Avelumab

Dosage Forms

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

Solution, Intravenous [preservative free]:

Bavencio: 200 mg/10 mL (10 mL)

Pharmacology

Mechanism of Action

Avelumab is a fully human monoclonal antibody that binds to programmed death ligand 1 (PD-L1) to selectively prevent the interaction between the programmed cell death-1 (PD-1) and B7.1 receptors, while still allowing interaction between PD-L2 and PD-1 (Kaufman 2016). PD-L1 is an immune check point protein expressed on tumor cells and tumor infiltrating cells and down regulates anti-tumor t-cell function by binding to PD-1 and B7.1; blocking PD-1 and B7.1 interactions restores antitumor t-cell function (Fehrenbacher 2016; Rosenberg 2016).

Pharmacokinetics/Pharmacodynamics

Distribution

V_dss: 4.72 L (10 mg/kg dose)

Excretion

Total systemic clearance was 0.59 L/day in patients receiving a 10 mg/kg dose.

Half-Life Elimination

6.1 days

Use in Specific Populations

Special Populations Note

Clearance: In patients with advanced renal cell carcinoma, avelumab clearance was 15% higher in those who tested positive for treatment-emergent anti-drug antibodies (ADA) compared to those who tested negative for treatment-emergent ADA.

Use: Labeled Indications

Merkel cell carcinoma, metastatic: Treatment of metastatic Merkel cell carcinoma (MCC) in adults and children ≥12 years of age.

Renal cell carcinoma, advanced: First-line treatment of advanced renal cell carcinoma (in combination with axitinib).

Urothelial carcinoma, locally advanced or metastatic: Treatment of locally advanced or metastatic urothelial carcinoma in patients who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy

Contraindications

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

Canadian labeling: Hypersensitivity to avelumab or any component of the formulation.

Dosage and Administration

Dosing: Adult

Note: Premedicate with an antihistamine and acetaminophen prior to the first 4 infusions; consider premedication for subsequent infusions based on clinical judgment and the presence and/or severity of infusion-related reactions with previous infusions.

Merkel cell carcinoma, metastatic: IV: 800 mg once every 2 weeks until disease progression or unacceptable toxicity

Off-label dosing: 10 mg/kg once every 2 weeks until disease progression or unacceptable toxicity (Kaufman 2016)

Renal cell carcinoma, advanced: IV: 800 mg once every 2 weeks (in combination with axitinib) until disease progression or unacceptable toxicity

Off-label dosing: 10 mg/kg once every 2 weeks (in combination with axitinib) (Motzer 2019)

Urothelial carcinoma, locally advanced or metastatic: IV: 800 mg once every 2 weeks until disease progression or unacceptable toxicity

Off-label dosing: 10 mg/kg once every 2 weeks until disease progression or unacceptable toxicity (Patel 2018)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Prior to first 4 infusions, premedicate with an antihistamine and acetaminophen; for subsequent infusions, consider premedication based on clinical judgment and a history of and/or severity of infusion-related reactions with previous infusions.

Merkel cell carcinoma, metastatic: Children ≥12 years and Adolescents: IV: 800 mg once every 2 weeks until disease progression or unacceptable toxicity; fixed dose of 800 mg based on pharmacokinetic/dynamic data (primarily adult patients) which showed no meaningful difference in exposure between 800 mg/dose and 10 mg/kg/dose; avelumab abbreviated approval and additional adult trial data report a weight-directed dose of 10 mg/kg/dose once every 2 weeks; specific pediatric data is scant (D'Angelo 2018; Kaufman 2016; Kaufman 2018)

Dosing adjustment for toxicity: Children ≥12 years and Adolescents:

Endocrinopathies:

Adrenal insufficiency, grade 3 or 4: Withhold treatment; administer corticosteroids as appropriate. Resume avelumab treatment with complete or partial resolution to grade 0 or 1 after corticosteroid taper.

Hyperglycemia, grade 3 or 4: Withhold treatment and administer insulin or other anti-hyperglycemic treatment as necessary. Resume avelumab with complete or partial solution to grade 0 or 1 and metabolic control has been achieved.

Hyperthyroidism or hypothyroidism, grade 3 or 4: Withhold treatment. Initiate medical management for hyperthyroidism; manage hypothyroidism with hormone replacement therapy. Resume avelumab with complete or partial resolution to grade 0 or 1.

