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Carfilzomib

Pronunciation

Pronunciation

(kar FILZ oh mib)

Index Terms

  • CFZ
  • PR-171

Dosage Forms

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

Solution Reconstituted, Intravenous:

Kyprolis: 30 mg (1 ea); 60 mg (1 ea)

Brand Names: U.S.

  • Kyprolis

Pharmacologic Category

  • Antineoplastic Agent, Proteasome Inhibitor

Pharmacology

Carfilzomib inhibits proteasomes, which are responsible for intracellular protein homeostasis. Specifically, it is a potent, selective, and irreversible inhibitor of chymotrypsin-like activity of the 20S proteasome, leading to cell cycle arrest and apoptosis.

Distribution

Vdss: 28 L; penetrates all tissues extensively except the brain (Kortuem 2013)

Metabolism

Rapid and extensive; peptidase cleavage and epoxide hydrolysis; minimal metabolism through cytochrome P450-mediated mechanisms

Excretion

Urine (~25%, primarily as metabolites)

Half-Life Elimination

Doses ≥15 mg/m2: ≤1 hour on day 1 of cycle 1

Protein Binding

97%

Use: Labeled Indications

US labeling:

Multiple myeloma, relapsed/refractory: Treatment (monotherapy) of relapsed or refractory multiple myeloma in patients who have received 1 or more lines of therapy; treatment of relapsed or refractory multiple myeloma (in combination with dexamethasone or lenalidomide plus dexamethasone) in patients who have received 1 to 3 prior lines of therapy

Canadian labeling:

Multiple myeloma, relapsed/refractory: Treatment of relapsed or refractory multiple myeloma (in combination with lenalidomide plus dexamethasone) in patients who have received 1 to 3 prior lines of therapy

Contraindications

There are no contraindications listed in the manufacturer’s US labeling

Canadian labeling: Hypersensitivity to carfilzomib or any component of the formulation

Dosing: Adult

Note: Hydrate with oral fluids (30 mL/kg) at least 48 hours prior to initiating cycle 1, as well as with 250 to 500 mL normal saline (or other appropriate IV fluid) before dosing (recommended) and after (if needed) administration during cycle 1 (continue oral and/or IV hydration in subsequent cycles if necessary); monitor for evidence of volume overload and adjust hydration based on individual needs. Consider antiviral prophylaxis for patients with a history of herpes zoster infection. Thromboprophylaxis is recommended when administering in combination with dexamethasone or lenalidomide plus dexamethasone.

Premedication: When administering as monotherapy, premedicate with dexamethasone 4 mg orally or IV when infusing carfilzomib over 10 minutes or with dexamethasone 8 mg orally or IV when infusing carfilzomib over 30 minutes. When using combination therapy, administer the recommended dexamethasone dose (refer to prescribing information). Premedicate 30 minutes to 4 hours prior to all doses in cycle 1, and as needed with future cycles to reduce the incidence and severity of infusion reaction.

Note: Calculate dose using actual body surface area (BSA) at baseline. Patients with a BSA >2.2 m2 should be dosed based upon a maximum BSA of 2.2 m2. Dose adjustments for weight changes of ≤20% are not necessary, per manufacturer labeling. Continue until disease progression or unacceptable toxicity.

Multiple myeloma, relapsed/refractory (single-agent; 20/27 mg/m2 regimen): IV:

Cycle 1: 20 mg/m2 over 10 minutes on days 1 and 2; if tolerated, increase dose to 27 mg/m2 over 10 minutes on days 8, 9, 15, and 16 of a 28-day treatment cycle

Cycles 2 to 12: 27 mg/m2 over 10 minutes on days 1, 2, 8, 9, 15, and 16 of a 28-day treatment cycle

Cycle 13 and beyond: 27 mg/m2 over 10 minutes on days 1, 2, 15, and 16 of a 28-day treatment cycle; continue until disease progression or unacceptable toxicity

Multiple myeloma, relapsed/refractory (single-agent; 20/56 mg/m2 regimen): IV:

Cycle 1: 20 mg/m2 over 30 minutes on days 1 and 2; if tolerated, increase dose to 56 mg/m2 over 30 minutes on days 8, 9, 15, and 16 of a 28-day treatment cycle.

Cycles 2 to 12: 56 mg/m2 over 30 minutes on days 1, 2, 8, 9, 15, and 16 of a 28-day treatment cycle.

Cycle 13 and beyond: 56 mg/m2 over 30 minutes on days 1, 2, 15, and 16 of a 28-day treatment cycle; continue until disease progression or unacceptable toxicity.

