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Clofarabine


General


Pronunciation

(klo FARE a been)


Brand Names: U.S.

  • Clolar

Indications


Use: Labeled Indications

Acute lymphoblastic leukemia: Treatment of relapsed or refractory acute lymphoblastic leukemia (ALL) in patients 1 to 21 years of age (after at least 2 prior regimens)


Contraindications


There are no contraindications listed in the manufacturer 's U.S. labeling.

Canadian labeling: Hypersensitivity to clofarabine or any component of the formulation; symptomatic CNS involvement; history of serious heart, liver, kidney, or pancreas disease; severe hepatic impairment (AST and/or ALT >5 x ULN, and/or bilirubin >3 x ULN); severe renal impairment (CrCl < 30 mL/minute)


Dosing and Administration


Dosing: Adult

Note: Calculate body surface area (BSA) prior to each cycle, utilizing actual body weight.

Premedications: Clofarabine is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting (Basch 2011; Roila 2010). Consider prophylactic corticosteroids (hydrocortisone 100 mg/m2 on days 1 to 3) to prevent signs/symptoms of capillary leak syndrome or systemic inflammatory response syndrome (SIRS), and hydration and antihyperuricemic therapy (to reduce the risk of tumor lysis syndrome/hyperuricemia).

Acute lymphoblastic leukemia (ALL) relapsed or refractory: Adults ≤21 years: IV: 52 mg/m2/day days 1 through 5; repeat every 2 to 6 weeks; subsequent cycles should begin no sooner than 14 days from day 1 of the previous cycle (subsequent cycles may be administered when ANC ≥750/mm3)

Acute lymphoblastic leukemia, relapsed/refractory (ALL; off-label population): IV:

Induction: 40 mg/m2 once daily for 5 days; may repeat induction cycle once in 3 to 6 weeks if needed (depending on marrow response and recovery) (Kantarjian 2003)

Consolidation: 30 mg/m2 once daily for 5 days (or last tolerated induction dose, whichever is lower); repeat every 4 weeks for up to a maximum of 6 consolidation cycles (Kantarjian 2003)

Acute myeloid leukemia (AML), refractory (off-label use): Adults <70 years: IV:

Induction: 25 mg/m2/day for 5 days (in combination with cytarabine and filgrastim) may repeat one time after 21 days if needed (Becker 2011)

Consolidation: 20 mg/m2/day for 5 days (in combination with cytarabine and filgrastim) for 1 or 2 cycles (Becker 2011)


Dosing: Pediatric

Note: Calculate body surface area (BSA) prior to each cycle, utilizing actual body weight.

Premedications: Clofarabine is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting (Dupuis 2011). Consider prophylactic corticosteroids (hydrocortisone 100 mg/m2 on days 1 to 3) to prevent signs/symptoms of capillary leak syndrome or systemic inflammatory response syndrome (SIRS), and hydration and antihyperuricemic therapy (to reduce the risk of tumor lysis syndrome/hyperuricemia).

Acute lymphoblastic leukemia (ALL), relapsed or refractory: Children ≥1 year and Adolescents: IV: 52 mg/m2/day days 1 through 5; repeat every 2 to 6 weeks; subsequent cycles should begin no sooner than 14 days from day 1 of the previous cycle (subsequent cycles may be administered when ANC ≥750/mm3)

Langerhans cell histiocytosis, refractory (off-label use): Children 1 to 18 years: IV: 25 mg/m2/day days 1 through 5; repeat every 28 days for 2 to 8 cycles (Simko 2014). Additional data may be necessary to further define the role of clofarabine in this condition.


Dosing: Renal Impairment

Clofarabine undergoes renal elimination and exposure is increased as creatinine clearance decreases (Bonate 2011).

Renal impairment at baseline:

U.S. labeling:

CrCl 30 to 60 mL/minute: Reduce dose by 50%

CrCl <30 mL/minute: There are no dosage adjustments provided in the manufacturers labeling; use with caution (has not been studied).

Dialysis: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Canadian labeling:

CrCl ≥30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling; use with caution (has not been studied).

CrCl <30 mL/minute: Use is contraindicated.

Renal toxicity during treatment: Grade 3 or higher increase in serum creatinine: Discontinue clofarabine; may reinitiate with a 25% dose reduction after patient is stable and organ function recovers to baseline


Dosing: Hepatic Impairment

Hepatic impairment at baseline:

US labeling: There are no dosage adjustments provided in the manufacturers labeling; use with caution (has not been studied).

