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Atezolizumab

Pronunciation

(a te zoe LIZ ue mab)

Index Terms

  • Anti-PD-L1 Monoclonal Antibody MPDL3280A
  • MPDL3280A
  • RG7446
  • RO5541267
  • Tecentriq

Dosage Forms

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

Solution, Intravenous [preservative free]:

Tecentriq: 1200 mg/20 mL (20 mL)

Brand Names: U.S.

  • Tecentriq

Pharmacologic Category

  • Antineoplastic Agent, Anti-PD-L1 Monoclonal Antibody
  • Antineoplastic Agent, Monoclonal Antibody

Pharmacology

Atezolizumab is a humanized monoclonal antibody immune checkpoint inhibitor 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 (also known as CD80) receptors, while still allowing interaction between PD-L2 and PD-1. 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).

Distribution

Vdss: 6.9 L

Half-Life Elimination

27 days

Use: Labeled Indications

Non-small cell lung cancer, metastatic: Treatment of metastatic non-small cell lung cancer (NSCLC) in patients with disease progression during or following platinum-containing chemotherapy. Patients should have disease progression on approved therapy for EGFR or ALK genomic tumor mutations (if present) prior to receiving atezolizumab.

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 manufacturer's labeling.

Dosing: Adult

Non-small cell lung cancer, metastatic: IV: 1,200 mg every 3 weeks (Fehrenbacher 2016); continue until disease progression or unacceptable toxicity

Urothelial carcinoma, locally advanced or metastatic: IV: 1,200 mg every 3 weeks (Rosenberg 2016); continue until disease progression or unacceptable toxicity

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

No dosage adjustment is necessary.

Dosing: Hepatic Impairment

Hepatic impairment prior to treatment:

Mild impairment (bilirubin ≤ upper limit of normal (ULN) and AST > ULN or bilirubin <1 times ULN and any AST): No dosage adjustment is necessary.

Moderate to severe impairment (bilirubin > ULN and AST > ULN or bilirubin ≥1 to 1.5 times ULN and any AST): There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Hepatotoxicity during treatment:

AST or ALT >3 to 5 times ULN or total bilirubin >1.5 to 3 times ULN: Withhold treatment.

AST or ALT >5 times ULN or total bilirubin >3 times ULN: Discontinue permanently.

Immune-mediated hepatitis:

Grade 2 or greater transaminase elevations (with or without total bilirubin elevations): Withhold treatment and initiate high-dose systemic corticosteroids (prednisone 1 to 2 mg/kg daily or equivalent, followed by a taper)

Severe (grade 3) or life-threatening (grade 4): Permanently discontinue treatment and initiate high-dose systemic corticosteroids (prednisone 1 to 2 mg/kg daily or equivalent, followed by a taper)

Dosing: Adjustment for Toxicity

Dosage reductions are not recommended for toxicities. Treatment is withheld or permanently discontinued. If therapy is withheld, may resume if toxicity recovers to grade 0 or 1.

Dermatologic toxicity:

Rash, grade 3: Withhold treatment.

Rash, grade 4: Discontinue permanently.

Endocrinopathies:

Adrenal insufficiency: Withhold treatment. Administer IV methylprednisolone 1 to 2 mg/kg/day and convert to oral prednisone 1 to 2 mg/kg/day or equivalent upon improvement in symptoms. When symptoms improve to grade 1 or lower, begin to taper steroids over at least 1 month. Resume atezolizumab treatment if symptoms improve to grade 0 or 1 within 12 weeks, and corticosteroids have been reduced to oral prednisone ≤10 mg/day (or equivalent) and patient is stable on adrenal replacement therapy (if needed).

Hyperglycemia, grade 3 or 4: Withhold treatment. May require insulin treatment.

Hyperthyroidism or hypothyroidism: Withhold treatment. May require additional treatment for symptomatic hypo- or hyperthyroidism.

Hypophysitis (symptomatic): Withhold treatment. Administer corticosteroids and hormone replacement as clinically necessary.

