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Atezolizumab

Pronunciation

(a te zoe LIZ ue mab)

Index Terms

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

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

Excretion

Clearance: 0.2 L/day

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 with EGFR or ALK genomic aberrations should have disease progression on approved therapy for EGFR or ALK genomic tumor mutations prior to receiving atezolizumab.

Urothelial carcinoma, locally advanced or metastatic: Treatment of locally advanced or metastatic urothelial carcinoma in patients who are not eligible for cisplatin-containing chemotherapy, have disease progression during or following any platinum-containing chemotherapy, or have disease progression within 12 months of neoadjuvant or adjuvant chemotherapy

Contraindications

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

Canadian labeling: Additional contraindications (not in the US labeling): Hypersensitivity to atezolizumab or any component of the formulation

Dosing: Adult

Non-small cell lung cancer, metastatic: IV: 1,200 mg every 3 weeks (Fehrenbacher 2016; Rittmeyer 2017); continue until disease progression or unacceptable toxicity

Urothelial carcinoma, locally advanced or metastatic: IV: 1,200 mg every 3 weeks (Balar 2017; Rosenberg 2016); continue until disease progression or unacceptable toxicity

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

No dosage adjustment is necessary (the effect on atezolizumab pharmacokinetics in patients with estimated glomerular filtration rate 15 to 29 mL/minute has not been studied and is unknown).

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, depending on the toxicity grade, may resume if toxicity recovers to grade 0 or 1. Permanently discontinue for recurrent grade 3 or 4 toxicity.

Endocrinopathies:

Adrenal insufficiency, ≥ grade 2: Withhold treatment. Administer high-dose systemic corticosteroids (prednisone 1 to 2 mg/kg daily or equivalent) followed by a corticosteroid taper and administer hormone replacement as clinically indicated. May resume atezolizumab when ≤ grade 1 and clinically stable on hormone replacement therapy.

Hyperglycemia, ≥ grade 2: Withhold treatment. May require insulin treatment. May resume atezolizumab when ≤ grade 1 and clinically stable.

Hyperthyroidism, ≥ grade 2: Withhold treatment. May require additional treatment for symptomatic hyperthyroidism. May resume atezolizumab when ≤ grade 1 and clinically stable.

Hypophysitis, ≥ grade 2: Withhold treatment. Administer high-dose systemic corticosteroids (prednisone 1 to 2 mg/kg daily or equivalent) followed by a corticosteroid taper and administer hormone replacement as clinically indicated. May resume atezolizumab when ≤ grade 1 and clinically stable on hormone replacement therapy.

Hypothyroidism: Continue atezolizumab and initiate hormone replacement therapy.

Gastrointestinal toxicity:

Diarrhea or colitis, grade 2 or 3: Withhold treatment. If symptoms persist for >5 days or recur, administer high-dose systemic corticosteroids (prednisone 1 to 2 mg/kg daily or equivalent) followed by a corticosteroid taper. May resume when ≤ grade 1 and prednisone dose is ≤10 mg/day (or equivalent).

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

Infection, ≥ grade 3: Withhold treatment until ≤ grade 1 or resolved.

Infusion-related reactions:

Grade 1 or 2: Interrupt or slow the infusion rate; consider premedication with subsequent doses.

Grade 3 or 4: Permanently discontinue.

Ophthalmic disorders: Uveitis in combination with other immune-mediated adverse reactions may require systemic corticosteroids to reduce the risk of permanent vision loss.

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. May resume when ≤ grade 1 and prednisone dose is ≤10 mg/day (or equivalent).

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 toxicities:

Grade 3 (immune-mediated; involving a major organ): Withhold treatment. Administer high-dose systemic corticosteroids (prednisone 1 to 2 mg/kg daily or equivalent) followed by a corticosteroid taper. May resume when ≤ grade 1 and prednisone dose is ≤10 mg/day (or equivalent).

Grade 4 (immune-mediated; involving a major organ): Discontinue permanently. Administer high-dose systemic corticosteroids (prednisone 1 to 2 mg/kg daily or equivalent) followed by a corticosteroid taper.

Persistent grade 2 or 3 toxicity (excluding endocrinopathies) that does not recover to ≤ grade 1 within 12 weeks after last atezolizumab dose: Discontinue permanently.

