solution over 15-60 minutes. Avoid use of aluminum
administration is containing needles or administration sets.
specific dose Continuous infusion: May infuse the diluted solution (to a concentration as low
modifications must as 0.5 mg/mL) by continuous infusion over 24 hours. Continuous infusion
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be considered in the regimens may be less emetogenic. Avoid use of aluminum containing needles or
face of toxicities. administration sets.
Subtenon: The premixed solution (10 mg/mL) or the reconstituted lyophilized

powder to a concentration of 10 mg/mL should be used. A new vial should be
used for each dose. Institutions should be consistent and use ONLY one of the
forms and not a combination of both.
Special precautions: When administered as sequential infusion, taxane

derivatives (docetaxel or paclitaxel) should be administered before carboplatin to
limit myelosuppression and enhance efficacy.
Medication errors have occurred due to confusion between CISplatin

(Platinol®) and CARBOplatin (PARAplatin®).
Suggested monitoring during administration: Hypersensitivity reaction.
Possible monitoring could include: CBC with differential and platelets, serum
electrolytes, urinalysis, BUN, serum creatinine, liver function tests, hearing test.
Carmustine IV: Infuse the diluted solution over 1-2 hours using non-PVC containers and
administration equipment. The maximum rate of infusion should not exceed
The drug 3 mg/m2/minute. Rapid IV infusion may result in intense pain and burning at the
administration is site of infusion in addition to flushing, hypotension, and agitation. Flush the line
optimal and protocol before and after carmustine administration to ensure vein patency or administer
specific dose through a free flowing D5W or 0.9% NaCl line. Protect from light.
modifications must
be considered in the High dose IV (≥ 300 mg/m2) with BMT: Infuse the diluted solution over at
face of toxicities. least 2 hours using non-PVC containers and administration equipment. The
maximum rate of infusion should not exceed 3 mg/m2/minute. Rapid IV infusion
may result in intense pain and burning at the site of infusion in addition to
flushing, hypotension, and agitation. Flush the line before and after carmustine
administration to ensure vein patency or administer through a free flowing D5W
or 0.9% NaCl line. Protect from light.
Emetogenicity: < 200 mg/m2-high risk; ≥ 200 mg/m2-very high risk
Suggested monitoring during administration: Check BP (hypotension) with

high dose IV due to the alcohol content of the diluent. The infusion site should
be monitored to prevent injection site burning or extravasation. Administration
through a central line is suggested. If infused through a peripheral line, burning
sensation at the site is decreased with reduction of the infusion rate, further
dilution or placing an ice pack on the site.

pulmonary function, liver function tests, BUN, serum creatinine.
Cetuximab IV: Infuse undiluted (2 mg/mL) through a 0.22 micron low protein-binding in-
line filter closest to the patient using an infusion/syringe pump. Administer first
The drug dose over 2 hours (loading dose). Administer subsequent doses over 1 hour if
administration is previous dose was well tolerated. DO NOT EXCEED a maximum rate of
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optimal and protocol administration of 10 mg/minute. Flush line with 0.9% NaCl at the end of the
specific dose cetuximab infusion. If administered with radiation, the loading dose should be
modifications must administered 1 week before radiation and the maintenance dose should be
be considered in the completed 1 hour before radiation.
face of toxicities.
Suggested premedications: The drug is a chimeric monoclonal antibody and
will cause more infusion-related side effects than humanized monoclonal
antibodies. Premedication with an H1 antagonist (eg, diphenhydramine 1 mg/kg
[max. 50 mg]) 30-60 minutes before the dose is suggested.
Suggested monitoring during administration: Monitor for infusion related

reactions (fever, chills, rigors, vital signs during and post infusion, anaphylaxis).
Observe patient for 1 hour post infusion.
Possible monitoring could include: CBC with differential, chemistries (serum

magnesium, calcium and potassium [hypomagnesemia was observed]), liver
function tests, and pulmonary function tests. Rash may be treated with topical
and/or oral antibiotics but use of topical steroids is usually not recommended.
Radiation exposure to skin rash and sun exposure to skin rash may exacerbate
toxicity.
CISplatin IV (Dose ≤ 60 mg/m²/day): Infuse over 1 hour. Protect from light.
The drug IV (Dose > 60 mg/m²/day): Infuse over 1-8 hours. Protect from light.
administration is
optimal and protocol Special precautions: Avoid use of aluminum containing needles or
specific dose administration sets, since aluminum interacts with CISplatin causing black
modifications must precipitate formation and loss of potency. The infusion solution should include at
be considered in the least 0.2% sodium chloride. CISplatin solutions should not be refrigerated to
face of toxicities. avoid precipitation. CISplatin is incompatible with sodium bicarbonate and
alkaline solutions. Accidental extravasation with solutions that are > 0.5 mg/mL
may result in significant tissue toxicity.
Medication errors have occurred due to confusion between CISplatin

(Platinol®) and CARBOplatin (PARAplatin®).
Suggested hydration: Administer 3000 mL/m²/day (125 mL/m²/hour) using

fluid containing at least 0.45% NaCl. Achieve urine specific gravity ≤ 1.010
prior to start of CISplatin. Hydration fluids may contain supplemental
magnesium, calcium, and potassium to decrease acute electrolyte losses
associated with CISplatin therapy.
Suggested hydration would be D5W ½NS +10 mEq KCl/L + 1-2 grams (8-
16 mEq) magnesium sulfate/L at 125 mL/m2/hour. May add calcium gluconate
250 mg/L.
Use of mannitol: CISplatin doses may require use of mannitol to augment
diuresis.
Emetogenicity: < 50 mg/m2-high risk; ≥ 50 mg/m2-very high risk
Possible monitoring could include: BUN, serum creatinine, creatinine
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clearance, urinalysis, urine output, body weight, serum electrolytes (particularly

magnesium, calcium, potassium), hearing test, neurologic exam (with high dose),
liver function tests, CBC with differential and platelets.
Cladribine IV: Infuse over 1-2 hours or by continuous infusion over 24 hours.
The drug Emetogenicity: Mild risk
administration is
optimal and protocol Possible monitoring could include: CBC with differential and platelets,
specific dose creatinine clearance before initial dose, periodic renal and hepatic function tests,
modifications must fever, injection site reaction.
face of toxicities.
Clofarabine IV: Infuse the diluted solution over 2 hours.
The drug Suggested hydration: When tumor lysis is a concern, continuous IV infusion
administration is fluids throughout the 5 days of administration and alkalinization are suggested.
optimal and protocol The hydration goal is to maintain urine output of > 3 mL/kg/hr.
specific dose
modifications must Suggested premedications: The manufacturer recommends that prophylactic
be considered in the steroids (eg, hydrocortisone 100 mg/m2 IV on Days 1-3) be used to prevent or
face of toxicities. lessen the signs of systemic inflammatory response syndrome (SIRS) or capillary
leak syndrome. Prophylactic steroids may be given 30-60 minutes before
clofarabine. Allopurinol should be administered if hyperuricemia is expected.
Suggested monitoring during administration: Check BP (hypotension),

cardiac function (tachycardia) and respiratory status (tachypnea, pulmonary
edema) during and after infusion to monitor for tumor lysis and systemic
inflammatory response syndrome (SIRS) or capillary leak syndrome.
function tests, renal function studies, uric acid, and serum electrolytes. Weigh
patient daily and assess for symptoms of effusions, monitor urine output.
Monitor for palmar-plantar erythrodysesthesia syndrome.
Selected drug interactions: Clofarabine is excreted mainly by the kidneys and

therefore the use of nephrotoxic drugs (eg, amphotericin, aminoglycosides,
NSAIDs) concurrently with clofarabine should be avoided when possible. Great
care, including adequate hydration, should be used when the use of nephrotoxic
drugs is unavoidable. Consult drug information references for further
information.
Cyclophosphamide IV (Dose ≤ 500 mg/m2): Infuse over 15-30 minutes. May be administered as
undiluted drug (20 mg/mL, reconstitute with 0.9% NaCl only to avoid hypotonic
The drug solution) or further diluted.
administration is
optimal and protocol IV (Dose > 500 mg/m2 to < 1,800 mg/m²): Infuse over 30-60 minutes. May be
specific dose administered as undiluted drug (20 mg/mL, reconstitute with 0.9% NaCl only to
modifications must avoid hypotonic solution) or further diluted.
face of toxicities. IV (Dose ≥ 1,800 mg/m²): Infuse over 1-6 hours. May be administered as
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undiluted drug (20 mg/mL, reconstitute with 0.9% NaCl only to avoid hypotonic
solution) or further diluted.
Oral: Administer during or immediately after meals. The tablets are not scored
and should not be cut or crushed. If the tablets cannot be swallowed, the
reconstituted injection can be administered orally (see drug monograph).
To minimize the risk of bladder irritation, encourage drinking and emptying of
the bladder frequently, and avoid administration at bedtime.
Use of mesna: Individual cyclophosphamide doses ≤ 1,000 mg/m²/dose may not

require use of mesna. See mesna administration guidelines.
Suggested hydration: For high dose cyclophosphamide (≥ 1,800 mg/m²)

administer 3,000 mL/m²/day (125 mL/m²/hour) using fluid containing at least
0.45% NaCl. Achieve urine specific gravity ≤ 1.010 prior to start of
cyclophosphamide. May use diuretics (eg, furosemide) to increase urine output.
Emetogenicity: ≤ 750 mg/m2-moderate risk; > 750 mg/m2 but ≤ 1,500 mg/m2-
high risk; > 1,500 mg/m2-very high risk
Possible monitoring could include: CBC with differential and platelets, BUN,
serum creatinine, urinalysis, serum electrolytes, urine specific gravity, urine
output, hematuria, and body weight. With high dose therapy: SIADH and cardiac
toxicity.
Selected drug interactions: Substrate of CYP2A6 (minor), CYP2B6 (major),