Hypophysitis, grade 4: Discontinue permanently. Administer corticosteroids and hormone replacement as clinically necessary.

Gastrointestinal toxicity:

Amylase or lipase elevations, grade 3 or 4 (>2 times ULN): Withhold treatment. Administer IV methylprednisolone 1 to 2 mg/kg/day and convert to oral corticosteroids (prednisone 1 to 2 mg/kg/day or equivalent) upon improvement in symptoms. Resume atezolizumab if amylase and lipase levels improve to grade 1 or lower within 12 weeks and corticosteroids have been reduced to oral prednisone ≤10 mg/day (or equivalent).

Diarrhea or colitis, grade 2 or 3: Withhold treatment. For grade 2 diarrhea or colitis, if symptoms persist for >5 days or recur, administer systemic corticosteroids (1 to 2 mg/kg/day prednisone or equivalent). For grade 3 diarrhea or colitis, administer IV methylprednisolone 1 to 2 mg/kg/day and convert to oral corticosteroids upon improvement in symptoms. If grade 2 and 3 symptoms improve to grade 0 or 1, taper corticosteroids over at least 1 month. Resume atezolizumab treatment if improves to grade 0 or 1 within 12 weeks and corticosteroids have been reduced to oral prednisone ≤10 mg/day (or equivalent).

Diarrhea or colitis, grade 4: Discontinue permanently. Administer IV methylprednisolone 1 to 2 mg/kg/day and convert to oral corticosteroids upon improvement in symptoms.

Pancreatitis, grade 2 or 3: Withhold treatment. Administer IV methylprednisolone 1 to 2 mg/kg/day and convert to oral corticosteroids (prednisone 1 to 2 mg/kg/day or equivalent) upon improvement in symptoms. Resume atezolizumab if pancreatitis symptoms have resolved and corticosteroids have been reduced to oral prednisone ≤10 mg/day (or equivalent).

Pancreatitis, grade 4: Discontinue permanently. Administer IV methylprednisolone 1 to 2 mg/kg/day and convert to oral corticosteroids (prednisone 1 to 2 mg/kg/day or equivalent) upon improvement in symptoms.

Pancreatitis, recurrent (any grade): Discontinue permanently. Administer IV methylprednisolone 1 to 2 mg/kg/day and convert to oral corticosteroids (prednisone 1 to 2 mg/kg/day or equivalent) upon improvement in symptoms.

Ophthalmic disorders:

Ocular inflammatory toxicity, grade 2: Withhold treatment.

Ocular inflammatory toxicity, grade 3 or 4: Discontinue permanently.

Pulmonary toxicities:

Pneumonitis, grade 2: Withhold treatment. Administer high-dose systemic corticosteroids (prednisone 1 to 2 mg/kg daily or equivalent) followed by a corticosteroid taper.

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

Other/miscellaneous toxicities:

Guillain-Barre, any grade: Discontinue permanently.

Infection, grade 3 or 4: Withhold treatment.

Infusion-related reactions, grade 2 or mild to moderate: Withhold treatment or slow the rate of infusion.

Infusion-related reactions, grade 3 or 4: Discontinue permanently.

Meningoencephalitis, any grade: Discontinue permanently. Administer IV corticosteroids (methylprednisolone 1 to 2 mg/kg/day) and convert to oral therapy (prednisone 60 mg/day or equivalent) upon improvement; when symptoms improve to grade 1 or lower, taper corticosteroids over at least 1 month.

Myasthenic syndrome/myasthenia gravis: Discontinue permanently. Consider systemic corticosteroids (prednisone 1 to 2 mg/kg/day).

Reconstitution

Withdraw 1,200 mg (20 mL) from vial and dilute into 250 mL of sodium chloride 0.9% (NS) in a polyvinyl chloride (PVC), polyethylene (PE), or polyolefin (PO) infusion bag. Dilute only with NS. Mix by gently inverting; do not shake.

Administration

IV: Infuse the initial dose over 60 minutes, if tolerated, may infuse subsequent doses over 30 minutes. May be infused with or without a 0.2- to 0.22-micron sterile, non-pyrogenic, low-protein binding in-line filter. Do not administer as an IV push or bolus. Do not administer other medications at the same time through the same IV line. Monitor for infusion reactions.