Multiple myeloma, relapsed/refractory (in combination with lenalidomide and dexamethasone) (Stewart 2015): IV:

Cycle 1: 20 mg/m2 over 10 minutes on days 1 and 2; if tolerated, increase dose to 27 mg/m2 over 10 minutes on days 8, 9, 15, and 16 of a 28-day treatment cycle.

Cycles 2 to 12: 27 mg/m2 over 10 minutes on days 1, 2, 8, 9, 15, and 16 of a 28-day treatment cycle.

Cycles 13 to 18: 27 mg/m2 over 10 minutes on days 1, 2, 15, and 16 of a 28-day treatment cycle; beginning with cycle 19, lenalidomide and dexamethasone may be continued (until disease progression or unacceptable toxicity) without carfilzomib.

Multiple myeloma, relapsed/refractory (in combination with dexamethasone): IV:

Cycle 1: 20 mg/m2 over 30 minutes on days 1 and 2; if tolerated, increase dose to 56 mg/m2 over 30 minutes on days 8, 9, 15, and 16 of a 28-day treatment cycle.

Cycle 2 and beyond: 56 mg/m2 over 30 minutes on days 1, 2, 8, 9, 15, and 16 of a 28-day treatment cycle; continue until disease progression or unacceptable toxicity.

Waldenström macroglobulinemia (off-label use): IV:

Induction (Treon 2014):

Cycle 1: 20 mg/m2 over 20 minutes on days 1, 2, 8, and 9 of a 21-day treatment cycle (in combination with dexamethasone and rituximab)

Cycles 2 to 6: 36 mg/m2 over 30 minutes on days 1, 2, 8, and 9 of a 21-day treatment cycle (in combination with dexamethasone and rituximab)

Maintenance (started 8 weeks after completion of induction therapy in patients with stable disease or better response): 36 mg/m2 on days 1 and 2 every 8 weeks for 8 cycles (in combination with dexamethasone and rituximab) (Treon 2014).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

The International Myeloma Working Group recommends the use of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (preferred) or the Modification of Diet in Renal Disease (MDRD) formula to evaluate renal function estimation in multiple myeloma patients with a stable serum creatinine (Dimopoulos 2016).

Preexisting renal impairment: There are no dosage adjustments provided in the manufacturer's labeling; however, results from a phase 2 study in patients with renal impairment indicate that the pharmacokinetics and safety of carfilzomib were unchanged in this patient population; no dosage adjustment is necessary in patients with baseline dysfunction, including patients on hemodialysis (Badros 2013). Note: Dialysis clearance of carfilzomib has not been studied; per manufacturer labeling, administer postdialysis.

The International Myeloma Working Group Recommendations suggest that (based on evaluating the 20/27 mg/m2 dose), carfilzomib may be safely administered to patients with a CrCl ≥15 mL/minute; although there is less data, carfilzomib may also be administered to patients with CrCl <15 mL/minute (Dimopoulos 2016).

Renal toxicity during treatment: Serum creatinine ≥2 times baseline, CrCl <15 mL/minute or CrCl decreases to ≤50% of baseline, or patient requires dialysis: Withhold dose and monitor renal function. If renal toxicity is due to carfilzomib, resume dosing when renal function has improved to within 25% of baseline; resume with a reduced dose by 1 dose level (see Dosing- Adjustment for Toxicity for dose level reductions). Per the Canadian labeling, the reduced dose may be increased to the previous dose (if tolerated) at the discretion of the prescriber. If toxicity is not due to carfilzomib, restart at the discretion of the prescriber.

Dosing: Hepatic Impairment

Preexisting hepatic impairment: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied; patients with ALT or AST ≥3 times ULN and bilirubin ≥2 times ULN were excluded from clinical trials).

Hepatotoxicity during treatment: Grade 3 or 4 elevation of bilirubin, transaminases, or other liver abnormalities: Withhold dose until resolved or at baseline. After resolution, if appropriate to reinitiate, consider restarting at 1 dose level reduction (see Dosing: Adjustment for Toxicity for dose level reductions) with frequent monitoring of hepatic function.

Dosing: Adjustment for Toxicity

Carfilzomib dose level reductions for toxicity:

If initial dose is 56 mg/m2:

First dose reduction: 45 mg/m2

Second dose reduction: 36 mg/m2

Third dose reduction: 27 mg/m2; if toxicity persists on 27 mg/m2 dose, discontinue carfilzomib

If initial dose is 27 mg/m2:

First dose reduction: 20 mg/m2

Second dose reduction: 15 mg/m2; if toxicity persists on 15 mg/m2 dose, discontinue carfilzomib

Canadian labeling only: If initial dose is 20 mg/m2: First dose reduction: 15 mg/m2; if toxicity persists on 15 mg/m2 dose, discontinue carfilzomib

Hematologic toxicity:

ANC <500/mm3: Withhold dose; continue at same dose level if ANC recovers to ≥500/mm3. For subsequent ANC levels <500/mm3, withhold dose and consider reducing dose by 1 dose level when ANC ≥500/mm3.

