Etoposide

VePesid (etoposide) has been shown to cause metaphase arrest in chick fibroblasts. Its main effect, however, appears to be at the G2 portion of the cell cycle in mammalian cells. Two different dose-dependent responses are seen. At high concentrations (10 µg/mL or more), lysis of cells entering mitosis is observed. At low concentrations (0.3-10 µg/mL), cells are inhibited from entering prophase. It does not interfere with microtubular assembly. The predominant macromolecular effect of etoposide appears to be the induction of DNA strand breaks by an interaction with DNA topoisomerase II or the formation of free radicals.

Pharmacokinetics

On intravenous administration, the disposition of etoposide is best described as a biphasic process with a distribution half-life of about 1.5 hours and terminal elimination half-life ranging from 4 to 11 hours. Total body clearance values range from 33 to 48 mL/min or 16 to 36 mL/min/m2 and, like the terminal elimination half-life, are independent of dose over a range of 100 to 600 mg/m2. Over the same dose range, the areas under the plasma concentration versus time curves (AUC) and the maximum plasma concentration (Cmax) values increase linearly with dose. Etoposide does not accumulate in the plasma following daily administration of 100 mg/m2 for 4 to 5 days.

The mean volumes of distribution at steady state fall in the range of 18 to 29 liters or 7 to 17 L/m2. Etoposide enters the CSF (cerebrospinal fluid) poorly. Although it is detectable in CSF and intracerebral tumors, the concentrations are lower than in extracerebral tumors and in plasma. Etoposide concentrations are higher in normal lung than in lung metastases and are similar in primary tumors and normal tissues of the myometrium. In vitro, etoposide is highly protein bound (97%) to human plasma proteins. An inverse relationship between plasma albumin levels and etoposide renal clearance is found in children. In a study determining the effect of other therapeutic agents on the in vitro binding of 14C-etoposide to human serum proteins, only phenylbutazone, sodium salicylate, and aspirin displaced protein-bound etoposide at concentrations achieved in vivo.

Etoposide binding ratio correlates directly with serum albumin in patients with cancer and in normal volunteers. The unbound fraction of etoposide significantly correlated with bilirubin in a population of cancer patients. Data have suggested a significant inverse correlation between serum albumin concentration and free fraction of etoposide (see PRECAUTIONS).

After intravenous administration of 14C-etoposide (100-124 mg/m2), mean recovery of radioactivity in the urine was 56% of the dose at 120 hours, 45% of which was excreted as etoposide; fecal recovery of radioactivity was 44% of the dose at 120 hours.

In children, approximately 55% of the dose is excreted in the urine as etoposide in 24 hours. The mean renal clearance of etoposide is 7 to 10 mL/min/m2 or about 35% of the total body clearance over a dose range of 80 to 600 mg/m2. Etoposide, therefore, is cleared by both renal and nonrenal processes, i.e., metabolism and biliary excretion. The effect of renal disease on plasma etoposide clearance is not known.

Biliary excretion of unchanged drug and/or metabolites is an important route of etoposide elimination as fecal recovery of radioactivity is 44% of the intravenous dose. The hydroxy acid metabolite [4'-demethylepipodophyllic acid-9-(4,6-O-(R)-ethylidene-β-D-glucopyranoside)], formed by opening of the lactone ring, is found in the urine of adults and children. It is also present in human plasma, presumably as the trans isomer. Glucuronide and/or sulfate conjugates of etoposide are also excreted in human urine. Only 8% or less of an intravenous dose is excreted in the urine as radiolabeled metabolites of 14C-etoposide. In addition, O-demethylation of the dimethoxyphenol ring occurs through the CYP450 3A4 isoenzyme pathway to produce the corresponding catechol.

After either intravenous infusion or oral capsule administration, the Cmax and AUC values exhibit marked intra- and inter-subject variability. This results in variability in the estimates of the absolute oral bioavailability of etoposide oral capsules.

Cmax and AUC values for orally administered etoposide capsules consistently fall in the same range as the Cmax and AUC values for an intravenous dose of one-half the size of the oral dose. The overall mean value of oral capsule bioavailability is approximately 50% (range, 25-75%). The bioavailability of etoposide capsules appears to be linear up to a dose of at least 250 mg/m2.

