Lapatinib

Pronunciation

(la PA ti nib)

Index Terms

• GW572016
• Lapatinib Ditosylate

Dosage Forms

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

Tablet, Oral:

Tykerb: 250 mg [contains fd&c yellow #6 (sunset yellow), fd&c yellow #6 aluminum lake]

Brand Names: U.S.

• Tykerb

Pharmacologic Category

• Antineoplastic Agent, Anti-HER2
• Antineoplastic Agent, Epidermal Growth Factor Receptor (EGFR) Inhibitor
• Antineoplastic Agent, Tyrosine Kinase Inhibitor

Pharmacology

Tyrosine kinase (dual kinase) inhibitor; inhibits EGFR (ErbB1) and HER2 (ErbB2) by reversibly binding to tyrosine kinase, blocking phosphorylation and activation of downstream second messengers (Erk1/2 and Akt), regulating cellular proliferation and survival in ErbB- and ErbB2-expressing tumors. Combination therapy with lapatinib and endocrine therapy may overcome endocrine resistance occurring in HER2+ and hormone receptor positive disease.

Absorption

Incomplete and variable

Metabolism

Hepatic; extensive via CYP3A4 and 3A5, and to a lesser extent via CYP2C19 and 2C8 to oxidized metabolites

Excretion

Feces (27% as unchanged drug; range 3% to 67%); urine (<2%)

Time to Peak

~4 hours (Burris, 2009)

Half-Life Elimination

~24 hours

Protein Binding

>99% to albumin and alpha₁-acid glycoprotein

Special Populations: Hepatic Function Impairment

AUC increased (after a single 100 mg oral dose) by ~14% and 63% in patients with moderate (Child-Pugh class B) and severe (Child-Pugh class C) hepatic impairment, respectively.

Use: Labeled Indications

Breast cancer: Treatment of human epidermal growth receptor type 2 (HER2) overexpressing advanced or metastatic breast cancer (in combination with capecitabine) in patients who have received prior therapy (with an anthracycline, a taxane, and trastuzumab); HER2 overexpressing hormone receptor–positive metastatic breast cancer in postmenopausal women where hormone therapy is indicated (in combination with letrozole)

Limitations of use: Patients should have disease progression on trastuzumab prior to initiation of treatment with lapatinib in combination with capecitabine.

Use: Unlabeled

Treatment of HER2 overexpressing metastatic breast cancer (in combination with trastuzumab) which had progressed on prior trastuzumab-containing therapy; treatment of HER2 overexpressing metastatic breast cancer with brain metastases

Contraindications

Known severe hypersensitivity to lapatinib or any component of the formulation

Dosing: Adult

Breast cancer, metastatic, HER2+ (with prior anthracycline, taxane, and trastuzumab therapy): Oral: 1250 mg once daily (in combination with capecitabine) until disease progression or unacceptable toxicity (Geyer, 2006)

Breast cancer, metastatic, HER2+, hormonal therapy indicated: Oral: 1500 mg once daily (in combination with letrozole) until disease progression (Johnston, 2009)

Breast cancer, metastatic, HER2+ with brain metastases, first-line therapy (off-label use): Oral: 1250 mg once daily (in combination with capecitabine) until disease progression or unacceptable toxicity (Bachelot, 2013)

Breast cancer, metastatic, HER2+, with progression on prior trastuzumab therapy (off-label use): Oral: 1000 mg once daily (in combination with trastuzumab) (Blackwell, 2010; Blackwell, 2012)

Missed doses: If a dose is missed, resume with the next scheduled daily dose; do not double the dose the next day.

Dosage adjustment for concomitant CYP3A4 inhibitors/inducers:

CYP3A4 inhibitors: Avoid the use of concomitant strong CYP3A4 inhibitors. If concomitant use cannot be avoided, consider reducing lapatinib to 500 mg once daily with careful monitoring. When a strong CYP3A4 inhibitor is discontinued, allow ~1 week to elapse prior to adjusting the lapatinib dose upward.

CYP3A4 inducers: Avoid the use of concomitant strong CYP3A4 inducers.

U.S. labeling: If concomitant use cannot be avoided, consider gradually titrating lapatinib from 1250 mg once daily up to 4500 mg daily (in combination with capecitabine) or from 1500 mg once daily up to 5500 mg daily (in combination with letrozole), based on tolerability and with careful monitoring. If the strong CYP3A4 enzyme inducer is discontinued, reduce the lapatinib dose to the indicated dose.

Canadian labeling: If concomitant use cannot be avoided, titrate lapatinib dose gradually upward based on tolerability. If the strong CYP3A4 enzyme inducer is discontinued, reduce the lapatinib dose over 2 weeks.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied); however, due to the minimal renal elimination (<2%), dosage adjustments may not be necessary.