Neutropenic fever (ANC <500/mm3 with an oral temperature >38.5°C or 2 consecutive readings of >38°C for 2 hours): Withhold dose; if ANC recovers to baseline and fever resolves, resume at the same dose level.

Platelets: <10,000/mm3 or evidence of bleeding with thrombocytopenia: Withhold dose; continue at same dose level if platelets recover to ≥10,000/mm3 and bleeding is controlled. For subsequent platelet levels <10,000/mm3, withhold dose and consider reducing dose by 1 dose level when platelets ≥10,000/mm3.

Nonhematologic toxicity:

Grade 3 or 4 nonhematologic toxicities: Withhold dose until resolved or at baseline. After resolution, consider restarting the next scheduled treatment at 1 dose level reduction. Per the Canadian labeling, the reduced dose may be increased to the previous dose (if tolerated) at the discretion of the prescriber.

Cardiac: Grade 3 or 4, new-onset or worsening of heart failure, decreased left ventricular function, or myocardial ischemia: Withhold dose until resolved or at baseline. After resolution, if considered appropriate to reinitiate, consider restarting at 1 dose level reduction.

Hemorrhage or symptoms of blood loss: Reduce dose or withhold treatment as clinically appropriate.

Hypertension, severe or life-threatening: If hypertension cannot be adequately controlled, withhold dose and evaluate. After resolution, consider if appropriate to reinitiate based on risk versus benefit. Per the Canadian labeling, may consider a dose reduction when resuming therapy.

Pulmonary toxicity

Acute respiratory distress syndrome, acute respiratory failure, and acute diffuse infiltrative pulmonary disease (drug-induced): Discontinue therapy.

Pulmonary hypertension: Withhold dose until resolved or at baseline. After resolution, consider if appropriate to reinitiate based on risk versus benefit.

Grade 3 or 4 dyspnea: Withhold dose until resolved or at baseline. After resolution, consider if appropriate to reinitiate based on risk versus benefit.

Tumor lysis syndrome: Interrupt treatment until resolved.

Dosing: Obesity

ASCO Guidelines for appropriate chemotherapy dosing in obese adults with cancer: In general, 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). Note: According to the manufacturer, patients with a body surface area (BSA) >2.2 m2 should be dosed based upon a maximum BSA of 2.2 m2; dose adjustments for weight changes of ≤20% are not necessary.

Reconstitution

Hazardous agent; use appropriate precautions for handling and disposal (meets NIOSH 2014 criteria). Reconstitute 60 mg vial with 29 mL and the 30 mg vial with 15 mL sterile water for injection, to a concentration of 2 mg/mL (directing solution onto the inside wall of the vial to avoid foaming). Gently invert and/or swirl vial slowly for ~1 minute to mix; do not shake. If foaming results, allow solution to sit for ~5 minutes until foaming resolves. Reconstituted solution should be clear and colorless. May further dilute dose in 50 or 100 mL (depending on dose and infusion duration) of D5W. Discard unused portion of the vial (do not pool unused solution from the vials).

Administration

IV: Administer over 10 or 30 minutes depending on the carfilzomib dose regimen (see Dosing). Do not administer as an IV bolus. Hydrate with oral fluids (30 mL/kg) at least 48 hours prior to initiating cycle 1, as well as with 250 to 500 mL NS (or other appropriate IV fluid) prior to (recommended) and after (if needed) each dose in cycle 1; continue oral and/or IV hydration in subsequent cycles (if necessary). Flush line immediately before and after carfilzomib with NS or D5W. Do not administer with other medications.

When administering as monotherapy, premedicate with dexamethasone 4 mg orally or IV when infusing carfilzomib over 10 minutes or with dexamethasone 8 mg orally or IV when infusing carfilzomib over 30 minutes. When using combination therapy, administer the recommended dexamethasone dose (refer to prescribing information). Premedicate 30 minutes to 4 hours prior to all doses in cycle 1, and as needed with future cycles to reduce the incidence and severity of infusion reaction.

Hazardous agent; use appropriate precautions for handling and disposal (meets NIOSH 2014 criteria).

Compatibility

Stable in D5W. Do not mix with or administer as an infusion with other medications.