CYP2C9 (minor), CYP2C19 (minor), CYP3A4 (major); Inhibits CYP3A4
(weak); Induces CYP2B6 (weak), CYP2C8 (weak), CYP2C9 (weak). Patients on
inhibitors or inducers of CYP3A4 and CYP2B6 agents should be monitored
closely for toxicity or reduced efficacy. Consult drug information references for
further information.
Cytarabine Study committee to select method of administration (intermittent or
continuous IV).
The drug
administration is IV low dose (≤ 200 mg/m²/dose): Administer over 15-30 minutes.
specific dose Subcutaneous low dose (≤ 200 mg/m²/dose): Reconstitute to a concentration
modifications must not to exceed 100 mg/mL. Rotate injection sites to thigh, abdomen, and flank
be considered in the regions. Avoid repeated administration to a single site. Aspirate prior to injection
face of toxicities. to avoid injection into a blood vessel.
IV intermittent for intermediate dose (> 200 mg/m²/dose) and high dose
(> 1,000 mg/m²/dose):
> 200 mg/m2 - < 3,000 mg/m2 infuse over 1-3 hours
3000 mg/m2 infuse over 3 hours
IV continuous infusion: Cytarabine may also be infused over 24 hours.
IT: Use preservative free formulation. The volume to be given IT should be in

the range of 5-10 mL. The volume of CSF removed should be equal to at least half
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the volume delivered (see drug monograph).

Note: Larger volumes approximating at least 10% of the CSF volume,
isovolumetric delivery, with the patient remaining prone after the procedure may
facilitate drug distribution. These procedures have not been validated in clinical
trials. They are allowed but not mandated for patients on COG studies.
Suggested premedications and supportive care:

High dose (≥ 1,000 mg/m²/dose): Administer steroid eye drops (0.1%
dexamethasone or 1% prednisolone ophthalmic solution), 2 drops to each eye
every 6 hours, beginning immediately before the first dose and continuing for
24 hours after the last dose. If patient does not tolerate steroid eye drops, may
administer artificial tears on an every 2-4 hour schedule.
Emetogenicity: < 100 mg/m2-low risk; ≥ 100 mg/m2 but < 1,000 mg/m2-mild
risk; ≥ 1,000 mg/m2-high risk
Suggested monitoring during administration: None.
Possible monitoring could include: Liver function tests, CBC with differential
and platelets, BUN, serum creatinine, signs of neurotoxicity (cerebellar toxicity
and encephalopathy with high dose), fevers, uric acid. With high dose therapy:
evidence of conjunctivitis, corneal toxicity, and capillary leak syndrome with
pericardial and pleural effusions.
Dacarbazine IV push or short infusion: Infuse the diluted solution over 15-60 minutes. Slow
infusion, as needed, for burning during administration. Local pain, burning, and
The drug irritation may be relieved by application of hot packs. Protect from light.
administration is
optimal and protocol Emetogenicity: < 500 mg/m2-high risk; ≥ 500 mg/m2-very high risk
specific dose
modifications must Suggested monitoring during administration: Infusion site. Avoid
be considered in the extravasation; the use of a central line is suggested.
face of toxicities.
function tests.
Selected drug interactions: Dacarbazine is a major substrate for CYP1A2 and

CYT2E1. Patients on CYP1A2 and CYP2E1 inhibitors or CYP1A2 inducers
should be monitored closely for toxicity or reduced efficacy. Consult drug
Dactinomycin IV push: The reconstituted solution (0.5 mg/mL) can be administered by slow
IV push over 1-5 minutes, or slower over 10-15 minutes. Dactinomycin can be
The drug injected directly into the vein or preferably administered through the tubing of a
administration is rapidly infusing solution of D5W or 0.9% NaCl. The line should be flushed
optimal and protocol thoroughly at the end of dactinomycin infusion. Protect from light.
specific dose
modifications must Emetogenicity: ≤ 1.5 mg/m2-moderate risk; > 1.5 mg/m2-high risk
face of toxicities. Suggested monitoring during administration: Infusion site. Avoid
extravasation; the use of a central line is suggested.
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function tests, renal function tests.

Dasatinib Oral: Administer with or without food. Tablets should be swallowed whole and
must not be crushed or broken. Tablets can be dispersed in juice for ease of
The drug swallowing (see drug monograph). The solubility of dasatinib is pH dependent.
administration is Systemic antacids (both H2 receptor antagonists and proton pump inhibitors)
optimal and protocol decrease dasatinib exposure and should not be used for the duration of dasatinib
specific dose treatment. Locally-acting antacids decrease dasatinib exposure and should not be
modifications must taken simultaneously with dasatinib. Locally-acting antacids can be given up to 2
be considered in the hours prior or 2 hours following dasatinib administration. Grapefruit or its juice
face of toxicities. should be avoided throughout the duration of dasatinib treatment.
Emetogenicity: Low risk.
Possible monitoring could include: CBC with differential, liver function tests,
electrolytes include calcium, phosphorus, and magnesium, fluid retention, ECG
(QTc prolongation).
Selected drug interactions: Substrate of CYP3A4 (major) and inhibitor of

CYP3A4 (weak). The levels/effects of dasatinib may be increased by CYP3A4
inhibitors and decreased by CYP3A4 inducers. Consult drug information
references for further information.
DAUNOrubicin Study committee to choose between IV push/short infusion and IV
continuous infusion.
The drug
administration is IV push /short infusion: The reconstituted solution or the commercially
optimal and protocol available solution (5 mg/mL) can be administered (undiluted or diluted) by slow
specific dose IV push or infusion over 1-15 minutes. Short infusion times may be lengthened
modifications must slightly (and up to 60 minutes) if institutional policies mandate. It is suggested
be considered in the that DAUNOrubicin be administered through the tubing of rapidly infusing
face of toxicities. solution of D5W or 0.9% NaCl and that it is infused into a large vein. Protect
from sun light.
IV continuous infusion: Infuse the diluted solution over 24 hours. Continuous

infusions require central venous access. Protect from sunlight.
Special precautions: Medication errors have occurred due to confusion

between DAUNOrubicin and DOXOrubicin. DAUNOrubicin is available in
a liposomal formulation (DAUNOrubicin citrate). The conventional and
liposomal formulations are NOT interchangeable.
Emetogenicity: < 45 mg/m2-mild risk; ≥ 45 mg/m2-high risk.
Suggested monitoring during administration: Infusion site. Avoid


bilirubin, liver function tests including alkaline phosphatase, ECG, ventricular
ejection fraction, serum uric acid (during induction).
Dexrazoxane IV: Prevention of anthracycline-induced cardiomyopathy-administer by slow IV
push (eg, over 5-15 minutes) immediately prior to the anthracycline dose.
The drug Administer the anthracycline after completing the infusion of dexrazoxane but
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administration is within 30 minutes of beginning the dexrazoxane infusion.

specific dose Emetogenicity: Low risk
modifications must
be considered in the Possible monitoring could include: Prevention of cardiomyopathy-CBC with
face of toxicities. differential, cardiac function tests, serum triglycerides; iron, calcium, and zinc
levels, liver function tests. Anthracycline-induced extravasation-monitor area of
extravasation.
DOCEtaxel IV: Infuse diluted solution over 1 hour using nonsorbing (non-PVC) containers
and administration set; in-line filter is not necessary.
The drug
administration is Special precautions: Medication errors have occurred due to confusion
optimal and protocol between DOCEtaxel (TaxoTERE®) and PACLItaxel (TaxoL).
specific dose
modifications must Suggested premedications: Corticosteroids (oral or IV) for 3-5 days, starting
be considered in the 1 day prior to docetaxel administration, to prevent hypersensitivity reaction and
face of toxicities. pulmonary/peripheral edema. For example:
Docetaxel 3 week regimen: dexamethasone orally twice daily x 3 days, to begin
the day before treatment (6 doses)
Docetaxel weekly regimen: dexamethasone the evening before treatment, the
morning of treatment and the evening of the treatment (3 doses).
Suggested monitoring during administration: Hypersensitivity reaction,

including anaphylaxis; check vital signs
Possible monitoring could include: Fluid retention, CBC with differential and
platelets, liver function tests including alkaline phosphatase, bilirubin, renal
function tests, neurologic exam, epiphora.
Selected drug interactions: Docetaxel is a substrate for CYP3A4 (major) and

an inhibitor of CYP3A4 (minor). Patients on inhibitors or inducers of CYP3A4
agents should be monitored closely for toxicity or reduced efficacy. Consult drug
DOXOrubicin Study committee to choose between IV push/short infusion AND IV
The drug
administration is IV push/short infusion: Administer at a concentration not to exceed 2 mg/mL
optimal and protocol by slow IV push or infusion over 1-15 minutes. Short infusion times may
specific dose be lengthened slightly (and up to 60 minutes) if institutional policies
modifications must mandate. It is suggested that DOXOrubicin be administered through the tubing of
be considered in the rapidly infusing solution of D5W or 0.9% NaCl and that it is infused into a large
face of toxicities. vein.
IV continuous infusion: Infuse the diluted solution over 24 hours. Continuous

infusions require central venous access. Protect diluted solution from sun light.
When dexrazoxane is given with DOXOrubicin for the prevention of

cardiomyopathy administer DOXOrubicin after completing the infusion of
dexrazoxane but within 30 minutes of beginning the dexrazoxane infusion.
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Special precautions: Medication errors have occurred due to confusion

between DAUNOrubicin and DOXOrubicin. DOXOrubicin is available in a
liposomal formulation. The conventional and liposomal formulations are
NOT interchangeable.
Emetogenicity: 20-60 mg/m2-moderate risk; > 60 mg/m2-high risk


bilirubin, liver function tests including alkaline phosphatase, ECG, ventricular
ejection fraction, serum uric acid (during induction).
Selected drug interactions: DOXOrubicin is a major substrate for CYP2D6 and