Dosing: Hepatic Impairment

Mild or moderate preexisting impairment (Child-Pugh class A or B): There are no dosage adjustments provided in the manufacturer’s labeling.

Severe preexisting impairment (Child-Pugh class C):

US labeling: The following adjustments should be considered (and are predicted to normalize the AUC), however, there are no clinical data associated with the adjustments.

In combination with capecitabine: Reduce dose from 1250 mg once daily to 750 mg once daily.

In combination with letrozole: Reduce dose from 1500 mg once daily to 1000 mg once daily.

Canadian labeling: There are no specific dosage adjustments provided in the manufacturer’s labeling; however, a dosage reduction is recommended based on pharmacokinetic modeling (safety and efficacy of dose reduction has not been demonstrated).

Severe hepatotoxicity during treatment: Discontinue permanently (do not rechallenge).

Dosing: Adjustment for Toxicity

Cardiac toxicity: Discontinue treatment for at least 2 weeks for LVEF < LLN or decreased LVEF ≥ grade 2 (U.S. labeling) or decreased LVEF ≥ grade 3 (Canadian labeling); may be restarted at 1000 mg once daily (in combination with capecitabine) or 1250 mg once daily (in combination with letrozole) if LVEF recovers to normal and patient is asymptomatic.

Dermatologic toxicity: Discontinue treatment for suspected erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis.

Diarrhea:

Grade 3 diarrhea or grade 1 or 2 diarrhea with complicating features (moderate-to-severe abdominal cramping, grade 2 or higher nausea/vomiting, decreased performance status, fever, sepsis, neutropenia, frank bleeding, or dehydration):

U.S. labeling: Interrupt treatment; may restart at a reduced dose (from 1500 mg once daily to 1250 mg once daily or from 1250 mg once daily to 1000 mg once daily) when diarrhea resolves to ≤ grade 1.

Canadian labeling: Interrupt treatment; may restart at a reduced dose (from 1500 mg once daily to 1250 mg once daily or from 1250 mg once daily to 1000 mg once daily or from 1000 mg once daily to 750 mg once daily) when diarrhea resolves to ≤ grade 1.

Grade 4 diarrhea: Permanently discontinue.

Pulmonary toxicity: Discontinue treatment with pulmonary symptoms indicative of interstitial lung disease or pneumonitis which are ≥ grade 3

Other toxicities: Withhold for any toxicity (other than cardiac) ≥ grade 2 until toxicity resolves to ≤ grade 1 and reinitiate at the standard dose of 1250 or 1500 mg once daily; for persistent toxicity, reduce dosage to 1000 mg once daily (in combination with capecitabine) or 1250 mg once daily (in combination with letrozole)

Administration

Administer once daily, on an empty stomach, 1 hour before or 1 hour after a meal. Take full dose at the same time each day; dividing dose throughout the day is not recommended.

Note: For combination treatment with capecitabine, capecitabine should be administered in 2 doses (approximately 12 hours apart) and taken with food or within 30 minutes after a meal.

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

Dietary Considerations

Avoid grapefruit juice.

Storage

Store at room temperature of 25°C (77°F); excursions permitted between 15°C and 30°C (59°F and 86°F).

Drug Interactions

Afatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib. Management: Per US labeling: reduce afatinib by 10mg if not tolerated. Per Canadian labeling: avoid combination if possible; if used, administer the P-gp inhibitor simultaneously with or after the dose of afatinib. Consider therapy modification

Amodiaquine: CYP2C8 Inhibitors may increase the serum concentration of Amodiaquine. Avoid combination

Aprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

ARIPiprazole: CYP3A4 Inhibitors (Weak) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations. Monitor therapy

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Bosutinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Bosutinib. Avoid combination

Brentuximab Vedotin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased. Monitor therapy

Colchicine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Colchicine. Colchicine distribution into certain tissues (e.g., brain) may also be increased. Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a p-glycoprotein inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. Consider therapy modification

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

CYP2C8 Substrates: CYP2C8 Inhibitors (Moderate) may decrease the metabolism of CYP2C8 Substrates. Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Lapatinib. Management: If therapy overlap cannot be avoided, consider titrating lapatinib gradually from 1,250 mg/day up to 4,500 mg/day (HER2 positive metastatic breast cancer) or 1,500 mg/day up to 5,500 mg/day (hormone receptor/HER2 positive breast cancer) as tolerated. Avoid combination

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Lapatinib. Management: If an overlap in therapy cannot be avoided, consider reducing lapatinib adult dose to 500 mg/day during, and within 1 week of completing, treatment with the strong CYP3A4 inhibitor. Avoid combination