Storage

Store intact vials at 2°C to 8°C (36°F to 46°F). Store in original carton until use to protect from light. Reconstituted drug (in the vial or in a syringe) and preparations diluted for infusion in D5W are stable for 4 hours at room temperature or for 24 hours refrigerated at 2°C to 8°C (36°F to 46°F).

Drug Interactions

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

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

Contraceptives (Estrogens): Carfilzomib may enhance the thrombogenic effect of Contraceptives (Estrogens). Management: Consider alternative, non-hormonal methods of contraception in patients requiring therapy with carfilzomib. Consider therapy modification

Contraceptives (Progestins): Carfilzomib may enhance the thrombogenic effect of Contraceptives (Progestins). Management: Consider alternative, non-hormonal methods of contraception in patients requiring therapy with carfilzomib. Consider therapy modification

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

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

Lumacaftor: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. Lumacaftor may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

Ranolazine: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Thrombocytopenia (including grade 4) was observed in patients receiving carfilzomib, with platelet nadirs occurring between day 8 and day 15 of each 28-day treatment cycle, and recovery to baseline by the start of the next cycle. Monitor platelets closely and adjust dose or withhold therapy if necessary. Hemorrhage due to thrombocytopenia may occur. Anemia, lymphopenia, leukopenia, and neutropenia were also observed.

• Cardiovascular effects: Death caused by cardiac arrest has occurred within 24 hours of administration. Carfilzomib has been associated with new-onset or worsening of heart failure (HF), pulmonary edema, decreased left ventricular ejection fraction (LVEF), restrictive cardiomyopathy, myocardial ischemia, and myocardial infarction (including fatalities). Some events occurred in patients with normal ventricular function at baseline. Cardiac events typically were observed throughout the course of therapy. Patients 75 years of age and older have an increased risk of heart failure. Monitor closely for cardiac complications and for volume overload (due to pretreatment hydration), particularly in patients at risk for HF; withhold carfilzomib therapy for grade 3 or 4 cardiac events until recovery. Patients with New York Heart Association Class III and IV heart failure, recent myocardial infarction (within 3 to 6 months), and conduction abnormalities, angina, or arrhythmias not managed by medication were excluded from clinical trials and may be at increased risk for cardiac complications; evaluate with a comprehensive medical assessment prior to initiation and closely monitor.

• Hemorrhage: Serious or fatal cases of hemorrhage have been reported, including gastrointestinal, intracranial and pulmonary hemorrhage and epistaxis. Bleeding may be spontaneous; intracranial hemorrhage has occurred without trauma. Hemorrhage has been reported in patients with and without low platelets and has also been reported in patients who were not receiving anticoagulation or antiplatelet therapy. Monitor for signs/symptoms of hemorrhage and promptly evaluate symptoms of blood loss. Reduce dose or withhold treatment as clinically indicated.

• Hepatic effects: Hepatic failure, including fatal cases, has been reported rarely. Increased transaminases and hyperbilirubinemia have also been observed. Interrupt therapy with grade 3 or higher hepatic toxicity until resolved or recovered to baseline (may require dose reduction if appropriate to reinitiate); monitor liver enzymes regularly.

• Hypertension: Hypertension has occurred with use; hypertensive crisis and hypertensive emergency have also been reported (some events were fatal). Monitor blood pressure throughout therapy; if hypertension cannot be adequately controlled, interrupt carfilzomib therapy and evaluate; assess risks versus benefits when determining to restart treatment.

• Infusion reactions: May occur immediately following or within 24 hours of carfilzomib infusion; may be life-threatening. Symptoms have included fever, chills, arthralgia, myalgia, flushing, facial edema, vomiting, weakness, dyspnea, hypotension, syncope, chest tightness, or angina. To lessen the incidence and intensity of infusion reactions, administer dexamethasone prior to drug administration.

• Posterior reversible encephalopathy syndrome: Posterior reversible encephalopathy syndrome (PRES) has been reported rarely with use; symptoms include seizure, headache, lethargy, confusion, blindness, altered consciousness, hypertension, and other visual/neurological disturbances. Discontinue therapy if PRES diagnosis is suspected; the safety of reinitiating therapy after PRES diagnosis is not known.

• Pulmonary toxicities: Acute respiratory distress syndrome (ARDS), acute respiratory failure, and acute diffuse-infiltrative pulmonary disease (eg, pneumonitis and interstitial lung disease) have occurred in a small number of patients (some events were fatal); discontinue therapy if any of these drug-induced pulmonary toxicities occur. In clinical trials, pulmonary arterial hypertension (PAH) was observed (including grade 3 or higher events); perform cardiac imaging or other testing as appropriate, and withhold carfilzomib until PAH is resolved or returns to baseline. Dyspnea (including grade 3 or higher events) has been reported; monitor closely. Withhold carfilzomib until pulmonary symptom resolution or return to baseline.