CYP3A4 and an inhibitor of CYP2B6 (moderate), CYP2D6 (weak) and
CYP3A4 (weak). Patients on CYP2D6 and CYP3A4 inhibitors, on CYP2B6
substrates and on CYP3A4 inducers should be monitored closely for toxicity or
reduced efficacy. Consult drug information references for further information.
Etoposide IV standard dose (≤ 200 mg/m²): Infuse diluted solution (concentration ≤
0.4 mg/mL) over at least 60-120 minutes; slow rate of administration if
The drug hypotension occurs. Rate should not exceed 300 mg/m2/hour (10 mg/kg/hour)
administration is (hypotension risk). The use of an in-line filter during the infusion is suggested.
specific dose IV intermediate and high dose (high dose usually associated with
modifications must conditioning regimens involving hematopoietic stem cell support): Infuse at a
be considered in the maximum rate of rate of 300 mg/m2/hour (10 mg/kg/hour). Fluid volumes may
face of toxicities. be prohibitive at a 0.4 mg/mL concentration; an alternative dilution of
0.6 mg/mL (8 hour stability) may be used. Infusion of undiluted etoposide has
been associated with cracking of hard plastic in chemotherapy venting pins and
infusion lines. For concentration > 0.4 mg/mL, use an in-line filter during
infusion secondary to precipitate formation risk.
Oral: Administer with or without food. Doses ≤ 400 mg per day can be
administered once daily. Doses > 400 mg should be divided to 2-4 doses (not to
exceed 400 mg per dose). The injection can be used for oral administration (see
drug monograph).
Special precautions: Etoposide can be mixed in 0.9% NaCl or D5W. Avoid use
of large volumes of D5W due to potential development of hyponatremia.
Stability: Leaching of diethylhexyl phthalate (DEHP) from PVC bags occurred

with etoposide 0.4 mg/mL in 0.9% NaCl solution. To avoid leaching, prepare the
etoposide solution as close as possible, preferably within 4 hours, to the time of
administration or alternatively as per institutional policy. Glass or polyethylene-
lined (non-PVC) containers and polyethylene-lined tubing may be used.
Emetogenicity: Standard dose-mild risk, high dose (≥ 1,800 mg/m2)-high risk
Suggested monitoring during administration: Hypersensitivity reactions; vital
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signs and anaphylactic reaction manifested by chills, fever, tachycardia,

bronchospasm, dyspnea and hypotension. Higher concentrations were associated
with higher rates of reactions in children. Hypotension is associated with rapid
infusion. Inspect solution and tubing for precipitation before and during
infusion.
bilirubin, liver function tests, renal function tests.
Selected drug interactions: Etoposide is a substrate for CYP1A2 (minor),

CYP2E1 (minor) and CYP3A4 (major). It inhibits CYP2C9 (weak) and
CYP3A4 (weak). Patients on CYP3A4 inducers or inhibitors should be
monitored closely for toxicity or reduced efficacy. Consult drug information
Etoposide IV push or intermittent infusion: Administer the reconstituted or further
phosphate diluted solution over 5-210 minutes. Slow the rate of infusion if hypotension
occurs. Administration time can be extended to 240 minutes (Fields SZ, et al.
The drug BMT 1996; 18:851-6).
administration is
optimal and protocol Special precautions: Etoposide phosphate is a prodrug of etoposide. Each
specific dose 100 mg of etoposide is equivalent to 113.5 mg of etoposide phosphate.
modifications must
be considered in the Emetogenicity: Standard dose-mild risk; high dose (≥ 1,800 mg/m2)-high risk
face of toxicities.
Suggested monitoring during administration: Hypersensitivity reactions; vital
signs and anaphylactic reaction manifested by chills, fever, tachycardia,
bronchospasm, dyspnea and hypotension. Higher concentrations have been
associated with higher rates of reactions in children.

bilirubin, liver function tests, renal function tests.
Selected drug interactions: Etoposide phosphate is a substrate for CYP1A2

(minor), 2E1 (minor) and 3A4 (major). It inhibits CYP2C9 (weak) and CYP3A4
(weak). Patients on CYP3A4 inducers or inhibitors should be monitored closely
for toxicity or reduced efficacy. Consult drug information references for further
information.
Fludarabine IV: The diluted solution should be infused over approximately 30 minutes.
The drug IV continuous infusion: The diluted solution can be infused over 24 hours.
administration is
optimal and protocol Emetogenicity: Low risk
specific dose
modifications must Possible monitoring could include: CBC with differential and platelets, liver
be considered in the function tests, BUN, serum creatinine, serum electrolytes, serum uric acid,
face of toxicities. albumin, examination for visual changes, neurologic exam.
Fluorouracil Study committee to choose between IV push or short infusion and IV
The drug
administration is IV push or short infusion: Fluorouracil may be administered undiluted
optimal and protocol (50 mg/mL) or diluted by IV push or by short infusion over 3-15 minutes.
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specific dose
modifications must IV continuous infusion: The diluted solution can be infused over 24 hours or as
be considered in the multi-day continuous infusion.
face of toxicities.
Emetogenicity: ≤ 1,000 mg/m2-mild risk; > 1,000 mg/m2-high risk
Suggested monitoring during administration: For angina or other cardiac

symptoms and stop the drug immediately.
serum creatinine, liver function tests, observe for changes in bowel frequency.
Gemcitabine IV: Infuse the diluted solution over 30 minutes. Prolongation of infusion time
(> 60 minutes) has been shown to increase toxicity.
The drug Not a vesicant but can cause local burning and irritation at injection site due to
administration is low pH (3) of final solution.
specific dose Emetogenicity: Mild risk
modifications must
be considered in the Possible monitoring could include: CBC with differential and platelets,
face of toxicities. bilirubin, liver function tests, BUN, serum creatinine, LDH, and reticulocyte
count.
Gemtuzumab IV: Infuse the diluted solution over 2 hours. Requires an in-line 0.2-1.2 micron
ozogamicin low protein-binding filter during administration. Protect from direct and indirect
ultraviolet light during preparation and administration.
The drug
administration is Suggested premedications: Administer H1-receptor antagonist (eg,
optimal and protocol diphenhydramine 1 mg/kg [50 mg max]) and acetaminophen 15 mg/kg
specific dose [1,000 mg max]) 1 hour prior to the administration of gemtuzumab.
modifications must Acetaminophen dosage may be repeated if needed every 4 hours for 2 additional
be considered in the doses. Pretreatment with methylprednisolone may ameliorate infusion-related
face of toxicities. symptoms.
Suggested monitoring during administration: Hypersensitivity reactions

including anaphylaxis. Monitor vital signs during the infusion and for 4 hours
following the infusion. Post infusion reactions may include fever chills,
hypotension, or dyspnea.
Possible monitoring could include: CBC with differential, serum electrolytes,

liver function tests, daily weights, bilirubin.
IDArubicin IV push: Infuse as slow push over 3-15 minutes, preferably into the tubing of a
rapidly infusing solution of D5W or 0.9% NaCl. Protect from light.
The drug
administration is Emetogenicity: Moderate risk
specific dose Suggested monitoring during administration: Infusion site. Avoid
modifications must extravasation; the use of a central line is suggested.
face of toxicities. Possible monitoring could include: CBC with differential and platelets, ECG,
ventricular ejection fraction, serum electrolytes, BUN, serum creatinine, serum
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uric acid, liver function tests, bilirubin.
Ifosfamide IV (Dose ≤ 1,800 mg/m²): Infuse the diluted solution over 1 hour.
The drug IV (Dose > 1,800 mg/m²): Study committee to choose between administration
administration is by short infusion or by continuous infusion.
specific dose Short infusion: Infuse the diluted solution over 2-4 hours.
modifications must
be considered in the Continuous infusion: Infuse the diluted solution by continuous infusion over
face of toxicities. 12-24 hours.
Use of Mesna: Mesna must always be administered in conjunction with

ifosfamide. See mesna administration guidelines.
Suggested hydration: Administer 3,000 mL/m²/day (125 mL/m²/hour) using

fluid containing D5W/0.45% NaCl or 0.9% NaCl. Achieve urine specific gravity
≤ 1.010 prior to start of ifosfamide. May use diuretics (eg, furosemide) to
increase urine output. Consider adding potassium and magnesium to prevent
electrolyte deficiencies.
Emetogenicity: < 1,500 mg/m2-moderate risk; ≥ 1,500 mg/m2-very high risk
serum creatinine, liver enzymes, electrolytes, urinalysis, urine output, Fanconi
syndrome, hematuria, neurotoxicity (confusion, somnolence).
Selected drug interactions: Ifosfamide is a major substrate for CYP2A6,