There is no evidence of a first-pass effect for etoposide. For example, no correlation exists between the absolute oral bioavailability of etoposide capsules and nonrenal clearance. No evidence exists for any other differences in etoposide metabolism and excretion after administration of oral capsules as compared to intravenous infusion.

In adults, the total body clearance of etoposide is correlated with creatinine clearance, serum albumin concentration, and nonrenal clearance. Patients with impaired renal function receiving etoposide have exhibited reduced total body clearance, increased AUC and a lower volume of distribution at steady state (see PRECAUTIONS). Use of cisplatin therapy is associated with reduced total body clearance. In children, elevated serum SGPT levels are associated with reduced drug total body clearance. Prior use of cisplatin may also result in a decrease of etoposide total body clearance in children.

Although some minor differences in pharmacokinetic parameters between age and gender have been observed, these differences were not considered clinically significant.

Usual Adult Dose for Testicular Cancer:

IV:
In combination with other approved chemotherapeutic agents:
50 to 100 mg/m2 IV once a day on days 1 through 5 to 100 mg/m2 IV once a day on days 1,3, and 5

Comments:
-The dosage should be modified to take into account the myelosuppressive effects of other drugs in the combination or the effects of prior x-ray therapy or chemotherapy which may have compromised bone marrow reserve.

Use: In combination therapy with other approved chemotherapeutic agents in patients with refractory testicular tumors who have already received appropriate surgical, chemotherapeutic, and radiotherapeutic therapy

Usual Adult Dose for Small Cell Lung Cancer:

-IV:
In combination with other approved chemotherapeutic agents:
35 mg/m2 IV once a day for 4 days to 50 mg/m2 IV once a day for 5 days
-Oral:
In combination with other approved chemotherapeutic agents:
The recommended dose is two times the IV dose rounded to the nearest 50 mg (i.e., two times 35 mg/m2 IV once a day for 4 days to 50 mg/m2 IV once a day for 5 days equaling 70 mg/m2 orally once a day for 4 days to 100 mg/m2 orally once a day for 5 days)

Comments:
-The dosage should be modified to take into account the myelosuppressive effects of other drugs in the combination or the effects of prior x-ray therapy or chemotherapy which may have compromised bone marrow reserve.

Use: In combination with other approved chemotherapeutic agents as first line treatment in patients with small cell lung cancer.

Specific Drugs

Absorption

Bioavailability

Oral capsules: about 50% (range: 25–75%).17 18 19 160 161 189 190 191 192 193 194 195 196 197

Distribution

Extent

Not fully characterized.18 21 24 27 28 Following IV administration, distributed minimally into pleural fluid21 27 and has been detected in the saliva,197 liver,173 spleen,173 kidney,173 myometrium,189 197 healthy brain tissue,27 and brain tumor tissue.27 175

Does not readily penetrate the CNS;1 18 21 22 27 29 30 197 variable CSF concentrations generally ranging from undetectable18 22 to <5% of concurrent plasma concentrations21 29 30 162

Apparently crosses the placenta in animals,1 2 not known whether distributed into milk.1

Plasma Protein Binding

Approximately 97% at 10 mcg/mL in vitro.c f

Elimination

Metabolism

Metabolized principally to inactive hydroxy acid21 25 26 30 32 33 177 (probably the trans-hydroxy acid).33

Elimination Route

Following IV infusion, excreted principally (40–60%) in urine as unchanged drug (20–30% within 24 hours,18 29 30 30–45% within 48 hours)20 161 and metabolites in 48–72 hours.18 20 21 26 27 29 30 32 2–16% is excreted in feces within 72 hours;29 30 .28 173 174 197

Following oral administration, about 5–25% of the dose is excreted in urine within 24–48 hours.191 194 195 196 197

Half-life

Biphasic,18 21 22 24 25 27 29 30 31 176 197 may exhibit triphasic elimination with a prolonged terminal phase.19 197

In adults, 0.6–2 hours (range: 0.2–2.5 hours) in the initial phase and 5.3–10.8 hours (range: 2.9–19 hours) in the terminal phase.18 20 21 24 29 161 189 191 192

In children, 0.6–1.4 hours in the initial phase and 3–5.8 hours in the terminal phase.18 22 25 31

Special Populations

The effects of renal impairment on elimination have not been fully evaluated,20 21 28 163 176 197 but a substantial fraction of the drug is excreted unchanged in urine;18 20 21 29 30 161 176 256 consider dosage reductions.b (See Renal Impairment under Dosage and Administration.)