Dabigatran Etexilate: P-glycoprotein/ABCB1 Inhibitors may increase serum concentrations of the active metabolite(s) of Dabigatran Etexilate. Management: Dabigatran dose reductions may be needed. Specific recommendations vary considerably according to US vs Canadian labeling, specific P-gp inhibitor, renal function, and indication for dabigatran treatment. Refer to full monograph or dabigatran labeling. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Dexamethasone (Systemic): May decrease the serum concentration of Lapatinib. Management: If therapy overlap cannot be avoided, consider titrating lapatinib gradually from 1,250 mg/day up to 4,500 mg/day (HER2 positive metastatic breast cancer) or 1,500 mg/day up to 5,500 mg/day (hormone receptor/HER2 positive breast cancer) as tolerated. Avoid combination

DOXOrubicin (Conventional): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to P-glycoprotein inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

Edoxaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban. Management: See full monograph for details. Reduced doses are recommended for patients receiving edoxaban for venous thromboembolism in combination with certain inhibitors. Similar dose adjustment is not recommended for edoxaban use in atrial fibrillation. Consider therapy modification

Everolimus: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Everolimus. Management: Everolimus dose reductions are required for patients being treated for subependymal giant cell astrocytoma or renal cell carcinoma. See prescribing information for specific dose adjustment and monitoring recommendations. Consider therapy modification

Flibanserin: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Flibanserin. Monitor therapy

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Grapefruit Juice: May increase the serum concentration of Lapatinib. Avoid combination

Highest Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

HYDROcodone: CYP3A4 Inhibitors (Weak) may increase the serum concentration of HYDROcodone. Monitor therapy

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Lomitapide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lomitapide. Management: Patients on lomitapide 5 mg/day may continue that dose. Patients taking lomitapide 10 mg/day or more should decrease the lomitapide dose by half. The lomitapide dose may then be titrated up to a max adult dose of 30 mg/day. Consider therapy modification

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Moderate Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Monitor therapy

Naloxegol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naloxegol. Monitor therapy

Netupitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

NiMODipine: CYP3A4 Inhibitors (Weak) may increase the serum concentration of NiMODipine. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

PAZOPanib: Lapatinib may enhance the QTc-prolonging effect of PAZOPanib. Lapatinib may increase the serum concentration of PAZOPanib. Avoid combination

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

P-glycoprotein/ABCB1 Substrates: 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

Pimozide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Pimozide. Avoid combination

Prucalopride: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Prucalopride. Monitor therapy

Ranolazine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Ranolazine. Monitor therapy

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

RifAXIMin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RifAXIMin. Monitor therapy

Silodosin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Silodosin. Avoid combination

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

St John's Wort: May decrease the serum concentration of Lapatinib. Management: If therapy overlap cannot be avoided, consider titrating lapatinib gradually from 1,250 mg/day up to 4,500 mg/day (HER2 positive metastatic breast cancer) or 1,500 mg/day up to 5,500 mg/day (hormone receptor/HER2 positive breast cancer) as tolerated. Avoid combination

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Topotecan: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Topotecan. Avoid combination

Venetoclax: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Venetoclax. Management: Reduce the venetoclax dose by at least 50% in patients requiring these combinations. Consider therapy modification

VinCRIStine (Liposomal): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of VinCRIStine (Liposomal). Avoid combination

Adverse Reactions

Percentages reported for combination therapy.

>10%:

Central nervous system: Fatigue (≤20%), headache (14%)

Dermatologic: Palmar-plantar erythrodysesthesia (with capecitabine: 53%; grade 3: 12%), skin rash (28% to 44%), alopecia (13%), xeroderma (10% to 13%), pruritus (12%), nail disease (11%)

Gastrointestinal: Diarrhea (64% to 65%; grade 3: 9% to 13%; grade 4: ≤1%), nausea (31% to 44%), vomiting (17% to 26%), mucositis (15%), abdominal pain (≤15%), stomatitis (14%), anorexia (11%), dyspepsia (11%)

Hematologic: Decreased hemoglobin (with capecitabine: 56%; grade 3: <1%), decreased neutrophils (with capecitabine: 22%; grade 3: 3%; grade 4: <1%), decreased platelet count (with capecitabine: 18%; grade 3: <1%)

Hepatic: Increased serum AST (49% to 53%; grade 3: 2% to 6%; grade 4: <1%), increased serum ALT (37% to 46%; grade 3: 2% to 5%; grade 4: <1%), increased serum bilirubin (22% to 45%; grade 3: ≤4%; grade 4: <1%)

Neuromuscular & skeletal: Limb pain (12%), weakness (12%), back pain (11%)

Respiratory: Dyspnea (12%), epistaxis (11%)

1% to 10%: Central nervous system: Insomnia (10%)