Other endocrinopathies, grade 3 or 4: Withhold treatment; administer corticosteroids as appropriate. Resume avelumab treatment with complete or partial resolution to grade 0 or 1 after corticosteroid taper.

Gastrointestinal toxicity:

Diarrhea or colitis, grade 2 or 3: Withhold treatment. Administer high-dose systemic corticosteroids (prednisone initial dose of 1 to 2 mg/kg daily or equivalent) followed by a corticosteroid taper. Resume avelumab treatment with complete or partial resolution to grade 0 or 1 after corticosteroid taper.

Diarrhea or colitis, grade 4 or recurrent grade 3: Discontinue permanently. Administer high-dose systemic corticosteroids (prednisone initial dose of 1 to 2 mg/kg daily or equivalent) followed by a corticosteroid taper.

Infusion-related reaction:

Grade 1 or 2: Interrupt or slow the rate of infusion.

Grade 3 or 4: Permanently discontinue.

Pulmonary toxicities:

Pneumonitis, grade 2: Withhold treatment. Administer high-dose systemic corticosteroids (prednisone initial dose of 1 to 2 mg/kg daily or equivalent) followed by a corticosteroid taper. May resume avelumab treatment with complete or partial resolution to grade 0 or 1 after corticosteroid taper.

Pneumonitis, grade 3 or 4, or recurrent grade 2: Discontinue permanently. Administer high-dose systemic corticosteroids (prednisone initial dose of 1 to 2 mg/kg daily or equivalent) followed by a corticosteroid taper.

Other immune-mediated toxicities (eg, arthritis, bullous dermatitis, demyelination, encephalitis, erythema multiforme, exfoliative dermatitis, Guillain-Barré syndrome, hemolytic anemia, histiocytic necrotizing lymphadenitis, hypophysitis, hypopituitarism, iritis, myasthenia gravis, myocarditis, myositis, pancreatitis, pemphigoid, psoriasis, rhabdomyolysis, Stevens Johnson Syndrome (SJS)/toxic epidermal necrolysis (TEN), uveitis, vasculitis):

Immune-mediated toxicities, moderate or severe clinical signs/symptoms (not described previously): Withhold treatment and evaluate. Administer high-dose systemic corticosteroids, and if appropriate, initiate hormone replacement therapy. When toxicity improves to grade 1 or less, initiate a corticosteroid taper. Resume avelumab treatment with complete or partial response to grade 0 or 1 after corticosteroid taper.

Life-threatening reactions (excluding endocrinopathies), recurrent severe immune-mediated reactions, or persistent grade 2 or 3 immune-mediated reactions lasting 12 weeks or longer, or requirement for ≥10 mg/day prednisone in adults (or equivalent) for >12 weeks: Discontinue permanently. If appropriate, administer high-dose systemic corticosteroids followed by a corticosteroid taper.

Dosing: Adjustment for Toxicity

Endocrinopathies:

Adrenal insufficiency, grade 3 or 4: Withhold avelumab treatment; administer corticosteroids as appropriate. Resume avelumab treatment with complete or partial resolution (to grade 0 or 1) after corticosteroid taper.

Hyperglycemia, grade 3 or 4: Withhold avelumab treatment and administer anti-hyperglycemic treatment or insulin. Resume avelumab treatment with complete or partial resolution (to grade 0 or 1) and once metabolic control has been achieved.

Hyperthyroidism or hypothyroidism, grade 3 or 4: Withhold avelumab treatment. Initiate medical management for hyperthyroidism; manage hypothyroidism with hormone replacement therapy. Resume avelumab treatment with complete or partial resolution (to grade 0 or 1).

Other endocrinopathies, grade 3 or 4: Withhold avelumab treatment; administer corticosteroids as appropriate. Resume avelumab treatment with complete or partial resolution (to grade 0 or 1) after corticosteroid taper.

Gastrointestinal toxicity:

Diarrhea or colitis, grade 2 or 3: Withhold avelumab treatment. Administer high-dose systemic corticosteroids (prednisone initial dose of 1 to 2 mg/kg daily or equivalent) followed by a corticosteroid taper. Resume avelumab treatment with complete or partial resolution (to grade 0 or 1) of colitis or diarrhea after corticosteroid taper.