Storage

Oral

2–8°C.189 Do not freeze.c Stable for 2 years refrigerated at 2–8°C.189

Parenteral

Room temperature (25°C).1 Stable for 2 years unopened at room temperature.1

Following dilution to concentrations of 0.2 or 0.4 mg/mL, stable for 96 or 24 hours, respectively, at 25°C under normal room fluorescent light in glass or plastic containers.c

2–8°C; store in unopened vials in original package to protect from light;256 296 stable at least 36 months.296

Following reconstitution, 10 or 20 mg/mL solutions of etoposide phosphate in sterile water for injection, 5% dextrose injection, or 0.9% sodium chloride injection, bacteriostatic water for injection (with benzyl alcohol) or bacteriostatic sodium chloride for injection (with benzyl alcohol) are stable for 7 days at 2–8°C in glass or plastic containers.d

10 or 20 mg/mL solutions of etoposide phosphate in sterile water for injection, 5% dextrose injection, or 0.9% sodium chloride injection are stable for 24 hours at 20–25°C.d

10 or 20 mg/mL solutions of etoposide phosphate in bacteriostatic water for injection (with benzyl alcohol) or bacteriostatic sodium chloride for injection (with benzyl alcohol) are stable for 48 hours at 20–25°C.d

Etoposide phosphate solutions further diluted in 5% dextrose injection or 0.9% sodium chloride injection are stable for 24 hours at 2–8°C or 20–25°C.d

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Crystallization in aqueous solutions appears to be concentration dependent and may occur following dilution because etoposide is sparingly soluble in water;1 2 5 discard if crystallization occurs.5

Solutions of etoposide prepared at concentrations >0.4 mg/mL may precipitate; 189 concentration >0.4 mg/mL not recommended.1 2 189 c

1 mg/mL solutions in 5% dextrose injection or 0.9% sodium chloride have crystallized etoposide within 5 minutes upon stirring or within 30 minutes upon allowing the solution to stand;5 1 mg/mL solutions not recommended.5

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Etoposide (also commonly known as VP-16) is a semisynthetic derivative of podophyllotoxin used in the treatment of certain neoplastic diseases.  It is 4’-demethylepipodophyllotoxin 9-[4,6-O-(R)-ethylidene-β-D-glucopyranoside].  It is very soluble in methanol and chloroform, slightly soluble in ethanol, and sparingly soluble in water and ether.  It is made more miscible with water by means of organic solvents.

            Etoposide Injection, USP is available for intravenous use as a 20 mg/mL solution in 100 mg (5 mL), 500 mg (25 mL), or 1 gram (50 mL) sterile, multiple dose vials.  The pH of the clear, nearly colorless to yellow liquid is 3 to 4.  Each mL contains 20 mg Etoposide, 2 mg citric acid, 30 mg benzyl alcohol, 80 mg polysorbate 80/tween 80, 650 mg polyethylene glycol 300, and 30.5 percent (v/v) alcohol.  Vial headspace contains nitrogen.  The structural formula is:

C29H32O13                                                                                        M.W. 588.56

Etoposide Injection, USP is contraindicated in patients who have demonstrated a previous hypersensitivity to Etoposide or any component of the formulation.

1.   ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommendations for Practice Pittsburgh,  PA: Oncology Nursing Society; 1999:32-41.

2.   Recommendations for the safe handling of parenteral antineoplastic drugs.  Washington, DC: Division of Safety, National Institutes of Health; 1983.  US Dept of Health and Human Services, Public Health Service publication NIH 83-2621.

3.   AMA Council on Scientific Affairs. Guidelines for handling parenteral antineoplastics.   JAMA. 1985;253:1590-1591.

4.   National Study Commission on Cytotoxic Exposure.  Recommendations for handling cytotoxic agents.  1987.  Available from Louis P. Jeffrey, Chairman, National Study Commission on Cytotoxic Exposure.  Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, MA 02115.