CYP2C19 and CYP3A4 and a minor substrate of CYP2B6, CYP2C8, and
CYP2C9. It inhibits CYP3A4 (weak) and induces CYP2C8 (weak) and CYP2C9
(weak). Patients on warfarin and on CYP2A6, CYP2C19 and CYP3A4 inhibitors
or inducers should be monitored closely for toxicity or reduced efficacy. Consult
drug information references for further information.
Imatinib Oral: Administer during or immediately after meals. Imatinib is a local irritant
and must be taken in an upright position with water (at least 240 mL/8 oz for
The drug children > 3 years of age; at least 4 oz for children  3 years of age). Patients
administration is should remain in an upright position for 30 minutes post administration to
optimal and protocol prevent esophageal irritation. The tablet can be dispersed in water or apple juice
specific dose for ease of swallowing (see monograph). Grapefruit or its juice should be
modifications must avoided for the duration of treatment. Doses >600 mg should be given in 2
be considered in the divided doses (eg, 800 mg should be given as two 400 mg tablets twice daily).
face of toxicities. Doses of > 800 mg should be given using 400 mg tablets, to reduce the exposure
to iron.
function tests, renal function, calcium and phosphorous levels, thyroid function
tests, fatigue, weight, edema/fluid status, rash, musculoskeletal pain. Monitor
for heart failure in patients with risk of cardiac failure or preexisting cardiac
disease, and consider echocardiogram and serum troponin levels in patients with
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hypereosinophilic syndrome or chronic eosinophilic leukemia,

myelodyplastic/myeloproliferative disease and aggressive systemic mastocytosis
with high eosinophil levels.
Selected drug interactions: Imatinib is a substrate of CYP3A4 (major), and

CYP2C19, 1A2, 2D6, and 2C9 (all minor). It is an inhibitor of CYP3A4 (strong),
2D6 (moderate), and 2C9 (weak). The levels/effects of imatinib may be
increased by CYP3A4 inhibitors and decreased by CYP3A4 inducers. Imatinib
may increase the levels/effects of CYP450 substrates. Systemic exposure to
acetaminophen is expected to increase when co-administered with imatinib.
Consult drug information references for further information.
Irinotecan IV: Infuse the diluted solution over 90 minutes. Lower doses (≤ 20 mg/m2) can
be administered over 60 minutes.
The drug Higher incidence of cholinergic symptoms has been reported with more rapid
administration is infusion rates.
specific dose Emetogenicity: High risk
modifications must
be considered in the Suggested monitoring during administration: Infusion site. To avoid
face of toxicities. extravasation; the use of a central line is suggested.
Possible monitoring could include: Signs of diarrhea and dehydration, serum

electrolytes, BUN, serum creatinine, CBC with differential and platelets, liver
function tests, bilirubin.
Selected drug interactions: Irinotecan is a substrate for CYP3A4 (major) and

CYP2B6 (major). Patients on inhibitors or inducers of CYP3A4 and CYP2B6
should be monitored closely for toxicity or reduced efficacy. Consult drug
Isotretinoin Oral: To enhance absorption, administer capsules with high fat food (such as ice
cream or peanut butter) or with milk. Isotretinoin capsules should be swallowed
The drug whole whenever possible. If not possible, for ease of swallowing, the capsules
administration is can be punctured and the contents squeezed into a high fat food immediately
optimal and protocol before administration or the capsules can be softened or punctured and chewed
specific dose (best absorbed if chewed with high fat food). Isotretinoin should not be removed
modifications must from the capsules for more than one hour prior to administering to the patient
be considered in the (see drug monograph).
face of toxicities.
Special Precautions: MUST be prescribed under the Committed to
Pregnancy Prevention Program (iPLEDGE) (see drug monograph).
Pregnancy risk factor X. Pregnant women should not handle isotretinoin.
Women of childbearing potential should wear gloves when handling isotretinoin
capsules. Patients should be warned about photosensitivity; the use of sunscreen
and avoiding exposure to direct sunlight should be recommended. Isotretinoin is
contraindicated in patients with parabens allergy as the capsule is preserved with
the agent.
Possible monitoring could include: CBC with differential and platelets, lipids,
liver function tests, baseline sedimentation rate, glucose, creatine phosphokinase
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(CPK), triglycerides, signs of depression, mood alteration, psychosis, and

aggression. Pregnancy test for all female patients of childbearing potential prior
to the beginning of therapy and monthly during therapy.
Selected drug interactions: Concurrent use with tetracyclines should be avoided,

due to reports of cases of pseudotumor cerebri with concurrent use. Isotretinoin
may increase clearance of carbamazepine and diminish the therapeutic effect of oral
contraceptives. Intake of vitamin A should be limited for the duration of
isotretinoin treatment.
Leucovorin IV push or short infusion: Inject by IV push over a minimum of 3 minutes or by
short infusion over 15 to 120 minutes. Because of the calcium content of the
The drug leucovorin solution, no more than 160 mg of leucovorin should be injected
administration is intravenously per minute (16 mL of a 10 mg/mL solution per minute). IV
optimal and protocol leucovorin and sodium bicarbonate are incompatible.
specific dose
modifications must Oral: Administer with or without food. Doses > 25 mg should be given IV due
be considered in the to the saturation of absorption. Administer doses on schedule as determined by
face of toxicities. timing of methotrexate administration. If a dose is missed, administer dose
immediately. Give the next scheduled dose according to the original dosing
schedule. Do not deviate from the original schedule. Notify provider if a dose is
delayed or missed.
Special precautions: Typically with high dose methotrexate, leucovorin is

initiated at least 24 hours after the start of methotrexate. Leucovorin should not be
administered < 24 hours after intrathecal methotrexate injections unless there are
special circumstances. When given to potentiate the activity of fluorouracil,
leucovorin is administered first.
Possible monitoring could include: No special monitoring for leucovorin.

Depending on the use, methotrexate levels or toxicity of methotrexate is
monitored.
Lomustine Oral: Administer capsules whole on an empty stomach (at least 1 hour before or
2 hours after food) with plenty of fluids (at least 240 mL/8 oz for children > 3
The drug years of age; at least 4 oz for children  3 years of age). Administer at bedtime,
administration is if possible, to reduce nausea and vomiting. The dose is repeated not more
optimal and protocol frequently than every 6 weeks. Round dose to the nearest 10 mg. Typically, the
specific dose whole dose, even if comprised of several capsule sizes, is placed in one
modifications must prescription bottle to be taken at one time.
face of toxicities. Emetogenicity: ≤ 60mg/m2-high risk; > 60 mg/m2-very high risk.
Recommended monitoring: CBC with differential and platelets (for at least 6

weeks after the dose), hepatic and renal function tests, pulmonary function tests
(baseline and periodic).
Selected drug interactions: Lomustine is a substrate of CYP2D6 (major) and an

inhibitor of CYP2D6 (weak) and 3A4 (weak). CYP2D6 inhibitors may increase
the levels/effects of lomustine. Consult drug information references for further
information.
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Mechlorethamine IV push: Administer over 1-5 minutes into the tubing of a rapidly infusing
solution of D5W or 0.9% NaCl. Longer infusions are not recommended. Due to
The drug limited stability, prepare immediately prior to use and administer within 1 hour
administration is of preparation.
specific dose Emetogenicity: Very high risk
modifications must
be considered in the Suggested monitoring during administration: Infusion site. To avoid
Possible monitoring could include: CBC with differential and platelets.

Melphalan IV: The final concentration of the diluted solution should not exceed 2 mg/mL
for central line administration or 0.45 mg/mL for peripheral line administration.
The drug The diluted solution is administered by IV infusion at a rate not to exceed
administration is 10 mg/minute.
optimal and protocol Due to limited stability, prepare immediately prior to use and administer within
specific dose 1 hour of preparation.
modifications must
be considered in the Oral: Administer tablets whole on an empty stomach (at least 1 hour before or 2
face of toxicities. hours after food).
Possible monitoring could include: CBC with differential and platelets, serum
electrolytes, liver function tests, and serum uric acid.
Mercaptopurine Oral: Administer in the evening on an empty stomach (at least 1 hour before or
2 hours after food or drink except water). Food or milk delays absorption and
The drug decreases the peak concentration.. Tablets are scored and doses can be rounded
administration is to half tablet. A liquid formulation is available (see drug monograph).
specific dose Comment: Protocols may provide a dosing table to allow different doses on
modifications must alternate days to attain a weekly cumulative dose as close as possible to the total
be considered in the weekly dose.
face of toxicities.
Special precautions: Patients who develop severe myelosuppression while taking
mercaptopurine should have their thiopurine S-methyltransferase (TPMT) status
and/or thiopurine metabolite concentrations evaluated, so that the dose of
mercaptopurine can be reduced in patients with a TPMT deficiency. Patients with
the rare homozygous deficient TPMT phenotype may tolerate only 1/10th to
1/20th the average mercaptopurine dose (refer to protocol dose modifications for
recommendations). Mercaptopurine oral dose should be reduced by 67-75% if
given concurrently with allopurinol.
function tests, uric acid, urinalysis. Patients with severe myelosuppression should
have their TPMT status and/or their thiopurine metabolite concentrations
evaluated.
Selected drug interactions: Allopurinol blocks the metabolism of mercaptopurine

by inhibiting xanthine oxidase; mercaptopurine dose should be adjusted (see
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comment in Special precautions section, above). Mercaptopurine decreases the

anticoagulation effect of warfarin. Consult drug information references for further
information.
Mesna For prophylaxis of hemorrhagic cystitis, study committee to choose between
Option A (60% mesna) or Option B (for high dose oxazaphosphorine [100%
The drug mesna]). A suggested definition for high dose is: cyclophosphamide
administration is ≥ 1,800 mg/m2, ifosfamide > 2,000 mg/m2.
specific dose Option A (for low dose oxazaphosphorine):
modifications must IV short or continuous infusion: For prophylaxis of hemorrhagic cystitis, the
be considered in the total daily mesna dose is equal to 60% of the daily ifosfamide/cyclophosphamide
face of toxicities. dose. Mesna can be administered in 3 divided doses by short infusion over 15 to
30 minutes. The initial bolus dose of mesna may be administered 15 minutes
before or at the same time as the ifosfamide/cyclophosphamide dose; subsequent
doses are given 4 and 8 hours after the start of ifosfamide/cyclophosphamide).
For example: if the oxazaphosphorine dose is 1,000 mg, then the total daily
mesna dose is 600 mg; 200 mg of mesna will be given 15 minutes before or with
the oxazaphosphorine dose (Hour 0) and 2 boluses of 200 mg each will be given
at Hours 4 and 8.
This total daily dose of mesna can also be administered as IV continuous

infusion. The continuous infusion should be started 15-30 minutes before or at
the same time as ifosfamide/cyclophosphamide and finished no sooner than
8 hours after the end of the ifosfamide/cyclophosphamide infusion.
For example: if the ifosfamide/cyclophosphamide dose is 1,000 mg, then the
total daily mesna dose is 600 mg; the 600 mg mesna continuous infusion will
start 15-30 minutes before or at the same time as the
ifosfamide/cyclophosphamide and be completed no sooner than 8 hours after the
end of the ifosfamide/cyclophosphamide infusion. If
ifosfamide/cyclophosphamide is administered over 1 hour and mesna is started
30 minutes before the oxazaphosphorine infusion, the total mesna infusion will
last at least 9 hours and 30 minutes.
Use of oral mesna:

The oral dose of mesna is twice the IV dose. Patients able to tolerate oral mesna
may receive the last TWO bolus doses (originally at Hours 4 and 8) orally at
40% of the ifosfamide/cyclophosphamide dose. The oral doses will be
administered at Hours 2 and 6.
For example: if the oxazaphosphorine dose is 1,000 mg, then 200 mg of mesna
will be given IV 15 minutes before or with the oxazaphosphorine dose (Hour 0)
and the TWO oral doses of 400 mg each will be given at Hours 2 and 6.
Administer tablets or diluted parenteral solution. To decrease sulfur odor, dilute

mesna parental solution before oral administration. The solution can be diluted
1:1 to 1:10 in water, carbonated cola drinks, fruit juices (grape, apple, tomato
and orange) or plain or chocolate milk. The most palatable is chilled grape
juice. Tablets are 400mg and can be divided into 200mg/0.5 tabs so dosing can
be rounded up to nearest 200mg. Administer doses on a schedule as determined
by timing of cyclophosphamide/ifosfamide administration. If a dose is missed,
administer dose immediately. Give the next scheduled dose according to the
original dosing schedule. Do not deviate from the original schedule. Notify
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provider if a dose is delayed or missed.
Option B (for high dose oxazaphosphorine):

IV short or continuous infusion: For prophylaxis of hemorrhagic cystitis, the
total daily mesna dose is equal to 100% of the daily
ifosfamide/cyclophosphamide dose. Mesna can be administered in 5 divided
doses by short infusion over 15 to 30 minutes. The initial bolus dose of mesna
may be administered 15 minutes before or at the same time as the
ifosfamide/cyclophosphamide dose; subsequent doses are given 3, 6, 9, and
12 hours after the start of ifosfamide/cyclophosphamide.
For example: if the oxazaphosphorine dose is 1,000 mg, then the total daily
mesna dose is 1,000 mg; 200 mg of mesna will be given 15 minutes before or
with the oxazaphosphorine dose (Hour 0) and 4 boluses of 200 mg each will be
given at Hours 3, 6, 9 and 12.
This total daily dose of mesna can also be administered as IV continuous

infusion. The continuous infusion should be started 15-30 minutes before or at
the same time as ifosfamide/cyclophosphamide and finished no sooner than
12 hours after the end of the ifosfamide/cyclophosphamide infusion.
For example: if the ifosfamide/cyclophosphamide dose is 1,000 mg, then the
total daily mesna dose is 1,000 mg; the 1,000 mg mesna continuous infusion will
start 15-30 minutes before or at the same time as the ifosfamide
/cyclophosphamide and be completed no sooner than 12 hours after the end of
the ifosfamide/cyclophosphamide infusion. If ifosfamide/cyclophosphamide is
administered over 2 hour and mesna is started 30 minutes before the
oxazaphosphorine infusion, the total mesna infusion will last at least 14 hours
and 30 minutes.
If ifosfamide is given by continuous infusion, mesna will be administered by

continuous infusion and continue for at least 12 hours after the end of the
ifosfamide infusion.
Use of oral mesna:

The oral dose of mesna is twice the IV dose. Patients able to tolerate oral mesna
may receive the last FOUR bolus doses (originally at Hours 3, 6, 9, and 12)
orally at 40% of the ifosfamide/cyclophosphamide dose. The oral doses will be
administered at Hours 1, 4, 7, and 10.
For example: if the oxazaphosphorine dose is 1,000 mg, then the first 200 mg
dose of mesna will be given IV 15 minutes before or with the oxazaphosphorine
dose (Hour 0) and FOUR oral doses of 400 mg each will be given at Hours 1, 4,
7, and 10.
Administer tablets or diluted parenteral solution. To decrease sulfur odor, dilute

mesna parental solution before oral administration. The solution can be diluted
1:1 to 1:10 in water, carbonated cola drinks, fruit juices (grape, apple, tomato
and orange) or plain or chocolate milk. The most palatable is chilled grape
juice. Tablets are 400mg and can be divided into 200mg/0.5 tabs so dosing can
be rounded up to nearest 200mg. Administer doses on a schedule as determined
by timing of cyclophosphamide/ifosfamide administration. If a dose is missed,
administer dose immediately. Give the next scheduled dose according to the
original dosing schedule. Do not deviate from the original schedule. Notify
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provider if a dose is delayed or missed.
Possible monitoring could include: Urinalysis.

Methotrexate IV push: Undiluted: Inject over 2-5 minutes. Diluted: Infuse the diluted solution
over 10-15 minutes.
All Doses < 500
mg/m²/dose that do IM: The 25 mg/mL solution may be given by IM injection. Aspirate prior to
NOT require injection to avoid injection into a blood vessel.
leucovorin rescue
IT: Use preservative free formulation. The volume to be given IT should be in
The drug the range of 5-10 mL. The volume of CSF removed should be equal to at least half
administration is the volume delivered (see drug monograph).
optimal and protocol Note: Larger volumes approximating at least 10% of the CSF volume,
specific dose isovolumetric delivery, with the patient remaining prone after the procedure may
modifications must facilitate drug distribution. These procedures have not been validated in clinical
be considered in the trials. They are allowed but not mandated for patients on COG studies.
face of toxicities.
Oral: Administer the tablets on an empty stomach (at least 1 hour before or 2
hours after food or milk). Food or milk delays absorption and decreases the peak
concentration. For ease of swallowing, methotrexate injection can be
administered orally (see drug monograph)
Emetogenicity: Moderate risk
serum creatinine, creatinine clearance, liver function tests, serum electrolytes,
mucositis, pulmonary function.
Selected drug interactions: Avoid NSAIDs, TMP/SMX, penicillins,

probenicid, IV contrast media, proton pump inhibitors, phenytoin and
fosphenytoin. Consult drug information references for further information.
Methotrexate IV (Dose ≥ 500 mg/m²/dose, high dose methotrexate, solid tumor patients):
Solid Tumor Infuse the diluted solution over ≥ 4 hours. High dose methotrexate
Patients administration requires adequate hydration, alkalinization, leucovorin rescue,
and monitoring until serum methotrexate levels are less than 0.1 micromolar (1 x
Doses 10-7 molar).
> 500 mg/m²/dose
that REQUIRE Suggested hydration/alkalinization:
leucovorin rescue  Administer 3,000 mL/m²/day (125 mL/m²/hour) using fluid containing
50 mEq/L sodium bicarbonate (eg, D5W + 50 mEq/L sodium
The drug bicarbonate).
administration is  Achieve urine specific gravity ≤ 1.010 and urine pH ≥ 7 and ≤ 8 prior to
optimal and protocol start of high dose methotrexate infusion. Administer supplemental fluids
specific dose or sodium bicarbonate if unable to meet urine parameters prior to high
modifications must dose methotrexate infusion.
be considered in the  During and after high dose methotrexate infusion, maintain twice
face of toxicities. maintenance fluid intake and alkalinization (urine pH ≥ 7 and ≤ 8) until
serum methotrexate levels are documented at less than 0.1 micromolar (1
x 10-7 molar). This can be accomplished by intravenous or oral
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hydration/alkalinization or a combination of the two.
Methotrexate levels and leucovorin rescue:

 Initiation of leucovorin rescue may vary depending on the length of the
high dose methotrexate infusion. For a 4 hour high dose methotrexate
infusion initiate leucovorin 24 hours after the start of the methotrexate
infusion (ie, 20 hours after the end of the infusion).
 The starting dose of leucovorin is 10 mg/m²/dose (round to the nearest
5 mg) IV or PO every 6 hours.
 Measure serum methotrexate levels every 24 hours and plot on the
leucovorin dosing nomogram (if provided in protocol).
 Adjust leucovorin dosing interval and/or dose as indicated on the
nomogram (round to the nearest 5 mg).
Interpretation of methotrexate levels

Micromolar Molar
1000 1 x 10 -3
100 1 x 10 -4
10 1 x 10 -5
1 1 x 10 -6
0.1 1 x 10 -7
Special precautions: IV leucovorin and sodium bicarbonate are incompatible.

