SYNONYM:

VP-16

COMMON TRADE NAME: VEPESID(r)2, ETOPOPHOS(r) (etoposide phosphate)3 CLASSIFICATION: topoisomerase II inhibitor,1 cytotoxic4

Special pediatric considerations are noted when applicable, otherwise adult provisions apply.

MECHANISM OF ACTION:

Etoposide is a semisynthetic derivative of the podophyllotoxins, an epipodophyllotoxin. It inhibits DNA topoisomerase II, thereby inhibiting DNA synthesis. Etoposide is cell cycle dependent and phase specific, affecting mainly the S and G2 phases.1

PHARMACOKINETICS:

Interpatient variability bioavailability
Oral Absorption dose-dependent; absorption decreases as etoposide dose increases; mean 50%. 1 daily doses greater than 200 mg should be divided (BID) absorption does not appear to be altered by food or changes in stomach pH and emptying 5 ; however manufacturer recommends drug be taken on an empty stomach.
time to peak plasma concentration 1-1.5 h
Distribution detected in saliva, liver, spleen, kidney, myometrium, healthy brain tissue, and brain tumour tissue, minimally in pleural fluid
cross blood brain barrier? in low and variable concentrations 1
volume of distribution 7-17 L/m 2 , 32% of body weight
plasma protein binding 95% 6
Metabolism hepatic biotransformation 1
active metabolite 1 yes
inactive metabolite 1 yes
Excretion fecal and urinary excretion
urine 44-60% (67% of that unchanged) 1
feces up to 16% (as unchanged drug and metabolites) 1
biliary < 6% 1
terminal half life 7 h (range, 3-12) 1
clearance 19-28 mL/min/m 2
Gender no clinically important differences
Elderly no clinically important differences
Children volume of distribution 5-10 L/m 2 terminal half life 3-5.8 h

Adapted from standard references7,8 unless specified otherwise.

USES:

Primary uses: Other uses:

Bladder cancer Ewings's sarcoma Brain tumours Hepatoma Cervical cancer Kaposi's sarcoma, AIDS-related Ependyoma Leukemia, acute myeloid Germ cell tumour Leukemia, acute lymphocytic Gestational trophoblastic neoplasia Neuroblastoma Head and neck cancer Rhabdomyosarcoma *Lung cancer, small cell Wilm's tumour *Lung cancer, non-small cell *Lymphoma Ovarian cancer Prostate cancer *Testicular cancer

*Health Canada approved indication

Adapted from standard reference2,7 unless specified otherwise.

SPECIAL PRECAUTIONS:

Contraindicated: 2

In patients who have a history of hypersensitivity reactions to etoposide.

Carcinogenicity: 7

Etoposide is potentially carcinogenic.

Mutagenicity: Mutagenic in Ames test and mammalian in vitro mutation test. Etoposide is clastogenic in mammalian in vitro and in vivo chromosome tests.1

Fertility: 7

The effect of etoposide on fertility in humans is not known.

Pregnancy: FDA Pregnancy Category D.1 There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

Breastfeeding 2

should be discontinued as etoposide is excreted in human milk.

SIDE EFFECTS:

The table includes adverse events that presented during drug treatment but may not necessarily have a causal relationship with the drug. Because clinical trials are conducted under very specific conditions, the adverse event rates observed may not reflect the rates observed in clinical practice. Adverse events are generally included if they were reported in more than 1% of patients in the product monograph or pivotal trials, and/or determined to be clinically important.9