Inability to taper corticosteroid to prednisone ≤10 mg/day (or equivalent) within 12 weeks after last atezolizumab dose: Discontinue permanently.

Recurrent grade 3 or 4 (severe or life-threatening) toxicity: Discontinue permanently.

Reconstitution

Withdraw 1,200 mg (20 mL) from vial and dilute into a 250 mL NS infusion bag made of polyvinyl chloride (PVC), polyethylene (PE), or polyolefin (PO). 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.

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%), insomnia (NSCLC: 14%)

Dermatologic: Skin rash (15%), pruritus (13%)

Endocrine & metabolic: Hypoalbuminemia (NSCLC: 48%), hyponatremia (NSCLC: 48%), hypokalemia (NSCLC: 18%), hypercalcemia (NSCLC: 13%)

Gastrointestinal: Decreased appetite (26%), nausea (25%), constipation (21%), colitis (19% to 20%), diarrhea (18% to 20%), abdominal pain (17%), vomiting (17%)

Genitourinary: Urinary tract infection (22%), hematuria (14%)

Hematologic & oncologic: Lymphocytopenia

Hepatic: Increased serum alkaline phosphatase (NSCLC: 42%), increased serum AST (NSCLC: 33%), increased serum ALT (NSCLC: 31%), increased serum bilirubin (NSCLC: 11%)

Immunologic: Antibody development (42%; no clinically significant impact on pharmacokinetics, safety, or efficacy)

Infection: Infection (38%)

Neuromuscular & skeletal: Musculoskeletal pain (NSCLC: 22%), back pain (≤15%), neck pain (≤15%), arthralgia (14%)

Renal: Increased serum creatinine (NSCLC: 19%)

Respiratory: Pneumonia (NSCLC: 18%), 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: Hypothyroidism (3% to 4%), hyperthyroidism (≤1%), hyperglycemia

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

Genitourinary: Urinary tract obstruction

Hematologic & oncologic: Anemia

Hepatic: Hepatitis (≤1%)

Infection: Sepsis

Ophthalmic: Intraocular inflammation (≤1%)

Renal: Acute renal failure

Respiratory: Pneumonitis (≤4%), pleural effusion (NSCLC: >2%), hypoxia (NSCLC)

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

<1%, postmarketing, and/or case reports: Adrenocortical insufficiency, diabetes mellitus (with ketoacidosis), hypophysitis, myocarditis

Warnings/Precautions

Concerns related to adverse effects:

• Adrenal insufficiency: Adrenal insufficiency has been reported, including grade 3 events. The median time to onset was 5.7 months (range: 3 days to 19 months), and resolved in approximately one-quarter of patients. Withhold atezolizumab for grade 2 or higher adrenal insufficiency and administer systemic corticosteroids (1 to 2 mg/kg/day prednisone or equivalent) followed by a taper and administer hormone replacement as clinically indicated.

• Cardiovascular toxicity: Myocarditis has been reported with atezolizumab (case reports); may be related to the mechanism of action and/or may be immune-mediated. May require systemic corticosteroids and/or other immunosuppressive therapy (Perez 2017). Monitor for signs and symptoms of myocarditis.

• Diabetes mellitus: Type 1 diabetes mellitus has been observed with atezolizumab. For type 1 diabetes, initiate insulin treatment as clinically indicated. Monitor for hyperglycemia and other signs/symptoms of diabetes; withhold therapy for grade 2 or higher hyperglycemia.

• Gastrointestinal toxicity: Immune-mediated colitis or diarrhea (defined as requiring corticosteroids) has occurred in one-fifth of patients receiving atezolizumab, some events included grade 3 events. The median time to onset was 1.5 months (range: 1 day to 41 months). Monitor for signs/symptoms of colitis and diarrhea. Withhold treatment for grade 2 or 3 diarrhea or colitis. For grade 2 or higher diarrhea or colitis, if symptoms persist for >5 days or recur, administer systemic corticosteroids (1 to 2 mg/kg/day prednisone equivalent). Discontinue permanently for grade 4 diarrhea or colitis. When required, systemic corticosteroids were administered for a median duration of 3 days (range: 1 to 11 days) and then tapered. Diarrhea and colitis resolved in most patients.