Canadian labeling:

Mild or moderate impairment: There are no dosage adjustments provided in the manufacturer's labeling; use with caution (has not been studied)

Severe impairment [AST and/or ALT >5 times the upper limit of normal (ULN) and/or bilirubin >3 x ULN]: Use is contraindicated

Hepatotoxicity during treatment: Grade 3 or higher increase in hepatic enzymes/bilirubin:

US labeling: Discontinue clofarabine; may reinitiate with a 25% dose reduction after patient is stable and organ function recovers to baseline.

Canadian labeling: Discontinue clofarabine


Reconstitution

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]). Clofarabine should be diluted with NS or D5W to a final concentration of 0.15 to 0.4 mg/mL. Manufacturer recommends the product be filtered through a 0.2 micron filter prior to dilution.


Administration

Clofarabine is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting (Basch, 2011; Dupuis, 2011; Roila, 2010).

IV infusion: Infuse over 2 hours for relapsed/refractory ALL. May be infused over 1 hour for some off-label protocols (Becker, 2011; Kantarjian, 2003). Continuous IV fluids are encouraged to decrease adverse events and tumor lysis effects. Hypotension may be a sign of capillary leak syndrome or systemic inflammatory response syndrome (SIRS). Discontinue if the patient becomes hypotensive during administration; may consider therapy reinitiation with a 25% dose reduction after return to baseline. Do not administer any other medications through the same intravenous line.

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).


Storage

Store intact vials at room temperature of 25 ‚ °C (77 ‚ °F); excursions permitted to 15 ‚ °C to 30 ‚ °C (59 ‚ °F to 86 ‚ °F). Solutions diluted for infusion in D5W or NS may be stored for 24 hours at room temperature.


Dosage Forms/Strengths


Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous [preservative free]:

Clolar: 1 mg/mL (20 mL)


Compatibility

Stable in D5W or NS. Do not administer other medications through the same intravenous line.


Drug Interactions

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification

Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Monitor therapy

Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Blood Pressure Lowering Agents: May enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Monitor therapy

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Consider therapy modification

Levodopa: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa. Monitor therapy

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Monitor therapy

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Consider therapy modification

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Avoid combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination


Monitoring Parameters

CBC with differential and platelets (daily during treatment, then 1 to 2 times weekly or as necessary); liver and kidney function (during 5 days of clofarabine administration); coagulation parameters, blood pressure, cardiac function, and respiratory status during infusion; signs and symptoms of tumor lysis syndrome, infection, hepatic sinusoidal obstruction syndrome, enterocolitis, and cytokine release syndrome (tachypnea, tachycardia, hypotension, pulmonary edema); hydration status


Adverse Reactions


>10%:

Cardiovascular: Tachycardia (35%), hypotension (29%; grade 3: 11%; grade 4: 8%), flushing (19%), hypertension (13%), edema (12%)

Central nervous system: Headache (43%), chills (34%), fatigue (34%), anxiety (21%), pain (15%)

Dermatologic: Pruritus (43%), skin rash (38%), palmar-plantar erythrodysesthesia (16%), erythema (11%)

Gastrointestinal: Vomiting (78%; grades 3/4: 9%), nausea (73%; grades 3/4: 15%), diarrhea (56%), abdominal pain (8% to 35%), anorexia (30%), gingival bleeding (17%), mucosal inflammation (16%), oral candidiasis (11%)

Genitourinary: Hematuria (13%)

Hematologic & oncologic: Leukopenia (grades 3/4: 88%), anemia (83%; grades 3/4: 75%), lymphocytopenia (grades 3/4: 82%), thrombocytopenia (81%; grades 3/4: 80%), neutropenia (grades 3/4: 10% to 64%), febrile neutropenia (55%; grades 3/4: 54%), petechia (26%)

Hepatic: Increased serum ALT (81%; grades 3/4: 43% to 44%), increased serum AST (74%; grades 3/4: 36%), increased bilirubin (45%; grades 3/4: 13%)

Infection: Infection (83%; includes bacterial, fungal, and viral), sepsis (including septic shock; 17%),

Local: Catheter infection (12%)

Neuromuscular & skeletal: Limb pain (30%), myalgia (14%)

Renal: Creatinine increased (50%; grades 3/4: 8%)

Respiratory: Epistaxis (27%), dyspnea (13%), pleural effusion (12%)

Miscellaneous: Fever (39%)

1% to 10%:

Cardiovascular: Pericardial effusion (8%), capillary leak syndrome (4%), hepatic veno-occlusive disease (2%)

Central nervous system: Drowsiness (10%), irritability (10%), lethargy (10%), agitation (5%), mental status changes (1% to 4%)

Dermatologic: Cellulitis (8%), pruritic rash (8%)