ORGAN SITE SIDE EFFECT ONSET
Clinically important side effects are in bold, italics I = immediate (onset in hours to days); E = early (days to weeks) D = delayed (weeks to months); L = late (months to years)
allergy/immunology type 1 hypersensitivity reaction during or immediately after IV administration (1-3%) 10 I
blood/bone marrow febrile neutropenia myelosuppression, WBC nadir 7-14 days, platelet nadir 9-16 days, recovery 20 days E
cardiovascular congestive heart failure E
hypotension with rapid IV administration (1-2%) I
myocardial infarction E
ORGAN SITE SIDE EFFECT ONSET
Clinically important side effects are in bold, italics I = immediate (onset in hours to days); E = early (days to weeks) D = delayed (weeks to months); L = late (months to years)
constitutional symptoms fatigue E
fever I
dermatology/skin extravasation hazard: irritant 11
alopecia (8-66%) E
anal irritation or fissures 12 D
epidermal necrolysis, toxic (one fatal case reported) E
nail changes 12 E
palmar-plantar erythema 12 E
pigmentation D
pruritus, severe I
rash I
urticaria I
gastrointestinal emetogenic potential: low moderate 13
anorexia (10-13%) E
constipation E
diarrhea (1-13%) E
dysphagia E
esophagitis E
mucositis E
nausea and vomiting (31-43%) E
parotitis E
stomatitis (1-6%) E
taste alteration E
hepatic hepatotoxicity (0-3%) in higher than recommended doses E
metabolic/laboratory metabolic acidosis in higher than recommended doses E
musculoskeletal muscle cramps E
weakness E
neurology transient mental confusion I
peripheral neuropathy (1-2%) E
seizure I
transient vertigo I
ocular/visual transient cortical blindness E
optic neuritis E
pain abdominal pain (0-2%) E
headache I
pulmonary interstitial pneumonitis E
ORGAN SITE SIDE EFFECT ONSET
Clinically important side effects are in bold, italics I = immediate (onset in hours to days); E = early (days to weeks) D = delayed (weeks to months); L = late (months to years)
pulmonary fibrosis E
secondary malignancy acute leukemia (onset 2-3 years) reported 1 L
syndromes Stevens-Johnson syndrome D

Adapted from standard references2,7 unless specified otherwise. Allergic reactions are rare but can be life threatening.14 Usually include chest discomfort, dyspnoea, bronchospasm, hypotension and/or skin flushing. In most patients the reactions occur within 5-10 minutes of the infusions with complete recovery once the infusion is discontinued. There are reports of reactions occurring several hours after administration. Reactions are very rare with oral capsules.2 Treatment should be symptomatic and can include pressor agents, corticosteroids, antihistamines, or volume expanders.2 The subsequent management of patients experiencing a hypersensitivity reaction is usually to omit etoposide from the chemotherapy regimen.10 Higher rates of anaphylactoid reactions are reported in children receiving etoposide infusions at higher than recommended concentrations.7

Congestive heart failure and myocardial infarction 7

occurred in patients receiving etoposide by continuous IV infusion over 5 days. Some of these patients had pre-existing cardiovascular disease, and these cardiovascular side effects were attributed to the large volumes of NS used as the diluent for administration of the drug.

Hypotension can occur following rapid IV administration.2 Etoposide should be administered over at least 30 minutes (usually 30-60 minutes).2 Longer infusion times may be required based on patient tolerance. Hypotension usually responds to stopping the infusion, and administration of IV fluids or other supportive therapy as needed. When restarting the infusion a slower rate should be used. Geriatric patients may be more susceptible to etoposide- induced hypotension.7 Delayed hypotension has occurred following slow IV infusion at higher than recommended doses.

Gastrointestinal 7

side effects occur at a slightly higher incidence with oral administration compared to IV administration.

Acute reactions 2

to products containing polysorbate 80 have been reported. In premature infants, a life threatening syndrome of liver and renal failure, pulmonary deterioration, thrombocytopenia and ascites has been associated with injectable vitamin E product containing polysorbate 80.

Excipient related side effects have been hypothesized12;

y

Polysorbate 80 may be responsible for the immediate side effects including hypotension and hypertension, tachycardia, dyspnoea, bronchospasm, flushing and exanthema.

y

Ethanol, benzyl alcohol, polysorbate 80 and polyethylene glycol may be responsible for the cardiovascular, neurological and/or respiratory side effects.

y

Dextrans are often associated with allergic reactions.

INTERACTIONS:

AGENT EFFECT MECHANISM MANAGEMENT
aprepitant 15 elevated etoposide plasma levels inhibition of cytochrome P450-mediated metabolism of etoposide by aprepitant closely monitor for etoposide toxicities
AGENT EFFECT MECHANISM MANAGEMENT
atovaquone 16 possible increase in plasma level of etoposide unknown closely monitor for etoposide toxicities
cisplatin 2 synergistic antineoplastic activity against testicular, small cell lung and, non- small cell lung cancers possible impaired elimination of etoposide in patients previously treated with cisplatin some protocols are designed to take advantage of this effect; monitor toxicity closely
high dose cyclosporine with oral etoposide 16 increase in plasma level in etoposide decrease in clearance of etoposide etoposide dose should be reduced by 50% with concurrent use of high- dose cyclosporine infusion 15
glucosamine 17 may cause resistance to topoisomerase-II inhibitors induction of the glucose- regulated stress response avoid use of glucosamine during cancer chemotherapy treatments
grapefruit juice 16 may increase plasma level of etoposide po possible alteration of intestinal P-glycoprotein mediated transport avoid grapefruit juice for 48 hours before and on day of dose
St John's Wort 15 reduced effectiveness of etoposide induction of CYP3A4 which metabolizes etoposide avoid concomitant use of St John's Wort with etoposide
warfarin 16 suspected increased anticoagulant effect of warfarin may decrease warfarin metabolism monitor INR or PT closely

Adapted from standard references2,7 unless specified otherwise.

SUPPLY AND STORAGE:

Capsules: Bristol provides the capsules.18 The capsules are liquid-filled soft gelatin pink 50 mg capsules in a vehicle containing citric acid, glycerol, polyethylene glycol 400 and water.2 Capsules stored at room temperature. Injection: Bristol provides etoposide injection as multi-dose vials (100 mg/5mL, 500 mg/25 mL and 1g/50mL) at a concentration of 20 mg/mL; also contains alcohol, benzyl alcohol, citric acid, polyethylene glycol 300 and polysorbate 80.2 Vials stored at room temperature. Once punctured the vials are stable for 14 days.2,19 Mayne Pharma provides the etoposide injection as multi-dose vials (100 mg/5mL, 500 mg/25 mL and 1 g/50mL) at a concentration of 20 mg/mL; also contains benzyl alcohol, citric acid, dehydrated alcohol, polyethylene glycol, polysorbate 80.18 Vials stored at room temperature. Protect from light. Novopharm provides the etoposide injection as preservative-free multi-dose vials (100 mg/5mL, 200 mg/mL, 500 mg/25mL and 1 g/50mL) at a concentration of 20 mg/mL; also contains citric acid, ethyl alcohol, polyethylene glycol and polysorbate 80.18 Vials stored at room temperature. Protect from light. ETOPOPHOS(r) [etoposide phosphate] is available through the Health Canada Special Access Program [SAP].20 It is supplied as a 100 mg single dose vial.3 Etoposide phosphate is water soluble and does not contain excipients.

SOLUTION PREPARATION AND COMPATIBILITY:

For basic information on solution preparation and compatibility, see Chemotherapy Chart in Appendix.

Cracking and leaking of plastic containers made of acrylic or ABS (a polymer made of acrylonitrile, butadiene and styrene) have been reported when used with undiluted etoposide injection.2 The reports include BURRON(r) chemo- dispensing pin, plastic port on a disposable cassette for the OMNI-FLOW 4000(r) pump (acrylic plastic), connector on a minimal volumn extension set (ABS/acrylic plastic) and rigid plastics in general (e.g. ABS, acrylics, polycarbonates, etc. ).21 Stability data regarding storage information of undiluted VEPESID(r) at room temperature, in plastic syringes, under normal room fluorescent lighting21:

Baseline 3 days 5 days
Concentration of VEPESID(r) 19.8 mg/mL 19.9 mg/mL 20.1 mg/mL

Diluted solution for infusion:

Etoposide injection is lipid soluble and contains various excipients including the surfactant polysorbate 80. Polysorbate 80 leaches the plasticizer diethylhexyl phthalate [DEHP] from polyvinyl chloride [PVC]22 containers and tubing into etoposide IV solution.23,24 The amount of DEHP leached from PVC containers and tubing is dependent on surfactant concentration, bag size and contact time.25 Actual hazardous exposure levels to this substance are not known,26,27 however DEHP is hepatotoxic and exposure should be minimized.23 The standard practice at the BC Cancer Agency (1 October 2005) and many other hospitals is to prepare etoposide IV infusions in nonPVC containers28-33 and administer using nonPVC tubing.34 Bristol-Myers Squibb Canada states that the use of non-PVC containers and tubing remains an individual choice at this time.21 Dilute in NS or D5W at concentrations of 0.2 mg/mL to 0.4 mg/mL.1 0.2 mg/mL solutions are stable for 96 h RT, and 0.4 mg/mL solutions are stable for 24 h RT.2 At concentrations above 0.4 mg/mL precipitation may occur rapidly.2 When etoposide is diluted to 0.4 mg/mL or greater the use of peristaltic pumps should be avoided as they can exacerbate precipitation.25 Volumetric pumps are recommended. Etoposide is most stable at pH of about 3.5 to 6. Filtration of etoposide solutions of 0.1-0.4 mg/mL in D5W or NS have been filtered through several commercially available filters (such as the 0.22 um Millex-GS or Millex) without filter decomposition.25 ETOPOPHOS(r) [etoposide phosphate] is available through the Health Canada SAP.20 Etoposide phosphate is water soluble and does not contain excipients. Leaching of the plasticizer diethylhexyl phthalate [DEHP] from polyvinyl chloride [PVC] infusion bags does not occur with etoposide phosphate. The contents of each vial are reconstituted with either 5 mL or 10 mL SWI, D5W, NS, BWI or BNS to a concentration to 20 mg/mL or 10 mg/mL.3 Following reconstitution, the solution may be administered without further dilution or it can be further diluted to concentrations as low as 0.1 mg/mL etoposide with either D5W or NS. The infusion may be administered over 5 minutes without signs of hypotension or acute effects.35

Concentration [equivalent mg etoposide phosphate/mL] Diluent Refrigerated [5o C] Room Temp * 30 o C 37 o C
20 SWFI, D5W, NS 72 h 1 d 1 d 1 d
20 BWFL, BNS 10 d 4 d 2 d 2 d
10 SWFI, D5W, NS 72 h 1 d 1 d 1 d
10 BWFI, BNS 10 d 4 d 2 d 2 d
0.1, 0.2, 0.4 D5W, NS 72 h 1 d 1 d 1 d

SWFI = Sterile Water for Injection, USP D5W = 5% Dextrose Injection, USP NS = 0.9% Sodium Chloride Injection, USP BWFI = Bacteriostatic Water for Injection with benzyl alcohol BNS = Bacteriostatic Sodium Chloride for Injection with benzyl alcohol * Room Temp = Ambient room temperature [approximately 25 o C] and normal lighting conditions.

Compatibility25:

The following are compatible via Y-site injection: allopurinol, amifostine, aztreonam, cladribine, doxorubicin liposome, fludarabine, gemcitabine, granisetron, melphalan, methotrexate, mitoxantrone, ondansetron, paclitaxel, piperacillin, sargramostim, sodium bicarbonate, teniposide, thiotepa, topotecan, vinorelbine.

The following are compatible with etoposide in the same infusion bag in certain concentrations and diluents: carboplatin; cisplatin; cisplatin and cyclophosphamide; cisplatin, mannitol and KCL; cytarabine; cytarabine and daunorubicin; doxorubicin and vincristine; fluorouracil; hydroxyzine; ifosfamide; ifosfamide and carboplatin; ifosfamide and cisplatin; mitoxantrone; ondansetron.

Incompatibility25:

The following are incompatible via Y-site injection: cefepime, filgrastim and idarubicin.

The following are incompatible in the same infusion solution at the stated concentrations: cisplatin 200 mg, mannitol 1.875% and KCL 20 mEq with etoposide 400 mg in 1 L NS; doxorubicin 100 mg and vincristine 4 mg with etoposide 500 mg in 1 L NS.

PARENTERAL ADMINISTRATION

:

BCCA administration guideline noted in bold , italics
Subcutaneous no information found
Intramuscular no information found
Direct intravenous not to be administered by direct IV route 7
Intermittent infusion dilution of 0.2 mg/mL to 0.4 mg/mL 1 by slow IV infusion (usually over 30-60 minutes) 2
Continuous infusion dilution of 0.2 mg/mL to 0.4 mg/mL 1 over 24 36 , 26 37 or 34 h 38-40 has been administered by continuous infusion over 5 days 7
Intraperitoneal has been used 6 , not recommended 7
Intrapleural has been used 6 , not recommended 7
Intrathecal no information found
Intra-arterial no information found
Intravesical no information found

DOSAGE GUIDELINES:

Refer to protocol by which patient is being treated. Numerous dosing schedules exist and depend on disease, response and concomitant therapy. Guidelines for dosing also include consideration of absolute neutrophil count. Dosage may be reduced, delayed or discontinued in patients with bone marrow depression due to cytotoxic/radiation therapy or with other toxicities.