creatinine clearance (suggested creatinine clearance of ≥ 60 mL/min/1.73 m²
prior to administration of high dose methotrexate), BUN, serum creatinine, urine
pH, urine output, urine specific gravity, liver function tests, serum electrolytes,
urinalysis, mucositis, pneumothorax, daily plasma methotrexate levels for
patients receiving high dose therapy, maintenance of adequate stool output.
Selected drug interactions: Avoid NSAIDs, TMP/SMX, penicillins,

probenicid, IV contrast media, proton pump inhibitors, phenytoin and
fosphenytoin. Urinary acidifiers can cause methotrexate to precipitate in the
urinary tract. Consult drug information references for further information.
Methotrexate IV (high dose methotrexate, leukemia and lymphoma patients):
Leukemia/ For a dose of 5,000 mg/m2:
Lymphoma  Hour 0: start with methotrexate 500 mg/m2 IV infusion over 30 minutes.
Patients  This is followed, immediately, by methotrexate 4,500 mg/m2 given by
continuous IV infusion over 23.5 hours.
Doses  The goal is to complete the high dose methotrexate infusion in 24 hours,
> 500 mg/m²/dose however, due to infusion pump variability, acceptable total infusion time
that REQUIRE is 24 +/- 2 hours.
leucovorin rescue  With high dose methotrexate, patients should receive hydration with
sodium bicarbonate. A suggested regimen is D51/4NS with 30 mEq/L of
The drug sodium bicarbonate at 125 mL/m2/hour during methotrexate infusion,
administration is including the 30 minutes loading dose. An alternative regimen is to give
optimal and protocol a bolus of sodium bicarbonate 1 mEq/kg pre methotrexate followed by
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specific dose D5W with 50 mEq/L of sodium bicarbonate. Methotrexate may either be
modifications must mixed in this fluid or the fluid may be hung as a separate bag and run
be considered in the separately during the methotrexate infusion.
face of toxicities.
Suggested hydration/alkalinization:
 Administer D51/4NS with 30 mEq/L sodium bicarbonate at
125 mL/m2/hour for at least 6 hours or until urine specific gravity is
≤ 1.010 and pH is ≥ 7.0 and ≤ 8.0. Ringers Lactate may be used as the
initial fluid if a bicarbonate containing solution is unavailable.
 Adjust fluid volume and sodium bicarbonate to maintain urine specific
gravity and pH at above parameters.
 Give a bicarbonate bolus (25 mEq/m2 over 15 minutes) to raise the urine
pH relatively quickly.
 Continue hydration and alkalinization throughout high dose
methotrexate infusion, and for a minimum of 48 hours after its
completion.
 In patients with delayed methotrexate clearance, continue hydration until
the plasma methotrexate concentration is below 0.1 micromolar (1 x 10-7
molar).
Special precautions: IV leucovorin and sodium bicarbonate are incompatible
Methotrexate levels and leucovorin rescue:
Interpretation of methotrexate levels

Micromolar Molar
1000 1 x 10 -3
100 1 x 10 -4
10 1 x 10 -5
1 1 x 10 -6
0.1 1 x 10 -7
Hours 24, 36, 42 and 48: Draw methotrexate level and serum creatinine; NOTE:
36 hour level is only drawn if needed (see below).
 For methotrexate levels that exceed these expected values modify the
rescue regimen as in the table below and increase hydration to
200 mL/m2/hour, monitor urine pH to assure a value ≥ 7.0 and monitor
urine output to determine if volume is ≥ 80% of the fluid intake, measured
every 4 hours.
 If serum creatinine rises significantly, at any time point, assure
appropriate urine pH and urine volume as above and draw a 42 hour level.
If urine output fails to continue at 80% of the fluid intake, consider
furosemide.
Regardless of urine output, also consider glucarpidase (formerly
known as carboxypeptidase-G2) (Voraxaze™). Glucarpidase is an
investigational agent that can be obtained in the US by contacting
AAIPharma 24-hour Access Call Center at 866-918-1731. Additional
information can be found at:
http://www.btgplc.com/BTGPipeline/273/Voraxaze.html.
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 If the 24 hour level is < 50 micromolar draw the next level at hour 42 and
refer to table below.
 If the 24 hour level is > 150 micromolar and/or creatinine > 125%
baseline, repeat level if methotrexate contamination is possible. If the
value is “real” refer to the changes in hydration, etc described above and
repeat the level with a serum creatinine at hour 36. Then refer to the table
below.
 If the 42 and 48 hour levels are ≤ 1 and 0.4 micromolar, respectively,
give leucovorin at 15 mg/m2 IV/PO at 42, 48 and 54 hours post the start
of methotrexate loading dose. No additional levels are needed, nor is
additional leucovorin.
36 hr 42 hr 48 hr Leucovorin Rescue++
MTX** MTX MTX
micromolar micromolar
1.01 to 9.9 0.41 to 5.9 Continue 15 mg/m2 q6h until
MTX level < 0.1micromolar
(draw q12-24h)
10 to 39.9 6 to 19.9 Increase to 15 mg/m2 q3h until
MTX level < 0.1 micromolar
(draw q6-24h)
40 to 200 20 to 100 Increase to 100 mg/m2 q6h until
MTX level < 0.1micromolar
(draw q6-24h)
> 200 > 100 Increase to 1,000 mg/m2 q6h until
MTX level < 0.1 micromolar
(draw q6-24h)
** If the 36 hour level exceeds 3 micromolar, increase hydration to

200 mL/m2/hr, monitor urine pH to assure a value ≥ 7.0 and monitor
urine output to determine if volume is ≥ 80% of the fluid intake,
measured every 4 hours. If urine output fails to continue at 80% of the
fluid intake, consider furosemide. Regardless of urine output, also
consider glucarpidase if 36 hour methotrexate level exceeds
10 micromolar.
++ If the level is high at hour 36 or 42, but then the patient “catches up” and the
level falls to the expected values of ≤ 1 and/or ≤ 0.4 micromolar at
hours 42 and 48, respectively, resume standard leucovorin and hydration
as long as urine output remains satisfactory.

creatinine clearance (recommend creatinine clearance ≥ 60 mL/min/1.73 m² prior
to administration of high dose methotrexate), BUN, serum creatinine, urine pH,
urine output, urine specific gravity, liver function tests, serum electrolytes,
urinalysis, mucositis, pulmonary function, daily plasma methotrexate levels for
patients receiving high dose therapy, maintenance of adequate stool output.
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Selected drug interactions:

When IT therapy and high dose methotrexate are scheduled for the same day,
deliver the IT therapy within 6 hours of the beginning of the IV methotrexate
infusion (hour -6 to +6, with 0 being the start of the methotrexate bolus).
Hold TMP/SMX on the days of high dose methotrexate infusion and for at least
72 hours after the start of the high dose methotrexate infusion and until the
methotrexate level is less than 0.4 micromolar. In the presence of delayed
clearance, continue to hold TMP/SMX until methotrexate level is less than
0.1 micromolar.
Hold any NSAIDs, penicillin, or aspirin-containing medications on the day of

high dose methotrexate infusion and for at least 72 hours after the start of the
high dose methotrexate infusion and until the methotrexate level is less than
0.4 micromolar. In the presence of delayed clearance continue to hold TMP/SMX
until methotrexate level is less than 0.1 micromolar.
Avoid penicillins, probenicid, IV contrast media, proton pump inhibitors,

phenytoin and fosphenytoin. Urinary acidifiers can cause methotrexate to
precipitate in the urinary tract. Consult drug information references for further
information.
MitoMYCIN IV push or short infusion: Administer by slow IV push over 5-10 minutes or by
short infusion over 15-60 minutes, preferably through the tubing of a rapidly
The drug infusing solution of D5W or 0.9% NaCl.
administration is
optimal and protocol Emetogenicity: < 8 mg/m2-mild risk; ≥ 8 mg/m2-high risk
specific dose
modifications must Suggested monitoring during administration: Infusion site. Avoid
be considered in the extravasation; the use of a central line is suggested.
face of toxicities.
serum creatinine, pulmonary function tests, liver function tests, prothrombin
time. Absolute neutrophil count and platelet nadir is prolonged, between 4-
6 weeks from dosing.
Mitotane Oral: Mitotane is given as 3-4 doses per day with or without food.
The drug Special precautions: Since mitotane is adrenolytic, patients require corticoid
administration is replacement. In addition, mitotane may interfere with the metabolism of other
optimal and protocol hormones such as thyroid and parathyroid hormones.
specific dose
modifications must Emetogenicity: Moderate risk
face of toxicities. Selected drug interactions: Mitotane may accelerate the metabolism of
coumarin-derivative anticoagulants (eg, warfarin) by hepatic microsomal
enzyme induction resulting in an increase in dosage requirement; therefore
patients on coumarin-derivative anticoagulants should be closely monitored.
MitoXANTRONE IV push or short infusion: Infuse the diluted solution over 15-30 minutes.
Administer through the tubing of a rapidly infusing solution of D5W or 0.9%
The drug NaCl.
administration is
optimal and protocol Emetogenicity: Moderate risk
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specific dose Special precautions: Incompatible with heparin; precipitation may form.
modifications must
be considered in the Suggested monitoring during administration: Infusion site. Avoid
function tests, ECG, ventricular ejection fraction, serum uric acid.
Oxaliplatin IV: Infuse over at least 2 hours (the range is 2-6 hours). Flush the oxaliplatin
administration line with D5W before and after infusion.
The drug
administration is Special precautions: Cold temperatures during the infusion of oxaliplatin and
optimal and protocol thereafter may exacerbate acute neurologic symptoms. Patients should avoid the
specific dose use of ice for mucositis prophylaxis and should avoid cold food and drinks.
modifications must
be considered in the Emetogenicity: High risk
face of toxicities.
Suggested monitoring during administration: Vital signs. Hypersensitivity
reactions including urticaria, pruritus, facial flushing, shortness of breath,
bronchospasm, diaphoresis, hypotension, syncope. Anaphylactic-like reaction
may occur within minutes of oxaliplatin administration.
serum creatinine, liver function tests, bilirubin, signs of neuropathy.
PACLItaxel Study committee to choose between intermittent and continuous infusion.
The drug IV: (Dose ≤ 90 mg/m2/dose) Infuse over 1 or 3 hours using non-PVC containers
administration is and administration set. An inline 0.22 micron filter should be used during
optimal and protocol administration.
specific dose
modifications must IV (Dose >90 mg/m2/dose): Infuse over 3 hours using non-PVC containers and
be considered in the administration set. An inline 0.22-micron filter should be used during
face of toxicities. administration.
IV Continuous Infusion: Infuse over 24 or 96 hours (24 hours is more

common) using non-PVC containers and administration set. An inline
0.22 micron filter should be used during administration.
Special precautions: Concomitant use with platinum derivatives