Diarrhea or colitis, grade 4 or recurrent grade 3: Discontinue avelumab permanently. Administer high-dose systemic corticosteroids (prednisone initial dose of 1 to 2 mg/kg daily or equivalent) followed by a corticosteroid taper.

Infusion-related reaction:

Grade 1 or 2: Interrupt or slow the rate of the avelumab infusion.

Grade 3 or 4: Permanently discontinue avelumab.

Pulmonary toxicities:

Pneumonitis, grade 2: Withhold avelumab treatment. Administer high-dose systemic corticosteroids (prednisone initial dose of 1 to 2 mg/kg daily or equivalent) followed by a corticosteroid taper. Resume avelumab treatment with complete or partial resolution (to grade 0 or 1) of pneumonitis after corticosteroid taper.

Pneumonitis, grade 3 or 4, or recurrent grade 2: Discontinue avelumab permanently. Administer high-dose systemic corticosteroids (prednisone initial dose of 1 to 2 mg/kg daily or equivalent) followed by a corticosteroid taper.

Other immune-mediated toxicities (including but not limited to arthritis, bullous dermatitis, demyelination, encephalitis, erythema multiforme, exfoliative dermatitis, Guillain-Barré syndrome, hemolytic anemia, histiocytic necrotizing lymphadenitis, hypophysitis, hypopituitarism, iritis, myasthenia gravis, myocarditis, myositis, pancreatitis, pemphigoid, psoriasis, rhabdomyolysis, Stevens Johnson Syndrome (SJS)/toxic epidermal necrolysis (TEN), uveitis, vasculitis):

Immune-mediated toxicities, moderate or severe clinical signs/symptoms (not described previously) or grade 3 or 4 endocrinopathies: Withhold avelumab treatment and evaluate. Administer high-dose systemic corticosteroids (if indicated), and if appropriate, initiate hormone replacement therapy. When toxicity improves to grade 1 or less, initiate a corticosteroid taper. Resume avelumab treatment with complete or partial resolution (to grade 0 or 1) after corticosteroid taper.

Life-threatening reactions (excluding endocrinopathies), recurrent severe immune-mediated reactions, or persistent grade 2 or 3 immune-mediated reactions lasting 12 weeks or longer, or requirement for ≥10 mg/day prednisone (or equivalent) for >12 weeks: Discontinue avelumab permanently. If appropriate, administer high-dose systemic corticosteroids followed by a corticosteroid taper.

Combination therapy with axitinib: Discontinue avelumab and axitinib for grade 3 or 4 cardiovascular events.

Reconstitution

Withdraw appropriate volume from vial and transfer to IV bag containing 250 mL NS or ½ NS. Mix by gently inverting bag (do not shake); avoid foaming or excessive shearing. Discard unused portion of the vial.

Administration

IV: Infuse over 60 minutes through a 0.2 micron sterile, nonpyrogenic, low-protein binding inline filter. Do not infuse other medications through the same infusion line.

Storage

Store intact vials at 2°C to 8°C (36°F to 46°F); do not freeze. Protect vials from light (store in original packaging). Do not shake. Solutions diluted for infusion should be protected from light and may be stored at room temperature for up to 4 hours or refrigerated at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from the time of dilution. Do not freeze or shake diluted solution. If refrigerated, allow to reach room temperature prior to administration.

Drug Interactions

There are no known significant interactions.

Adverse Reactions

>10%:

Cardiovascular: Peripheral edema (17% to 20%), hypertension (10% to 13%)

Central nervous system: Fatigue (41% to 50%), dizziness (14%)

Dermatologic: Skin rash (15% to 22%)

Endocrine & metabolic: Weight loss (15% to 19%), hyponatremia (grades 3/4: 16%), increased gamma-glutamyl transferase (grades 3/4: 12%)

Gastrointestinal: Nausea (22% to 24%), diarrhea (18% to 23%), decreased appetite (20% to 21%), abdominal pain (16% to 19%), constipation (17% to 18%), increased serum lipase (14%), vomiting (13% to 14%)

Genitourinary: Urinary tract infection (21%)

Hematologic & oncologic: Lymphocytopenia (49%; grades 3/4: 11% to 19%), anemia (35%; grades 3/4: 6% to 9%), thrombocytopenia (27%; grades 3/4: 1%)

Hepatic: Increased serum aspartate aminotransferase (34%), increased serum alanine aminotransferase (20%)