Gastrointestinal: Rectal pain (8%), pseudomembranous colitis (7%), stomatitis (7%), pancreatitis (1% to 4%), typhlitis (1% to 4%)

Hematologic & oncologic: Tumor lysis syndrome (grade 3: 6%), oral mucosal petechiae (5%)

Hepatic: Jaundice (8%), hyperbilirubinemia (1% to 4%; grade 4: 2%)

Hypersensitivity: Hypersensitivity (1% to 4%)

Infection: Herpes simplex infection (10%), bacteremia (9%), candidiasis (7%), herpes zoster (7%), staphylococcal bacteremia (6%), staphylococcal sepsis (5%), sepsis syndrome (2%)

Neuromuscular & skeletal: Back pain (10%), ostealgia (10%), weakness (10%), arthralgia (9%)

Respiratory: Pneumonia (10%), respiratory distress (10%), tachypnea (9%), upper respiratory tract infection (5%), pulmonary edema (1% to 4%)

<1% (Limited to important or life-threatening): Bone marrow failure, enterocolitis (occurs more frequently within 30 days of treatment and with combination chemotherapy), exfoliative dermatitis, gastrointestinal hemorrhage, hallucination (Jeha 2006), hepatic failure, hepatitis, hepatomegaly (Jeha 2006), hypokalemia (Jeha 2006), hyponatremia, hypophosphatemia, increased right ventricular pressure (Jeha 2006), left ventricular systolic dysfunction (Jeha 2006), major hemorrhage (including cerebral and pulmonary; majority of cases associated with thrombocytopenia), pancytopenia, Stevens-Johnson syndrome, syncope, toxic epidermal necrolysis


Warnings/Precautions


Special Populations: Renal Function Impairment

Clofarabine undergoes renal elimination and exposure is increased as creatinine clearance decreases (Bonate 2011). In patients with CrCl 60 to <90 mL/minute, the AUC was increased by 60% and in patients with CrCl 30 to <60 mL/minute, the AUC was increased by 140%.


Warnings/Precautions

Concerns related to adverse effects:

- Bone marrow suppression: Dose-dependent, reversible myelosuppression (neutropenia, thrombocytopenia, and anemia) is common; may be severe and prolonged. Monitor blood counts and platelets. May be at increased risk for infection due to neutropenia. Monitor for signs and symptoms of infection and treat promptly if infection develops; may require discontinuation.

- Capillary leak syndrome/systemic inflammatory response syndrome (SIRS): Cytokine release syndrome (eg, tachypnea, tachycardia, hypotension, pulmonary edema) may develop into capillary leak syndrome/SIRS, and organ dysfunction; discontinue with signs/symptoms of SIRS or capillary leak syndrome (rapid-onset respiratory distress, hypotension, pleural/pericardial effusion, and multiorgan failure) and consider supportive treatment with diuretics, corticosteroids, and/or albumin. Prophylactic corticosteroids may prevent or diminish the signs/symptoms of cytokine release. May require dosage reduction.

- Dermatologic reactions: Serious and fatal cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported. Discontinue clofarabine for exfoliative or bullous rash, or if SJS or TEN are suspected.

- Gastrointestinal toxicity: Clofarabine is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting (Basch 2011; Dupuis 2011; Roila 2010). Serious and fatal enterocolitis (including neutropenic colitis, cecitis, and C. difficile colitis) has been reported, usually occurring within 30 days of treatment, and when used in combination with other chemotherapy. May lead to complication including necrosis, perforation, hemorrhage or sepsis. Monitor for signs/symptoms of enterocolitis and manage promptly.

- Hemorrhage: Serious and fatal hemorrhages (including cerebral, gastrointestinal, and pulmonary hemorrhage) have occurred, usually associated with thrombocytopenia. Monitor and manage coagulation parameters.

- Hepatotoxicity: Transaminases and bilirubin may be increased during treatment; hepatitis and hepatic failure have been reported. Transaminase elevations generally occur within 10 days of administration and persist for ≤15 days. In some cases, hepatotoxicity was severe and fatal. The risk for hepatotoxicity, including hepatic sinusoidal obstruction syndrome (SOS; formerly called veno-occlusive disease [VOD]), is increased in patients who have previously undergone a hematopoietic stem cell transplant; discontinue if SOS is suspected. Avoid the concomitant use of drugs that may cause hepatotoxicity. Monitor liver function closely; discontinue immediately for grade ≥ 3 elevations in hepatic enzymes and/or bilirubin.

- Hypotension: Monitor blood pressure during 5 days of treatment; discontinue if hypotension develops. Monitor if on concurrent medications known to affect blood pressure.