(CARBOplatin, CISplatin, oxaliplatin) may cause increased hematological
toxicity if the platinum agent is administered first. Administer paclitaxel first.
Medication errors have occurred due to confusion between DOCEtaxel

(TaxoTERE) and PACLItaxel (TaxoL). PACLItaxel is available in an
albumin-bound formulation (Abraxane). The conventional and albumin-
bound formulations are NOT interchangeable.
Suggested premedications: Premedicate patients with a corticosteroid 12 and

6 hours (manufacturer recommendation) or 30-60 minutes before paclitaxel (if
not taken earlier). Administer H1-receptor antagonist (eg, diphenhydramine,
1 mg/kg [max 50 mg]), and an H2-receptor antagonist 30-60 minutes prior to
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paclitaxel administration.
Suggested monitoring during administration: Hypersensitivity reaction

including anaphylaxis; check vital signs (more frequently during the first hour of
infusion). Monitor for hypotension and bradycardia. Monitor the infusion site.
Avoid extravasation; the use of a central line is suggested.
Possible monitoring could include: CBC with differential and platelets, ECG
(in patients with conduction abnormalities), liver function tests.
Selected drug interactions: Paclitaxel is a substrate for CYP3A4 (major) and

CYP2C8 (major) and an inducer of CYP3A4 (weak). Patients on inducers of
CYP3A4 and CYP2C8 agents should be monitored closely for reduced
level/efficacy of paclitaxel. CYP3A4 and CYP2C8 inhibitors may increase
paclitaxel toxicity. Consult drug information references for further information.
Pegaspargase IM: When administered intramuscularly, consider dose volume and size of
patient; total dose may need to be administered at more than one injection site. If
The drug dose volume is > 2 mL, use multiple injection sites. Platelets should be
administration is ≥ 50,000/μL when possible for administration. Aspirate prior to injection to
optimal and protocol avoid injection into a blood vessel.
specific dose
modifications must IV: Administer over 1-2 hours through the tubing of a rapidly infusing solution
be considered in the of D5W or 0.9% NaCl.
face of toxicities.
Special precautions:
1. Pegaspargase is contraindicated with a history of severe pancreatitis with
any prior asparaginase therapy, serious thrombosis with any prior
asparaginase therapy, or serious hemorrhagic events with any prior
asparaginase therapy.
2. Pegaspargase may affect coagulation factors and predispose to bleeding
and/or thrombosis. Caution should be used when administering any
concurrent anticoagulant therapy.
Suggested monitoring during administration: Because pegaspargase is long

acting, hypersensitivity reactions may not appear for hours after drug
administration. Monitor vital signs, fever, chills, and acute allergic reactions
including anaphylaxis. Have medications to treat hypersensitivity reactions
readily available at each administration (eg, epinephrine, IV corticosteroids,
antihistamines). May prescribe an EpiPen® for home use.

urinalysis, amylase, liver enzymes, bilirubin, BUN, serum creatinine, urine
glucose, blood glucose, serum uric acid, onset of abdominal pain, vomiting, and
mental status changes.
Rituximab IV: For ease of dose administration/rate titration consider final concentration of
1 mg/mL. Administer the diluted solution as follows:
The drug
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administration is First infusion: Begin infusion at an initial rate of 50 mg/hour for the
optimal and protocol first hour. If no hypersensitivity or infusion-related events, increase
specific dose infusion rate by 50 mg/hour every 30 minutes to a maximum rate of
modifications must 400 mg/hour. If a hypersensitivity or infusion-related event develops, the
be considered in the infusion should be slowed or interrupted. The infusion can continue at
face of toxicities. one half the previous rate, upon improvement of symptoms.
Subsequent infusions: If the patient tolerated the first infusion well,

begin infusion at an initial rate of 100 mg/hour for the first hour. If no
hypersensitivity or infusion related events, increase infusion rate by
100 mg/hour every 30 minutes as tolerated to a maximum rate of
400 mg/hour. If a hypersensitivity or infusion-related event develops, the
infusion should be slowed or interrupted. The infusion can continue at
one half the previous rate upon improvement of symptoms.
Follow the initial infusion guidelines if the patient did not tolerate the
first infusion.
COG protocols ANHL0221 and ANHL01P1 used an initial rate of

0.5 mg/kg/hour (maximum 50 mg/kg/hour) for the first infusion and increased
the rate by 0.5 mg/kg/hour every 30 minutes to a maximum of 400 mg/hour. For
subsequent infusions the starting rate was1 mg/kg/hour (maximum 50 mg/hour)
and the increases were by 1 mg/kg/hour to a maximum of 400 mg/hour. These
rates are not published.
Suggested premedications: Premedicate with H1-receptor antagonist (eg,

diphenhydramine, 1 mg/kg [50 mg max.]) and acetaminophen 15 mg/kg
[1,000 mg max.]) 30-60 minutes before dose.
Special precautions: Due to the risk of hypotension, hold antihypertensive

medications 12 hours prior to infusion.
Suggested monitoring during administration: Vital signs during and after the
infusion for infusion-related hypersensitivity reaction including anaphylaxis.
Monitor for chills, fever, rigors, hypotension, angioedema, bronchospasm, and
hypoxia. Severe infusion-related reactions occurred 30 to 120 minutes after the
start of the first infusion. Cardiac monitoring during and after the infusion in
patients with preexisting cardiac disease or if arrhythmias develop during the
infusion.

hepatitis B, BUN, creatinine, fluid balance, abdominal pain.
Streptozocin IV: The reconstituted solution (100 mg/mL) may be given by rapid IV push.
The drug IV Infusion: Infuse the diluted solution over 15-60 minutes. Intermittent
administration is infusions may be given over 15 minutes to 6 hours.
specific dose Emetogenicity: Very high risk
modifications must
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be considered in the Suggested monitoring during administration: Infusion site. Avoid

serum creatinine, urinalysis, proteinuria, liver enzymes, blood glucose.
Temozolomide Oral: Absorption is affected by food and therefore, consistency of
administration with respect to food is suggested. Preferably, administer on an
The drug empty stomach (at least 1 hour before or 2 hours after food) to decrease nausea
administration is and vomiting and improve absorption. The whole dose, even if comprised of
optimal and protocol several capsule sizes, should be taken at one time at approximately the same time
specific dose each day. Bedtime administration may decrease nausea and vomiting. The
modifications must temozolomide dose should be rounded off to the nearest 5 mg (round 2.5 mg
be considered in the down (see Appendix ______). For ease of swallowing, the capsule content may be
face of toxicities. mixed with applesauce or juice (see instructions in Appendix ____) or an oral
suspension may be compounded (see drug monograph in section ____).
Special precautions: Temozolomide capsules are available in 6 different

strengths. Daily doses are usually comprised of multiple capsules of different
strengths. To prevent errors, each strength of temozolomide capsules must be
dispensed in a separate bottle and the total number of each strength of capsules
needed for the full course must be dispensed at one time. See drug monograph
for additional details and examples. PCP prophylaxis is required when patients
are receiving radiotherapy in combination with daily temozolomide and should
continue in patients who develop lymphocytopenia until recovery. While
TMP/SMX is the recommended agent for prophylaxis, TMP/SMX should not be
used during chemoradiotherapy with temozolomide because of possible increased
risk of prolonged neutropenia. Monthly inhaled or IV pentamidine or other
appropriate alternative should be used during that time
(See https://members.childrensoncologygroup.org/prot/reference_materials.asp for
COG Supportive Care Guidelines).
Possible monitoring could include: CBC with differential and platelets, fatigue.
Thioguanine Oral: Administer in the evening preferably on an empty stomach (at least 1 hour
before or 2 hours after food or drink except water). . Tablets are scored and
The drug doses can be rounded to half tablet.
administration is
optimal and protocol Comment: Protocols may provide a dosing table to allow different doses on
specific dose alternate days to attain a weekly cumulative dose as close as possible to the total
modifications must weekly dose.
face of toxicities. Emetogenicity: Low risk
function tests, uric acid, urinalysis. Patients with severe myelosuppression
should have their TPMT status and/or thiopurine metabolite concentrations
evaluated.
Selected drug interactions: Concurrent long-term continuous therapy with

busulfan and thioguanine may cause hepatotoxicity, portal hypertension and
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esophageal varices. Aminosalicylates (olsalazine, mesalamine, sulfasalazine) may

inhibit TPMT. Consult drug information references for further information.
Thiotepa IV push or short infusion: Administer the reconstituted solution (10 mg/mL)
over 1-2 minutes or further dilute and administer over 10-60 minutes.
The drug
administration is IV intermittent infusion: Infuse the diluted solution over 1-4 hours.
specific dose Special precautions: If patient is receiving high dose thiotepa associated with a
modifications must transplant conditioning regimen, frequent bathing and linen changes should be
be considered in the done to avoid chemical skin burns.
face of toxicities.

urinalysis, serum uric acid.
Selected drug interactions: If given with cyclophosphamide, administer 1 hour

following the infusion of cyclophosphamide. Inhibits CYP2B6. Phenytoin
(CYP2B6 inducer) may decrease the level/effect of thiotepa and increase the
level of its active metabolite (TEPA). Thiotepa may increase the level/effects of
CYP2B6 substrates. Consult drug information references for further information.
Topotecan Study committee to choose between intermittent and continuous infusion.
The drug IV: Infuse the diluted solution over 30 minutes.