Neuromuscular & skeletal: Musculoskeletal pain (25% to 32%), arthralgia (16%)

Renal: Increased serum creatinine (≤16%), renal failure syndrome (≤16%)

Respiratory: Cough (14% to 18%), dyspnea (11% to 17%)

Miscellaneous: Infusion-related reaction (14% to 30%), fever (16%)

1% to 10%:

Central nervous system: Headache (10%)

Dermatologic: Pruritus (10%), cellulitis (>1%)

Endocrine & metabolic: Hyperglycemia (grades 3/4: 3% to 9%), increased amylase (8%), hypothyroidism (5%)

Gastrointestinal: Colitis (2%), intestinal obstruction (≥2%)

Hematologic & oncologic: Neutropenia (6%; grades 3/4: 1%)

Hepatic: Increased serum alkaline phosphatase (grades 3/4: 7%), increased serum bilirubin (6%)

Immunologic: Antibody development (4%)

Neuromuscular & skeletal: Asthenia (>1%)

Renal: Acute renal failure (>1%)

Respiratory: Pneumonitis (1%)

Frequency not defined: Cardiovascular: Pericardial effusion

<1%, postmarketing, and/or case reports: Adrenocortical insufficiency, arthritis, erythema multiforme, exfoliative dermatitis, Guillain-Barré syndrome, hepatitis, hyperthyroidism, myocarditis, myositis, nephritis, pemphigoid, pituitary insufficiency, psoriasis, sepsis (systemic inflammatory response), thyroiditis, type 1 diabetes mellitus, uveitis

Warnings/Precautions

Concerns related to adverse effects:

• Adrenal insufficiency: Adrenal insufficiency may occur. The median time to onset was 2.5 months (range: 1 day to 8 months). In clinical studies, all patients received corticosteroid therapy for adrenal insufficiency; in patients who received high-dose corticosteroids, the median duration of high-dose systemic corticosteroid therapy was 1 day (range: 1 day to 24 days). Monitor for signs/symptoms of adrenal insufficiency both during and after treatment. Administer corticosteroids as appropriate. Withhold avelumab for severe (grade 3) or life-threatening (grade 4) toxicity.
• Cardiovascular events: Avelumab/axitinib combination therapy (for advanced renal cell carcinoma) may cause severe and fatal cardiovascular events. Major adverse cardiovascular events occurred in a small percentage of patients who received avelumab/axitinib combination therapy; death due to cardiac events (including grade 3 or 4 myocardial infarction and heart failure) was reported (rare). The median time to onset of major cardiac event was 4.2 months (range: 2 days to 24.5 months). Consider baseline and periodic left ventricular ejection fraction evaluations; monitor for signs/symptoms of cardiovascular events. Optimize management of cardiovascular risk factors (eg, hypertension, diabetes, dyslipidemia). Discontinue avelumab and axitinib for grade 3 or 4 cardiovascular events.
• Diabetes mellitus: Type 1 diabetes mellitus has occurred (including diabetic ketoacidosis). Monitor closely for hyperglycemia and other signs/symptoms of diabetes. Insulin or other anti-hyperglycemic therapy may be required; if severe or life-threatening (≥ grade 3) hyperglycemia is observed, administer antihyperglycemics or insulin and withhold avelumab treatment until glucose control has been accomplished.
• Gastrointestinal toxicity: Immune-mediated colitis has occurred. The median time to onset of colitis was 2.1 months (range: 2 days to 11 months) and the median duration was 6 weeks (range: 1 day to over 14 months). In many patients, colitis was managed with high-dose systemic corticosteroids for a median duration of 19 days (range: 1 day to 2.3 months), followed by a corticosteroid taper. More than two-thirds of patients with colitis experienced resolution. May require treatment interruption, systemic corticosteroid therapy, and/or permanent discontinuation. Monitor for signs and symptoms of colitis; administer systemic corticosteroids (prednisone initial dose of 1 to 2 mg/kg/day [or equivalent] followed by a taper) for grade 2 or higher colitis.
• Hepatotoxicity: Immune-mediated hepatitis has occurred, including fatal cases. The median onset for hepatitis with single-agent therapy was 3.2 months (range: 7 days to 15 months); the median duration was 2.5 months (range: 1 day to over 7 months). Hepatitis resolved in approximately half of the patients. Administer corticosteroids (prednisone initial dose of 1 to 2 mg/kg/day [or equivalent] followed by a taper for grade 2 or higher hepatitis), and withhold or discontinue therapy based on the severity of liver enzyme elevations. Systemic corticosteroids were used to manage immune-mediated hepatitis; the median duration of high-dose corticosteroid therapy was 14 days (range: 1 day to 2.5 months). Monitor for liver function changes. May require treatment interruption, systemic corticosteroids (for grade 2 or higher toxicity), and/or permanent discontinuation. Avelumab in combination with axitinib (for advanced renal cell carcinoma) may cause hepatotoxicity with higher than expected frequencies of grade 3 and 4 ALT and AST elevations. Consider monitoring liver enzymes more frequently (compared to avelumab monotherapy). Withhold avelumab and axitinib for moderate (grade 2) hepatotoxicity and permanently discontinue avelumab (and axitinib) for severe or life-threatening (grade 3 or 4) hepatotoxicity. Administer systemic corticosteroids as indicated. Most patients with grades 2 to 4 ALT elevations experienced resolution to grade 0 or 1. Among patients who were rechallenged with avelumab or axitinib either as monotherapy or with both, a majority of patients did not experience recurrence of ALT ≥3 times ULN. Immune-mediated hepatitis was reported in some patients, including grade 3 or 4 events. Hepatotoxicity and immune-mediated hepatitis required permanent discontinuation of avelumab or axitinib in some patients. The median time to onset of immune-mediated hepatitis with avelumab/axitinib combination therapy was 2.8 months (range: 2.1 weeks to 14.5 months) and the median duration of hepatitis was 15 days (range: 2 days to 9 months). Most of these patients required systemic corticosteroids (rarely, a nonsteroidal immunosuppressant was necessary); the median duration of high-dose corticosteroids was 21 days (range: 4 days to 3 months). Immune-mediated hepatitis resolution occurred in most patients receiving combination therapy.
• Infusion-related reactions: Infusion-related reactions (including severe and life-threatening cases) have occurred. Prior to the initial four infusions, premedicate with an antihistamine and acetaminophen. Monitor for signs/symptoms of a reaction (eg, pyrexia, chills, wheezing, flushing, hypotension, dyspnea, back pain, abdominal pain, urticaria). Some infusion-related reactions occurred after completion of the infusion. Interrupt or slow the rate of infusion for mild or moderate infusion-related reactions. Stop infusion and permanently discontinue avelumab for severe (grade 3) or life-threatening (grade 4) infusion-related reactions.
• Nephrotoxicity: Immune-mediated nephritis has occurred. Grade 2 or higher nephritis should be managed with systemic corticosteroids (prednisone initial dose of 1 to 2 mg/kg/day [or equivalent], followed by a taper). Monitor serum creatinine at baseline and periodically during therapy. May require treatment interruption, systemic corticosteroids (for grade 2 or higher toxicity), and/or permanent discontinuation.
• Pulmonary toxicity: Immune-mediated pneumonitis has been observed, including fatal cases. The median time to development was 2.5 months (range: 3 days to 11 months) and the median duration was 7 weeks (range: 4 days to over 4 months). Pneumonitis was managed with systemic corticosteroids; the median duration of initial corticosteroid therapy was 8 days (range: 1 day to 2.3 months) followed by a corticosteroid taper. Pneumonitis resolved in approximately half of the affected patients. May require treatment interruption, corticosteroid therapy (prednisone initial dose of 1 to 2 mg/kg /day [or equivalent] followed by a taper, for grade 2 or higher pneumonitis), and/or permanent discontinuation. Monitor for signs and symptoms of pneumonitis; if pneumonitis is suspected, evaluate with radiographic imaging; administer systemic corticosteroids for grade 2 or higher pneumonitis.
• Thyroid disorders: Immune-mediated hyperthyroidism, hypothyroidism, and thyroiditis have occurred; and may develop at any time during avelumab treatment. The median onset for immune-mediated thyroid disorders was 2.8 months (range: 2 weeks to 13 months). Monitor for changes in thyroid function (at baseline, periodically during treatment, and as clinically indicated) and for signs/symptoms of thyroid disorders. Administer medical management for hyperthyroidism as appropriate; may require treatment interruption and/or permanent discontinuation. Manage hypothyroidism with hormone replacement therapy. Immune-mediated thyroid disorders may require treatment interruption.
• Other immune-mediated toxicities: Other clinically relevant immune-mediated disorders have been observed rarely with avelumab use (either as monotherapy or as combination therapy) and may affect any organ system (may be fatal), including myocarditis (some fatal), pancreatitis (some fatal), myositis, psoriasis, arthritis, exfoliative dermatitis, erythema multiforme, pemphigoid, hypopituitarism, uveitis, Guillain-Barré syndrome, and systemic inflammatory response. May occur during treatment or following discontinuation. Other immune-mediated disorders have been observed with other similar medications (same class), including bullous dermatitis, Stevens Johnson syndrome/toxic epidermal necrolysis, rhabdomyolysis, myasthenia gravis, histiocytic necrotizing lymphadenitis, demyelination, vasculitis, hemolytic anemia, hypophysitis, iritis, and encephalitis. If an immune-mediated adverse event is suspected, evaluate appropriately to confirm or exclude other causes; based on severity of reaction, withhold avelumab treatment and administer systemic corticosteroids and (if appropriate) hormone replacement therapy. Upon resolution to grade 0 or 1, initiate corticosteroid taper. When reaction remains at grade 1 or less during taper may reinitiate avelumab. Discontinue avelumab permanently for severe grade 3 immune-mediated adverse event that is recurrent and for life-threatening reactions.