5.   Clinical Oncological Society of Australia.  Guidelines and recommendations for safe handling of antineoplastic agents.  Med J Australia. 1983;1:426-428.

6.   Jones RB, Frank R, Mass T.  Safe handling of chemotherapeutic agents: a report from the Mount Sinai Medical Center.  CA-A Cancer J for Clin. 1983;33:258-263.

7.   American Society of Hospital Pharmacists.  ASHP technical assistance bulletin on handling cytotoxic and hazardous drugs.  Am J Hosp Pharm. 1990;47:1033-1049.

8.   Controlling Occupational Exposure to Hazardous Drugs.  (OSHA Work-Practice Guidelines.).  Am J Health-SystPharm. 1996;53:1669-1685.

Lake Zurich, IL 60047

www.fresenius-kabi.us

45636F

Revised: February 2016

PACKAGE LABEL - PRINCIPAL DISPLAY - Etoposide 5 mL Multiple Dose Vial Label

Etoposide
Injection, USP

100 mg per 5 mL
(20 mg per mL)

MUST BE DILUTED BEFORE INTRAVENOUS INFUSION.

5 mL
Multiple Dose Vial Rx only

PACKAGE LABEL - PRINCIPAL DISPLAY - Etoposide 5 mL Multiple Dose Vial Carton Panel

Etoposide
 Injection, USP

100 mg per 5 mL
(20 mg per mL)

MUST BE DILUTED BEFORE INTRAVENOUS INFUSION.

Rx only
5 mL
Multiple Dose Vial

PACKAGE LABEL - PRINCIPAL DISPLAY - Etoposide 5 mL Multiple Dose Vial Shelf Carton Panel

Etoposide
 Injection, USP

100 mg per 5 mL
(20 mg per 5 mL)
MUST BE DILUTED BEFORE INTRAVENOUS INFUSION.

Rx only
10 X 5 mL
Multiple Dose Vials

Acute myeloid leukemia (AML) induction (Children)

Data from a prospective randomized trial in children with acute myeloid leukemia (AML) supports the use as induction therapy of etoposide in the treatment of this condition. Induction success and median days to complete induction were similar in both groups; however, patients randomized to the intensive timing arm (administration of second cycle 10 days after the first cycle) a marked improvement in outcome was seen [Woods 1996]. Additional trials may be necessary to further define the role of etoposide for the treatment of children with AML.

Central nervous system tumors

Data from a prospective randomized trial in children (aged 3 to 16 years) with medulloblastoma who received etoposide (in combination with vincristine and carboplatin) prior to radiotherapy supports the use of etoposide for the treatment of this condition [Taylor 2003]. Furthermore, data from a nonrandomized prospective trial in children (<36 months of age) with malignant brain tumors who received etoposide (in combination with cisplatin ["B" treatment cycle]) also supports the use of etoposide for the treatment of this condition [Duffner 1993]. Data from an earlier prospective phase II trial in children (aged 3 to 16 years) with newly diagnosed high-risk medulloblastoma and other malignant embryonal tumors of the CNS who received etoposide (in combination with cisplatin) also supports the use of etoposide for this condition [Kovnar 1990]. Additional trials may be necessary to further define the role of etoposide for the treatment of patients with CNS tumors.

Hematopoietic stem cell transplant conditioning regimen (Children)

Data from two prospective studies in patients, including children and adolescents, with recurrent or refractory Hodgkin's disease, non-Hodgkin's lymphoma, or acute leukemia treated with high dose etoposide supports the use of etoposide as a conditioning regimen in children [Horning 1994], [Snyder 1993]. Additional trials may be necessary to further define the role of etoposide in this setting.

Hematopoietic stem cell transplant conditioning regimen, lymphoid malignancies

Data from three prospective studies in patients with recurrent or refractory Hodgkin's disease, non-Hodgkin's lymphoma, or acute leukemia treated with high dose etoposide supports the use of etoposide as a conditioning regimen [Horning 1994], [Snyder 1993], [Weaver 1994]. Additional trials may be necessary to further define the role of etoposide in this setting.

Hodgkin lymphoma (Children)

Data from a prospective study in patients (<21 years of age at diagnosis) with Hodgkin lymphoma treated with etoposide (in combination with bleomycin, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) supports the use of etoposide for the treatment of this condition [Kelly 2002]. Additional trials may be necessary to further define the role of etoposide for the treatment of Hodgkin lymphoma in children.