administration is
optimal and protocol IV continuous infusion: The diluted solution can be administered as continuous
specific dose infusion over 24 hours or as multi-day continuous infusion.
modifications must
be considered in the Oral: Administer capsules whole with or without food. Capsules should not be
face of toxicities. crushed, chewed or divided. For ease of swallowing, the injection can be used
for oral administration. To mask the taste, topotecan injection can be mixed with
apple, orange or grape juice immediately prior to administration.
serum creatinine.
Trastuzumab IV: Dilute the reconstituted solution and infuse the loading dose over
90 minutes; infuse maintenance doses over 30 minutes, if tolerated.
The drug
administration is Emetogenicity: Low risk
specific dose Suggested monitoring during administration: Vital signs during infusion for
modifications must hypersensitivity reaction including anaphylaxis.
face of toxicities. Suggested monitoring: ECG, baseline cardiac assessment, ventricular ejection
fraction.
Tretinoin Oral: There is no data on the effect of food on the absorption of tretinoin but, as
a class, absorption of retinoids is enhanced when taken with food. Tretinoin
The drug capsules should be swallowed whole whenever possible. If not possible, for ease
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administration is of swallowing, the capsule may be punctured and the contents placed in food or
optimal and protocol the capsule may be softened and chewed. Tretinoin should not be removed from
specific dose the capsules for more than 1 hour prior to administering to the patient. If the
modifications must patient cannot tolerate oral administration (eg, due to intubations), it is possible
be considered in the to administer tretinoin via a nasogastic tube (see drug monograph). Protect from
face of toxicities. heat and light (see drug monograph).
Special precautions: Patients should be warned about photosensitivity; the use

of sunscreen and avoiding exposure to direct sunlight should be recommended.
Intake of vitamin A should be limited for the duration of tretinoin treatment.
Possible monitoring could include: CBC with differential and platelets, lipids,
liver function tests, coagulation.
Selected drug interactions: Tretinoin is major substrate of CYP3A4 and 2C8

and a minor substrate of CYP2A6, 2B6, and 2C9. Tretinoin inhibits CYP2C9
(weak) and induces CYP2E1(weak). CYPP450 inhibitors may increase the
level/effects of tretinoin. Tretinoin may cause pseudotumor cerebri/intracranial
hypertension and, therefore, coadministration of agents known to cause this
effect (e.g., tetracyclins) may increase the risk. Antifibrinolytic agents like
aminocaproic acid and tranexamic acid may increase the risk of thrombosis.
Consult drug information references for further information.
VinBLAStine IV push: Administer the reconstituted solution (1 mg/mL) over 1 minute.
The drug Special precautions: FATAL IF GIVEN INTRATHECALLY.

administration is The container or the syringe containing vinBLAStine must be enclosed in an
optimal and protocol overwrap bearing the statement “Do not remove covering until moment of
specific dose injection. Fatal if given intrathecally. For intravenous use only.”
modifications must
be considered in the Medication errors have occurred due to confusion between vinCRIStine and
face of toxicities. vinBLAStine.


bilirubin, liver function tests (for dose adjustment), neurotoxicity, peripheral
neuropathy, serum uric acid.
Selected drug interactions: Previous (up to 2 weeks) or concurrent

administration with mitomycin C may result in acute shortness of breath and
severe bronchospasm. VinBLAStine is a substrate of CYP3A4 (major) and
CYP2D6 (minor) and an inhibitor of CYP3A4 (weak) and CYP2D6 (weak).
CYP3A4 inhibitors may increase the level/effects of vinBLAStine and
CY3P3A4 inducers may decrease the levels/effects of vinBLAStine. Consult
drug information references for further information.
37
Version Number: 5
VinCRIStine IV push: Administer IV push over 1 minute or infusion via minibag as per
institutional policy.
The drug
administration is Emetogenicity: Low risk
specific dose Special precautions: FATAL IF GIVEN INTRATHECALLY.
modifications must The container or the syringe containing vinCRIStine must be enclosed in an
be considered in the overwrap bearing the statement “Do not remove covering until moment of
face of toxicities. injection. Fatal if given intrathecally. For intravenous use only.”
Medication errors have occurred due to confusion between vinCRIStine and

vinBLAStine.

Possible monitoring could include: Serum electrolytes (sodium), liver function

tests including alkaline phosphatase and bilirubin (for dose adjustment), CBC
with differential and platelets, signs of neurotoxicity, peripheral neuropathy,
serum uric acid.

severe bronchospasm. VinCRIStine is a substrate of CYP3A4 (major) and an
inhibitor of CYP3A4 (weak). CYP3A4 inhibitors may increase the level/effects
of vinCRIStine. Consult drug information references for further information.
VinORELBine I.V.: Infuse the diluted solution over 6-10 minutes into the side port of a rapidly
infusing solution of D5W or 0.9% NaCl. Consider flushing the vinORELBine
The drug injection site with 75-125 mL of a compatible IV fluid for 15-60 minutes after
administration is administration to prevent burning at the injection site.
specific dose Special precautions: FATAL IF GIVEN INTRATHECALLY.
modifications must The container or the syringe containing vinORELBine should be labeled with the
be considered in the following statement: “WARNING - FOR IV USE ONLY. FATAL IF GIVEN
face of toxicities. INTRATHECALLY.”

function tests, pulmonary symptoms, neurotoxicity, peripheral neuropathy.

severe bronchospasm. Coadministration with CISplatin increases the incidence
of granulocytopenia. VinORELBine is a substrate of CYP3A4 (major) and
CYP2D6 (minor) and it inhibits CYP2D6 (weak) and CYP3A4 (weak). CYP3A4
inhibitors may increase the level/effect of vinORELBine. CYP3A4 inducers may
decrease the levels/effects of vinORELBine. Consult drug information
38

COG Chemo Admin Guidelines

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COG Chemo Admin Guidelines

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Version Date: 01/25/10

PARENTERAL AND ORAL CHEMOTHERAPY ADMINISTRATION GUIDELINES USED BY

Prepared by the COG Pharmacy Committee.

COG PARENTERAL AND ORAL CHEMOTHERAPY ADMINISTRATION GUIDELINES

Interaction with live vaccines

Interactions: selected drugs

Patient education on oral chemotherapy administration at home

Patient drugs returns

Pre-and Post-Chemotherapy Hydration

Premedications, supportive care and antiemetics

Preparation and administration checks

Preparation and stability information

Drug Administration Guidelines

Emetogenicity: ≤ 12 million units/m2-mild risk; > 12 million units/m2-high risk

Suggested monitoring during administration: Vital signs (temperature, pulse,

Possible monitoring could include: Baseline chest x-ray, pulmonary function

Suggested premedications: Administer H1-receptor antagonist (eg,

Emetogenicity: Low risk

Suggested monitoring during administration: Vital signs including blood

Special precautions: To prevent nausea, vomiting and hypotension, patients

Suggested hydration: For higher doses (≥ 70 mg/m²), prehydrate with 0.9%

Emetogenicity: ≤ 300 mg/m2-mild risk; > 300 mg/m2-high risk

Suggested monitoring during administration: Baseline blood pressure

Possible monitoring could include: Electrolytes, urinalysis, serum calcium,

Emetogenicity: Mild risk

Suggested monitoring during administration: Vital signs, fever, chills, or

Possible monitoring could include: CBC, urinalysis, amylase, liver enzymes,

Emetogenicity: High risk

Suggested monitoring during administration: Injection site for erythema and

Emetogenicity: Low risk

Suggested monitoring during administration: Depending on the length of the

Possible monitoring could include: Urinalysis (hold for moderate to severe

Emetogenicity: Low risk

Suggested monitoring during administration: Vital signs including

Possible monitoring could include: Pulmonary function tests, BUN, serum

Bortezomib IV: Administer the reconstituted solution (1 mg/mL) by IV bolus over 3-

Selected drug interactions: No drug interaction studies have been performed

Suggested premedications: The manufacturer recommends starting

Emetogenicity: ≤ 4 mg/kg/day-low risk; > 4 mg/kg/day-high risk

Selected drug interactions: Busulfan is a substrate to cytochrome P450 3A4

Subtenon: The premixed solution (10 mg/mL) or the reconstituted lyophilized

Special precautions: When administered as sequential infusion, taxane

Medication errors have occurred due to confusion between CISplatin

Emetogenicity: High risk

Suggested monitoring during administration: Hypersensitivity reaction.

Emetogenicity: < 200 mg/m2-high risk; ≥ 200 mg/m2-very high risk

Suggested monitoring during administration: Check BP (hypotension) with

Possible monitoring could include: CBC with differential and platelets,

Emetogenicity: Low risk

Suggested monitoring during administration: Monitor for infusion related

Possible monitoring could include: CBC with differential, chemistries (serum

Medication errors have occurred due to confusion between CISplatin

Suggested hydration: Administer 3000 mL/m²/day (125 mL/m²/hour) using

Emetogenicity: < 50 mg/m2-high risk; ≥ 50 mg/m2-very high risk

Possible monitoring could include: BUN, serum creatinine, creatinine

clearance, urinalysis, urine output, body weight, serum electrolytes (particularly

Emetogenicity: High risk

Suggested monitoring during administration: Check BP (hypotension),

Selected drug interactions: Clofarabine is excreted mainly by the kidneys and

Use of mesna: Individual cyclophosphamide doses ≤ 1,000 mg/m²/dose may not

Suggested hydration: For high dose cyclophosphamide (≥ 1,800 mg/m²)

Selected drug interactions: Substrate of CYP2A6 (minor), CYP2B6 (major),

IV continuous infusion: Cytarabine may also be infused over 24 hours.