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.

Monitoring Parameters

Liver (AST, ALT, and total bilirubin), renal, and thyroid function tests (at baseline, periodically during treatment and as clinically indicated); blood glucose; signs/symptoms of colitis, thyroid disorders, pneumonitis, adrenal insufficiency, hepatitis, hyperglycemia, monitor for infusion reactions.

Avelumab/axitinib combination therapy: Also consider baseline and periodic left ventricular ejection fraction evaluations and monitor for signs/symptoms of cardiovascular events.

Pregnancy

Pregnancy Considerations

Immunoglobulins are known to cross the placenta and fetal exposure to avelumab is expected. Based on the mechanism of action, avelumab may cause fetal harm. Immune-mediated fetal rejection causing increased abortion or stillbirth was observed in animal reproduction studies. Females of reproductive potential should use effective contraception during therapy and for at least 1 month after treatment is complete.

Patient Education

What is this drug used for?

• It is used to treat cancer.
• This drug may be used with other drugs to treat your health condition. If you are also taking other drugs, talk with your doctor about the risks and side effects that may happen.

Frequently reported side effects of this drug

• Bone pain
• Joint pain
• Muscle pain
• Diarrhea
• Constipation
• Nausea
• Vomiting
• Abdominal pain
• Mouth sores
• Weight loss

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• High blood sugar like confusion, fatigue, increased thirst, increased hunger, passing a lot of urine, flushing, fast breathing, or breath that smells like fruit
• Infusion reaction
• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin
• Thyroid, pituitary, or adrenal gland problems like mood changes, behavioral changes, weight changes, constipation, deeper voice, dizziness, passing out, cold sensation, severe fatigue, hair loss, persistent headache, or decreased sex drive
• Electrolyte problems like mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite, or severe nausea or vomiting
• Stevens-Johnson syndrome/toxic epidermal necrolysis like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in mouth, throat, nose, or eyes
• Severe pulmonary disorder like lung or breathing problems like trouble breathing, shortness of breath, or a cough that is new or worse
• Bowel problems like black, tarry, or bloody stools; fever; mucus in stools; vomiting; vomiting blood; severe abdominal pain; constipation; or diarrhea
• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain
• Pancreatitis like severe abdominal pain, severe back pain, severe nausea, or vomiting
• Severe cerebrovascular disease like change in strength on one side is greater than the other, trouble speaking or thinking, change in balance, or vision changes
• Voice changes
• Chest pain
• Fast heartbeat
• Abnormal heartbeat
• Shortness of breath
• Muscle weakness
• Redness or irritation of the palms or soles of feet
• Bruising
• Bleeding
• Vision changes
• Severe loss of strength and energy
• Chills
• Sore throat
• Flushing
• Back pain
• Excessive weight gain
• Swelling of arms or legs
• Severe dizziness
• Passing out
• Severe headache
• Urinary tract infection like blood in the urine, burning or painful urination, passing a lot of urine, fever, lower abdominal pain, or pelvic pain
• Signs of a significant reaction like 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. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.