Neuroblastoma (Children)

Data from a study in children (>1 year of age) with stage 4 neuroblastoma and MYCN amplification treated with etoposide supports the use of etoposide in the treatment of children with this condition [Kaneko 2002]. Additional trials may be necessary to further define the role of etoposide for the treatment of neuroblastoma in children.

Non-small cell lung cancer

Data from a randomized study in patients with non-small cell lung cancer treated with etoposide (in combination with cisplatin) supports the use of etoposide for the treatment of this condition [Arriagada 2004]. Additional data from a phase III trial in patients with stage IIIA non-small cell lung cancer with ipsilateral mediastinal nodal metastases also supports the use of etoposide (in combination with cisplatin and radiation therapy) for the treatment of this condition [Albain 2009]. Additional trials may be necessary to further define the role of etoposide for the treatment of patients with non-small cell lung cancer.

Based on American Society of Clinical Oncology Guidelines for Systemic Therapy for Stage IV Non-Small-Cell Lung Cancer, etoposide (in combination with platinum therapy) may be considered for stage IV non-small cell lung cancer patients with large-cell neuroendocrine carcinoma.

Ovarian cancer, refractory

Data from a phase II trial in patients with refractory ovarian cancer treated with oral etoposide supports the use of oral etoposide for the treatment of this condition [Rose 1998]. Additional trials may be necessary to further define the role of etoposide for the treatment of patients with ovarian cancer.

Sarcoma, refractory (Children)

Data from a study evaluating children with recurrent or refractory sarcoma treated with etoposide (in combination with ifosfamide and carboplatin) who were enrolled in one of three Children's Cancer Group (CCG) phase I/II trials supports the use of etoposide for the treatment of this condition [Van Winkle 2005]. Additional trials may be necessary to further define the role of etoposide for the treatment of children with refractory sarcoma.

Thymoma, locally advanced or metastatic

Data from prospective study in patients with recurrent or metastatic malignant thymoma treated with etoposide (in combination with cisplatin) supports the use of etoposide for the treatment of this condition [Giaccone 1996] . Additional trials may be necessary to further define the role of etoposide for the treatment of patients with locally advanced or metastatic thymoma.

Unknown primary adenocarcinoma

Data from a phase II trial in patients with metastatic carcinoma of unknown primary site treated with oral etoposide (in combination with paclitaxel and carboplatin) supports the use of oral etoposide for the treatment of this condition [Greco 2000]. Additional data from a multicenter, phase II study in patients with metastatic poorly differentiated neuroendocrine carcinoma (62% had unknown primary site) who had received no prior treatment demonstrated that etoposide (in combination with paclitaxel and carboplatin) also supports the use of etoposide in this condition [Hainsworth 2006]. Additional trials may be necessary to further define the role of etoposide for the treatment of patients with unknown primary adenocarcinoma.

Additional Off-Label Uses

Acute lymphocytic leukemia (ALL); Acute myeloid leukemia (AML), refractory; Breast cancer, recurrent or metastatic; Ewing's sarcoma; Gestational trophoblastic disease; Merkel cell cancer; Multiple myeloma, refractory; Neuroendocrine tumors (adrenal gland and carcinoid tumors); Non-Hodgkin lymphomas; Osteosarcoma; Prostate cancer; Retinoblastoma; Soft tissue sarcoma, metastatic; Thymic malignancies (locally advanced or metastatic); Wilms' tumor

American Society of Clinical Oncology (ASCO) Guidelines for appropriate chemotherapy dosing in obese adults with cancer (Note: Excludes HSCT dosing): Utilize patient’s actual body weight (full weight) for calculation of body surface area- or weight-based dosing, particularly when the intent of therapy is curative; manage regimen-related toxicities in the same manner as for nonobese patients; if a dose reduction is utilized due to toxicity, consider resumption of full weight-based dosing with subsequent cycles, especially if cause of toxicity (eg, hepatic or renal impairment) is resolved (Griggs, 2012).