Compatibility

Compatible in NS.

Storage

Store intact vials at 2°C to 8°C (36°F to 46°F). Do not freeze. Do not shake. Store in original carton to protect from light. Solutions diluted in NS for infusion should be used immediately after preparation; if not used immediately, may be stored for up to 6 hours (including administration time) at room temperature or 24 hours refrigerated at 2°C to 8°C (36°F to 46°F). Do not freeze.

Drug Interactions

Belimumab: Monoclonal Antibodies may enhance the adverse/toxic effect of Belimumab. Avoid combination

Adverse Reactions

>10%:

Cardiovascular: Peripheral edema (18%)

Central nervous system: Fatigue (52%)

Dermatologic: Skin rash (15%; grades 3/4: <1%), pruritus (13%)

Endocrine & metabolic: Hyponatremia

Gastrointestinal: Decreased appetite (26%), nausea (25%), constipation (21%), colitis (19% to 20%), diarrhea (18% to 20%; grades 3/4: 2%), abdominal pain (17%), vomiting (17%)

Genitourinary: Urinary tract infection (22%; grades 3/4: 9%), hematuria (14%)

Hematologic & oncologic: Lymphocytopenia

Infection: Infection (38%; grades 3/4: 12%)

Neuromuscular & skeletal: Back pain (≤15%), neck pain (≤15%), arthralgia (14%)

Respiratory: Dyspnea (16%), cough (14%)

Miscellaneous: Fever (21%)

1% to 10%:

Cardiovascular: Venous thromboembolism

Central nervous system: Guillain-Barre syndrome (≤1%), meningoencephalitis (≤1%), myasthenia (≤1%), myasthenia gravis (≤1%), confusion

Endocrine & metabolic: Hyperglycemia (grades 3/4: 5%), hypothyroidism (3% to 4%; grade 1/2: 2%; grade 3: <1%), hypoalbuminemia, hyperthyroidism (≤1%)

Gastrointestinal: Increased serum amylase (≤1%), increased serum lipase (≤1%), pancreatitis (≤1%), intestinal obstruction

Genitourinary: Urinary tract obstruction

Hematologic & oncologic: Anemia

Hepatic: Increased serum ALT (grades 3/4: 2% to 3%), increased serum AST (grades 3/4: 2% to 3%), hepatitis (1%), increased serum alkaline phosphatase, serum bilirubin

Infection: Sepsis

Ophthalmic: Intraocular inflammation (≤1%)

Renal: Increased serum creatinine (grades 3/4: 3%), acute renal failure

Respiratory: Pneumonitis (1% to 3%), pneumonia

Miscellaneous: Infusion related reaction (severe: 1% to 2%)

<1% (Limited to important or life-threatening): Adrenocortical insufficiency, diabetes mellitus (with ketoacidosis), hypophysitis

Warnings/Precautions

Concerns related to adverse effects:

• Adrenal insufficiency: Grades 1 to 3 adrenal insufficiency have been reported. For symptomatic adrenal insufficiency, withhold atezolizumab treatment and administer IV methylprednisolone 1 to 2 mg/kg/day and convert to oral prednisone 1 to 2 mg/kg/day or equivalent upon improvement in symptoms. When symptoms improve to grade 1 or lower, begin to taper steroids over at least 1 month. Resume atezolizumab treatment if symptoms improves to grade 0 or 1 within 12 weeks and corticosteroids have been reduced to oral prednisone ≤10 mg/day and patient is stable on adrenal replacement therapy (if needed).

• Diabetes mellitus: New-onset diabetes with ketoacidosis has been observed with atezolizumab. For type 1 diabetes, initiate insulin treatment. For grade 3 or higher hyperglycemia (fasting blood glucose >250 to 500 mg/dL), withhold atezolizumab; resume when metabolic control is achieved on insulin therapy.