<1% (Limited to important or life-threatening): Anaphylaxis, hepatotoxicity, hypersensitivity, interstitial pulmonary disease, left ventricular ejection fraction, paronychia, pneumonitis, prolonged Q-T interval on ECG, severe dermatological reaction

Warnings/Precautions

Concerns related to adverse effects:

• Cardiotoxicity: Decreases in left ventricular ejection fraction (LVEF) have been reported (usually within the first 3 months of treatment); baseline and periodic LVEF evaluations are recommended. Interrupt treatment with decreased LVEF ≥grade 2 or LVEF <LLN; may reinitiate with a reduced dose after a minimum of 2 weeks if the LVEF recovers and the patient is asymptomatic. Use with caution in conditions which may impair left ventricular function and in patients with a history of or predisposed to (prior treatment with anthracyclines, chest wall irradiation) left ventricular dysfunction.

• Dermatologic toxicity: Severe cutaneous reactions have been reported with use. Discontinue therapy if life-threatening dermatologic reactions (eg, progressive skin rash with blisters or mucosal lesions) such as erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis occur.

• Diarrhea: Diarrhea is common (onset is generally within 6 days and duration is 4 to 5 days); may be severe and/or fatal. Diarrhea is best managed with early intervention; instruct patients to immediately report any bowel pattern changes. After first unformed stool, administer antidiarrheal agents; severe diarrhea may require hydration, electrolytes, antibiotics (if duration >24 hours, fever, or grade 3/4 neutropenia), and/or treatment interruption, dose reduction, or discontinuation.

• Hepatotoxicity: [U.S. Boxed Warning]: Hepatotoxicity (ALT or AST >3 times ULN and total bilirubin >2 times ULN) has been reported with lapatinib; may be severe and/or fatal. Onset may occur within days to several months after treatment initiation. Monitor transaminases, bilirubin, and alkaline phosphatase (at baseline and every 4 to 6 weeks during treatment, and as clinically indicated); discontinue with severe changes in liver function during treatment; do not reinitiate.

• Pulmonary toxicity: Interstitial lung disease (ILD) and pneumonitis have been reported (with lapatinib monotherapy and combination chemotherapy); monitor for pulmonary symptoms which may indicate ILD or pneumonitis; discontinue treatment for grade 3 (or higher) pulmonary symptoms indicative of ILD or pneumonitis (eg, dyspnea, dry cough).

• QTc prolongation: QTc prolongation has been observed; use caution in patients with a history of QTc prolongation or with medications known to prolong the QT interval; baseline and periodic 12-lead ECG should be considered; correct electrolyte (potassium, calcium, and magnesium) abnormalities prior to and during treatment. Concurrent use with other drugs which may prolong QTc interval may increase the risk of potentially fatal arrhythmias.

Disease related concerns:

• Hepatic impairment: Use with caution in patients with hepatic impairment; dose reductions should be considered in patients with preexisting severe (Child-Pugh class C) hepatic impairment.

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 populations:

• Pharmacogenomics: Patients who carry the HLA alleles DQA1*02:01 and DRB1*07:01 may experience a greater incidence of severe liver injury than patients who are noncarriers. These alleles are present in ~15% to 25% of Caucasian, Asian, African, and Hispanic patient populations and 1% in Japanese populations.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (meets NIOSH 2014 criteria).

Monitoring Parameters

LVEF (baseline and periodic), CBC with differential, liver function tests, including transaminases, bilirubin, and alkaline phosphatase (baseline and every 4-6 weeks during treatment); electrolytes including calcium, potassium, magnesium; monitor for fluid retention; ECG monitoring if at risk for QTc prolongation; symptoms of ILD or pneumonitis; monitor for diarrhea and dermatologic toxicity

Pregnancy Risk Factor

D

Pregnancy Considerations

Adverse events were demonstrated in animal reproduction studies. Lapatinib may cause fetal harm if administered during pregnancy. Women of childbearing potential should be advised to avoid pregnancy during treatment.

European Society for Medical Oncology (ESMO) guidelines for cancer during pregnancy recommend delaying treatment with HER-2 targeted agents until after delivery in pregnant patients with HER-2 positive disease (Peccatori 2013).

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 dry skin, itching, headache, hair loss, back pain, nosebleed, fingernail changes, mouth sores, lack of appetite, or insomnia. Have patient report immediately to prescriber 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 infection, signs of pulmonary disorder (lung or breathing problems like trouble breathing, shortness of breath, or a cough that is new or worse), excessive weight gain, swelling of arms or legs, arrhythmia, angina, tachycardia, severe dizziness, passing out, severe abdominal pain, severe nausea, vomiting, diarrhea, abdominal cramps, dehydration, loss of strength and energy, bruising, bleeding, redness of irritation on palms or soles of feet, 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.