American Society for Blood and Marrow Transplantation (ASBMT) practice guideline committee position statement on chemotherapy dosing in obesity: Utilize actual body weight (full weight) for calculation of body surface area (BSA) for BSA-based dosing and utilize adjusted body weight 25% (ABW25) for mg/kg dosing for hematopoietic stem cell transplant conditioning regimens in adults (Bubalo, 2014).

ABW25: Adjusted wt (kg) = Ideal body weight (kg) + 0.25 [actual wt (kg) - ideal body weight (kg)]

Capsules: Store oral capsules at 2°C to 8°C (36°F to 46°F); do not freeze. Dispense in a light-resistant container.

Injection: Store intact vials of injection at 20°C to 25°C (68°F to 77°F; do not freeze. According to the manufacturer’s labeling, stability for solutions diluted for infusion in D5W or NS (in glass or plastic containers) varies based on concentration; 0.2 mg/mL solutions are stable for 96 hours at room temperature and 0.4 mg/mL solutions are stable for 24 hours at room temperature (precipitation may occur at concentrations above 0.4 mg/mL).

Etoposide injection contains polysorbate 80 which may cause leaching of diethylhexyl phthalate (DEHP), a plasticizer contained in polyvinyl chloride (PVC) bags and tubing. Higher concentrations and longer storage time after preparation in PVC bags may increase DEHP leaching. Preparation in glass or polyolefin containers will minimize patient exposure to DEHP. When undiluted etoposide injection is stored in acrylic or ABS (acrylonitrile, butadiene and styrene) plastic containers, the containers may crack and leak.

The following may occur with higher doses used in stem cell transplantation: Alopecia, ethanol intoxication, hepatitis, hypotension (infusion-related), metabolic acidosis, mucositis, nausea and vomiting (severe), secondary malignancy, skin lesions (resembling Stevens-Johnson syndrome).

>10%:

Dermatologic: Alopecia (8% to 66%)

Gastrointestinal: Nausea and vomiting (31% to 43%), anorexia (10% to 13%), diarrhea (1% to 13%)

Hematologic & oncologic: Leukopenia (60% to 91%; grade 4: 3% to 17%; nadir: 7 to 14 days; recovery: by day 20), thrombocytopenia (22% to 41%; grades 3/4: 1% to 20%; nadir: 9 to 16 days; recovery: by day 20), anemia (≤33%)

1% to 10%:

Cardiovascular: Hypotension (1% to 2%; due to rapid infusion)

Central nervous system: Peripheral neuropathy (1% to 2%)

Gastrointestinal: Stomatitis (1% to 6%), abdominal pain (≤2%)

Hepatic: Hepatotoxicity (≤3%)

Hypersensitivity: Anaphylactoid reaction (intravenous: 1% to 2%; oral capsules: <1%; including bronchospasm, chills, dyspnea, fever, tachycardia)

<1% (Limited to important or life-threatening): Amenorrhea, apnea (hypersensitivity-associated), back pain, constipation, cortical blindness (transient), cough, cyanosis, diaphoresis, drowsiness, dysphagia, erythema, esophagitis, extravasation (induration/necrosis), facial swelling, fatigue, fever, hyperpigmentation, hypersensitivity reaction, interstitial pneumonitis, ischemic heart disease, laryngospasm, maculopapular rash, malaise, metabolic acidosis, mucositis, myocardial infarction, optic neuritis, ovarian failure, pruritic erythematous rash, pruritus, pulmonary fibrosis, radiation-recall phenomenon (dermatitis), reversible posterior leukoencephalopathy syndrome (RPLS), seizure, skin rash, Stevens-Johnson syndrome, tongue edema, toxic epidermal necrolysis, toxic megacolon, urticaria, vasospasm, weakness

Administer etoposide under the supervision of a qualified health care provider who is experienced in the use of cancer chemotherapeutic agents.

Severe myelosuppression, with resulting infection or bleeding, may occur.

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience lack of appetite, mouth sores, or hair loss. Have patient report immediately to prescriber signs of infection, signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), burning or numbness feeling, severe abdominal pain, shortness of breath, severe nausea, vomiting, severe diarrhea, bruising, bleeding, loss of strength and energy, vision changes, severe dizziness, passing out, tachycardia, severe headache, flushing, seizures, severe injection site pain or irritation, or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.