• Gastrointestinal toxicity: Immune-mediated colitis or diarrhea (defined as requiring corticosteroids and with no clear alternative etiology) has occurred in nearly one-fifth of patients receiving atezolizumab, some events included grade 3 and 4 diarrhea. The median onset for some patients was 21 days to 1.7 months (range: 12 days to 3.4 months). Monitor for signs/symptoms of colitis and diarrhea. Withhold treatment for grade 2 or 3 diarrhea or colitis. For grade 2 diarrhea or colitis, if symptoms persist for >5 days or recur, administer systemic corticosteroids (1 to 2 mg/kg/day prednisone equivalent). For grade 3 diarrhea or colitis, administer IV methylprednisolone 1 to 2 mg/kg/day and convert to oral corticosteroids upon improvement in symptoms. If grade 2 and 3 symptoms improve to grade 0 or 1, taper corticosteroids over at least 1 month. Resume atezolizumab treatment if improves to grade 0 or 1 within 12 weeks and corticosteroids have been reduced to oral prednisone ≤10 mg/day. Discontinue permanently for grade 4 diarrhea or colitis. Pancreatitis, increases in amylase and lipase levels, and symptomatic pancreatitis (without other etiology) have occurred with atezolizumab. Monitor for signs/symptoms of acute pancreatitis. Discontinue permanently for grade 4 or any grade recurrent pancreatitis. Withhold treatment for grade 3 or higher serum amylase or lipase increases, or for grade 2 or 3 pancreatitis. Administer IV methylprednisolone 1 to 2 mg/kg/day and convert to oral corticosteroids (prednisone 1 to 2 mg/kg/day or equivalent) upon improvement in symptoms. Resume atezolizumab if amylase and lipase levels improve to grade 1 or lower within 12 weeks, pancreatitis symptoms have resolved, and corticosteroids have been reduced to oral prednisone ≤10 mg/day.

• Hepatotoxicity: Immune-mediated hepatitis (defined as requiring corticosteroids and with no clear alternative etiology), including fatal cases, has occurred with atezolizumab. Liver test abnormalities have been reported, including grade 3 and 4 events. The median time to onset was ~1 month (range: 0.4 to 7.7 months). Monitor for signs/symptoms of hepatitis; monitor liver function tests (AST, ALT, and bilirubin) prior to treatment initiation and periodically throughout therapy. Administer systemic corticosteroids (1 to 2 mg/kg/day prednisone or equivalent) followed by a taper for grade 2 or higher transaminase elevations (with or without elevated bilirubin). Withhold treatment until resolution for grade 2 and permanently discontinue for grade 3 or 4 immune-mediated hepatitis. Patients with treatment interruption for immune-mediated hepatitis did not have recurrence upon resuming treatment.

• Hypophysitis: Hypophysitis has occurred in patients receiving atezolizumab (rare). Monitor for signs/symptoms of hypophysitis. Administer corticosteroids and hormone replacement as indicated. Withhold treatment for grade 2 or 3 hypophysitis; discontinue permanently for grade 4 hypophysitis.

• Infection: Infections occurred in over 1/3 of patients receiving atezolizumab. Grade 3 and 4 infections have occurred, with urinary tract infection and pneumonia being the most common causes of grade 3 or higher infection in patients with urothelial carcinoma and non-small cell lung cancer, respectively. There have been case reports of fatal infections. Serious infections, including sepsis, herpes encephalitis, and mycobacterial infection leading to retroperitoneal hemorrhage have been reported. Monitor for signs/symptoms of infection. Manage suspected and confirmed infections with antibiotics. Withhold treatment for grade 3 or higher infections.

• Infusion-related reactions: Severe infusion reactions have been reported in clinical trials. Interrupt or slow the infusion rate in patients with mild to moderate infusion reactions. Permanently discontinue for grade 3 or 4 infusion reactions.