• Renal toxicity: Renal toxicity (eg, renal insufficiency, acute renal failure, renal failure) has been reported with carfilzomib. Acute renal failure was observed more frequently in patients receiving carfilzomib monotherapy for advanced relapsed/refractory multiple myeloma; renal failure risk is greater when patients have a baseline reduced creatinine clearance. Monitor renal function closely; may require therapy interruption or dose reduction.

• Thrombotic microangiopathy: Thrombotic microangiopathy, including cases of thrombocytopenic thrombotic purpura/hemolytic uremic syndrome (TTP/HUS) has been reported (some fatal); monitor for signs/symptoms. Interrupt therapy if TTP/HUS diagnosis is suspected and manage appropriately (eg, plasma exchange as clinically necessary). If TTP/HUS diagnosis is excluded, may consider reinitiating therapy; the safety of restarting carfilzomib after a TTP/HUS diagnosis is not known.

• Thromboembolic events: Venous thromboembolism (eg, deep vein thrombosis and pulmonary embolism) has been observed, particularly when used as part of combination therapy with dexamethasone or with lenalidomide plus dexamethasone. Thromboprophylaxis is recommended with combination therapy, and should be based on patients’ underlying risk factors, treatment regimen, and clinical status. Due to risk of thrombosis with hormonal contraception, consider an alternative method of effective contraception during combination treatment of carfilzomib with dexamethasone or lenalidomide plus dexamethasone.

• Tumor lysis syndrome: Tumor lysis syndrome (TLS), including fatalities, has been observed. TLS risk is increased in multiple myeloma patients with a high tumor burden. Adequately hydrate patients prior to carfilzomib therapy and monitor closely for signs and symptoms of TLS; consider use of antihyperuricemic agents. If TLS occurs, interrupt treatment until resolved.

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 (meets NIOSH 2014 criteria).

Dosage form specific issues:

• Injection: Vials contain the excipient cyclodextrin (sulfobutyl ether beta-cyclodextrin), which may accumulate in patients with renal insufficiency, although the clinical significance of this finding is uncertain (Luke 2010).

Monitoring Parameters

CBC with differential and platelets (monitor frequently throughout therapy), serum potassium levels regularly during treatment, renal function, pulmonary function (with new or worsening pulmonary symptoms), liver function tests, blood pressure. Signs/symptoms of infusion-related reactions, congestive heart failure, tumor lysis syndrome, peripheral neuropathy, posterior reversible encephalopathy syndrome, thrombocytopenic thrombotic purpura/hemolytic uremic syndrome, and venous thromboembolic events. Monitor for evidence of volume overload due to pre- and posthydration.

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. Based on the mechanism of action, adverse fetal events would be expected to occur with use in pregnant women. Females of reproductive potential are advised to avoid pregnancy during therapy; women of reproductive potential should abstain from sexual activity or use effective contraception during treatment and for at least 30 days following therapy completion. Male patients of reproductive potential should abstain from sexual activity or use effective contraception during treatment and for at least 90 days following therapy completion.

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 diarrhea, constipation, rhinitis, pharyngitis, lack of appetite, back pain, headache, or insomnia. Have patient report immediately to prescriber signs of infusion reaction, signs of infection, signs of posterior reversible encephalopathy syndrome (confusion, not alert, vision changes, seizures, or severe headache), signs of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (bruising or bleeding, loss of strength and energy, dark urine or jaundice, pale skin, change in amount of urine passed, vision changes, change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or fever), signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; hematuria; black, red, or tarry stools; bleeding from the gums, abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding), signs of tumor lysis syndrome (tachycardia or abnormal heartbeat; any passing out; urinary retention; muscle weakness or cramps; nausea, vomiting, diarrhea or lack of appetite; or feeling sluggish), signs of heart problems (cough or shortness of breath that is new or worse, swelling of the ankles or legs, abnormal heartbeat, weight gain of more than five pounds in 24 hours, dizziness, or passing out), signs of kidney problems (urinary retention, blood in urine, change in amount of urine passed, or weight gain), signs of electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite, or severe nausea or vomiting), signs of high blood sugar (confusion, fatigue, increased thirst, increased hunger, polyuria, flushing, fast breathing, or breath that smells like fruit), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), signs of a severe pulmonary disorder (lung or breathing problems like difficulty breathing, shortness of breath, or a cough that is new or worse, angina, flushing, muscle pain, joint pain, dizziness, passing out, burning or numbness feeling, or severe loss of strength and energy (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.

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