- Infection: The risk for infections, including opportunistic infection or sepsis (may be severe or fatal), is increased due to prolonged neutropenia and immunocompromised state. Monitor for signs and symptoms of infection and treat promptly if infection develops; may require therapy discontinuation.

- Renal toxicity: Elevated creatinine, acute renal failure, and hematuria were observed in clinical studies. Monitor renal function closely; may require dosage reduction or therapy discontinuation.

- Tumor lysis syndrome/hyperuricemia: Tumor lysis syndrome may occur as a consequence of leukemia treatment, including treatment with clofarabine, usually occurring in the first treatment cycle. May lead to life-threatening acute renal failure; adequate hydration and prophylactic antihyperuricemic therapy throughout treatment will reduce the risk/effects of tumor lysis syndrome; monitor closely.

Disease-related concerns:

- Hepatic impairment: Has not been studied in patients with hepatic impairment; use with caution. Canadian labeling contraindicates use in severe impairment or with history of serious hepatic disease.

- Renal impairment: A pharmacokinetic study demonstrated that systemic exposure increases as creatinine clearance decreases (CrCl <60 mL/minute) (Bonate 2011). Dosage reduction required for moderate renal impairment (CrCl 30 to 60 mL/minute); use with caution in patients with CrCl <30 mL/minute (has not been studied). Minimize the use of drugs known to cause renal toxicity during the 5-day treatment period. Canadian labeling contraindicates use in severe impairment or with history of serious kidney disease.

Concurrent drug therapy issues:

- Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special handling:

- Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).


Pregnancy Risk Factor

D


Pregnancy Considerations

Adverse events were observed in animal reproduction studies. May cause fetal harm if administered to a pregnant woman. Women of childbearing potential should be advised to use effective contraception and avoid becoming pregnant during therapy.


Actions


Pharmacology

Clofarabine, a purine (deoxyadenosine) nucleoside analog, is metabolized to clofarabine 5-triphosphate. Clofarabine 5'-triphosphate decreases cell replication and repair as well as causing cell death. To decrease cell replication and repair, clofarabine 5'-triphosphate competes with deoxyadenosine triphosphate for the enzymes ribonucleotide reductase and DNA polymerase. Cell replication is decreased when clofarabine 5'-triphosphate inhibits ribonucleotide reductase from reacting with deoxyadenosine triphosphate to produce deoxynucleotide triphosphate which is needed for DNA synthesis. Cell replication is also decreased when clofarabine 5'-triphosphate competes with DNA polymerase for incorporation into the DNA chain; when done during the repair process, cell repair is affected. To cause cell death, clofarabine 5'-triphosphate alters the mitochondrial membrane by releasing proteins, an inducing factor and cytochrome C.


Distribution

Vd: Decreased with increasing age, based on pharmacokinetic simulations: 5.8 L/kg (3 years old); 3.1 L/kg (30 years old); 2.7 L/kg (82 years old) (Bonate 2011); Children and Adolescents 2 to 19 years: 172 L/m2


Metabolism

Intracellulary by deoxycytidine kinase and mono- and diphosphokinases to active metabolite clofarabine 5 " ²-triphosphate; limited hepatic metabolism (0.2%)


Excretion

Urine (49% to 60%, as unchanged drug)


Half-Life Elimination

Children and Adolescents 2 to 19 years: 5.2 hours; Children and Adults: 7 hours; may be prolonged in in the elderly and in patients with renal impairment (Bonate, 2011)


Protein Binding

47%, primarily to albumin


Patient and Family Education


Patient Education

- 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 fatigue, flushing, lack of appetite, skin irritation, itching, anxiety, bone pain, muscle pain, joint pain, back pain, painful extremities, or mouth sores. Have patient report immediately to prescriber signs of infection, signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), signs of bowel problems (black, tarry, or bloody stools; fever; mucus in stools; vomiting; vomiting blood; severe abdominal pain; constipation; or diarrhea), signs of kidney problems (urinary retention, blood in urine, change in amount of urine passed, or weight gain), signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any bleeding that is very bad or that will not stop); shortness of breath, fast breathing, angina, tachycardia, severe dizziness, passing out, confusion, severe loss of strength and energy, severe nausea, severe vomiting, severe diarrhea, severe abdominal pain, severe headache, mood changes, pale skin, redness or irritation of palms or soles of feet, signs of tumor lysis syndrome (fast heartbeat or abnormal heartbeat; any passing out; trouble passing urine; muscle weakness or cramps; nausea, vomiting, diarrhea or lack of appetite; or feeling sluggish), 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 healthcare 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.

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