• Pulmonary toxicity: Immune-mediated pneumonitis and interstitial lung disease (defined as requiring corticosteroids and with no clear alternative etiology), including fatal cases, have been reported in patients receiving atezolizumab. The median time to onset was 2.6 to 3.3 months (range: 3 days to 18.7 months) and the median duration was 15 days to 1.4 months (range: up to 12.6 months or longer). Monitor for signs (with radiographic imaging) and symptoms of pneumonitis. Administer systemic corticosteroids (1 to 2 mg/kg/day prednisone or equivalent) followed by a taper for grade 2 or higher pneumonitis. Withhold treatment until resolution for grade 2 pneumonitis; permanently discontinue for grade 3 or 4 pneumonitis.

• Thyroid disorders: Hypothyroidism occurred in patients who received atezolizumab (including grades 1, 2, and 3 events), with a median time to first onset of 4.8 to 5.4 months (range: 15 days to 31 months). Hyperthyroidism was also reported, including grades 1 and 2 events, with a median onset of 3.2 to 4.9 months (range: 21 days to 31 months). Monitor thyroid function prior to and periodically during treatment. Patients with abnormal thyroid function tests who are asymptomatic can receive atezolizumab treatment. For symptomatic hypothyroidism, withhold atezolizumab treatment and initiate thyroid replacement therapy as needed. Isolated hypothyroidism should be managed with replacement therapy and without corticosteroids. For symptomatic hyperthyroidism, withhold atezolizumab and initiate antithyroid medications as needed. Resume atezolizumab treatment when symptoms of hypo- or hyperthyroidism are controlled and thyroid function is improving.

• Other immune-mediated toxicities: Other immune-mediated adverse events have occurred, including meningoencephalitis, myasthenic syndrome/myasthenia gravis, Guillain-Barre syndrome, and ocular inflammatory toxicity. Monitor for clinical signs/symptoms of meningitis and encephalitis; discontinue permanently for any grade meningitis or encephalitis; administer IV corticosteroids (methylprednisolone 1 to 2 mg/kg/day) and convert to oral therapy (prednisone 60 mg/day or equivalent) upon improvement; when symptoms improve to grade 1 or lower, taper corticosteroids over at least 1 month. Monitor for neuropathy (motor and sensory); permanently discontinue for any grade myasthenic syndrome/myasthenia gravis or Guillain-Barre syndrome and begin appropriate medical management; consider systemic corticosteroids (prednisone 1 to 2 mg/kg/day).

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

Monitor liver function tests (AST, ALT, and bilirubin; at baseline and periodically during treatment), thyroid function (prior to and periodically during treatment), serum glucose. Monitor for signs/symptoms of colitis, diarrhea, endocrinopathies, hepatitis, hypophysitis, infection, infusion reactions, meningitis and encephalitis, neuropathy (motor and sensory), pancreatitis (acute), rash, and pneumonitis.

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. Based on the mechanism of action, atezolizumab is expected to cause fetal harm if used during pregnancy. Women of reproductive potential should use effective contraception during therapy and for at least 5 months after the last dose.

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 lack of appetite, nausea, vomiting, constipation, abdominal pain, back pain, neck pain, or joint pain. Have patient report immediately to prescriber signs of infusion reaction, signs of bowel problems (black, tarry, or bloody stools; fever; mucus in stools; vomiting; vomiting blood; severe abdominal pain; constipation; or diarrhea), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), signs of high blood sugar (confusion, fatigue, increased thirst, increased hunger, polyuria, flushing, fast breathing, or breath that smells like fruit), signs of a severe pulmonary disorder (lung or breathing problems like difficulty breathing, shortness of breath, or a cough that is new or worse), signs of thyroid, pituitary, or adrenal gland problems (mood changes, behavorial changes, weight changes, constipation, deeper voice, dizziness, passing out, cold sensation, severe fatigue, hair loss, persistent headache, or decreased libido), signs of pancreatitis (severe abdominal pain, severe back pain, severe nausea, or vomiting), signs of infection, signs of low sodium (headache, difficulty focusing, memory impairment, confusion, weakness, seizures, or change in balance), swelling of arms or legs, hematuria, severe loss of strength and energy, angina, bruising, bleeding, vision changes, eye pain, or severe eye irritation (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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