Adults :
BCCA usual dose noted in bold, italics
Cycle Length:
Oral: 2-3 weeks: 50 mg - 100 mg PO once daily for 3-10 days (total dose per cycle 150 mg-1000 mg/m 2 ) Round dose to the nearest 50 mg. Administer on an empty stomach as stated in the package insert 2 May also be taken with food if needed. 5,7,41 Daily doses greater than 200 mg should be given in divided doses (BID). 2 VEPESID(r) for injection can be administered orally to patients unable to swallow the capsules; the capsules should not be punctured and the liquid inside removed for these patients. 21 The etoposide injection can be diluted with Sodium Chloride 0.9% injection to a concentration of 10 mg/mL. 42 Chemical stability information applies to oral etoposide solution diluted with bacteriostatic NS, 42-45 though preservative-free NS has also been used. 46-48
Adults : BCCA usual dose noted in bold, italics
Cycle
Length:
Store the prepared solution in oral syringes or in an amber
glass bottle. Solution stable for 22 days at room temperature. 42 Shake well before use. Can be further diluted
immediately prior to administration in apple juice, orange juice or lemonade ( not grapefruit juice ). 21 Concentration should
be < 0.4 mg/mL to enhance the taste. For example: Dilute 50
mg (5 mL) oral solution to at least 125 mL fruit juice. More
concentrated solutions in fruit juice may result in precipitation in less than 3 hours. 49
Some hospital pharmacies dispense the etoposide injection undiluted, either in the original vial 50 or in pre-drawn syringes. 48
There is no significant difference in bioavailability between taking the capsule and drinking the injection. 21
Some protocols combine IV and
oral etoposide: 2 weeks: 80 mg/m 2 IV daily on day 1 (total IV dose per cycle 80 mg/
m 2 )
with 160 mg/m 2 PO daily on day 2
3-4 weeks 100 mg/m 2 IV daily on day 1
4 weeks: with 100 mg mg/m 2 PO daily on day 3 and day 5 (total PO dose per cycle 200mg/ m 2 ) 60 mg/m 2 IV for one dose on days 1 to 3 (total IV dose per cycle 180 mg/m 2 )
with 50 mg PO days 4 to 10 (total PO dose per cycle 350 mg/m 2 )
4 weeks: 50 mg/m 2 IV for one dose on day 8
with 100 mg/ m 2 PO daily on day 9-12
Intravenous: 3 weeks: 100 mg/m 2 IV once daily for 2 consecutive days starting
3-6 weeks: on day 1 75-100 mg/m 2 IV for one dose on days 1 to 5 (total dose per cycle 375-500 mg/m 2 )
3 weeks: 75 mg/m 2 IV for one dose on days 21 and day 22
3-4 weeks: 50 mg/ m 2 IV for one dose daily on days 3-5 (total dose per cycle 150mg/ m 2 )
4 weeks: 100 mg/m 2 IV for one dose on day 1
3-7 weeks: 100 mg/m 2 IV for one dose on days 1 to 3
High dose protocols with or without bone marrow transplant: 1800-2400 mg/m 2 IV continuous infusion over 24-34 h (total dose per cycle 1800-2400 mg/m 2 ) 37-40,51,52
Concurrent radiation 3 weeks 100 mg/m2 IV on day 1
with 100 mg/m2/day PO on day 3 and 5 53,54

Adults: Cycle Length: BCCA usual dose noted in bold, italics 3 weeks 100 mg/m2/day x 3 days55,56

Dosage in myelosuppression:

modify according to protocol by which patient is being treated; if no guidelines

available, refer to Appendix 6 "Dosage Modification for Myelosuppression"

Dosage in renal failure35,57:

Measured creatinine clearance (mL/min) Dose
>50 100 %
10-50 75 %
<10 50 %

Suggested dose modification

Dosage in hepatic failure35,58:

Serum bilirubin (umol/L) Dose
< 25 100 %
25 to 50 50 %
50 to 85 25 %
> 85 Do not administer

Suggested dose modification Minor alterations in liver function, such as transaminase elevations, do not require dose reductions if renal function is normal.

Dosage in dialysis 7

not appreciably dialyzable

Children59:

Cycle Length:

Oral:

4 weeks 50 mg daily for 21 days

Intravenous: 3-6 weeks 60-120 mg/m2 daily for 3-5 days

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