• Hepatotoxicity: Immune-mediated hepatitis (defined as requiring corticosteroids) and liver test abnormalities, including fatal cases, have occurred with atezolizumab. Liver test abnormalities have been reported, including grade 3 or higher events. The median time to onset was 1.4 months (range: 1 day to 25.8 months) and the median duration of hepatitis was 24 days (range: 1 day to 13 months). Monitor for signs/symptoms of hepatitis (during and after treatment) including monitoring liver function tests (AST, ALT, and bilirubin). Administer systemic corticosteroids (1 to 2 mg/kg/day prednisone or equivalent) followed by a taper for grade 2 or higher transaminase and/or bilirubin elevations. Withhold treatment until resolution for grade 2 and permanently discontinue for grade 3 or 4 immune-mediated hepatitis. Hepatitis resolved in over two-thirds of patients. When required, systemic corticosteroids were administered for a median duration of 3 days (range: 1 to 35 days) and then tapered.

• Hypophysitis: Hypophysitis has occurred in patients receiving atezolizumab (rare). Monitor for signs/symptoms of hypophysitis. Withhold treatment for grade 2 or higher hypophysitis and administer systemic corticosteroid (1 to 2 mg/kg/day prednisone or equivalent) followed by a taper and administer hormone replacement therapy as clinically indicated.

• Infection: Infections have commonly occurred in patients receiving atezolizumab. Grade 3 and higher infections have occurred (including fatal cases), 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. Monitor for signs/symptoms of infection. Withhold treatment for grade 3 or higher infections; may resume once clinically stable.

• Infusion-related reactions: Severe or life-threatening infusion reactions have been reported. Monitor for signs/symptoms of infusion reactions. Interrupt or slow the infusion rate in patients with grade 1 or 2 infusion reactions; consider premedication with subsequent doses. Permanently discontinue for grade 3 or 4 infusion reactions.

• Ocular toxicity: Uveitis and iritis have been reported. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, which has been observed in patients receiving other medications in this drug class and may require systemic corticosteroids to reduce the risk of permanent vision loss.

• Pulmonary toxicity: Immune-mediated pneumonitis and interstitial lung disease (defined as requiring corticosteroids), including fatal cases, have been reported in patients receiving atezolizumab. The median time to onset was 3.6 months (range: 3 days to 20.5 months) and the median duration was 1.4 months (range: 1 day to 15.1 months). 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. Pneumonitis resolved in two-thirds of patients. When required, systemic corticosteroids were administered for a median duration of 4 days (range: 1 to 45 days) and then tapered.

• Thyroid disorders: Hypothyroidism, hyperthyroidism, and acute thyroiditis (rare) have occurred with atezolizumab. Monitor thyroid function prior to and periodically during treatment. For hypothyroidism, continue atezolizumab treatment and initiate thyroid replacement therapy as needed. For grade 2 or higher hyperthyroidism, withhold atezolizumab and initiate antithyroid medications as needed.

• Other immune-mediated toxicities: Other immune-mediated adverse events have occurred, including bullous dermatitis, pemphigoid, erythema multiforme, Stevens Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), pancreatitis (including elevations in serum amylase and lipase), systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis, autoimmune hemolytic anemia, immune thrombocytopenic purpura, myositis, rhabdomyolysis, demyelination, immune-related meningoencephalitis, myasthenic syndrome/myasthenia gravis, Guillain-Barre syndrome, aseptic meningitis, encephalitis, facial and abducens nerve paresis, polymyalgia rheumatic, autoimmune neuropathy, nephrotic syndrome, nephritis, and vasculitis. Immune-mediated reactions may involve any organ system; while they usually develop during atezolizumab treatment, immune-mediated reactions may also occur after therapy discontinuation. For suspected grade 2 immune-mediated toxicities, exclude other causes and initiate systemic corticosteroids as clinically indicated. Administer systemic corticosteroids (1 to 2 mg/kg/day prednisone or equivalent) followed by a taper for grade 3 or 4 adverse reactions. Withhold therapy for grade 3 events; permanently discontinue for grade 4 toxicity.

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. Pregnancy test (prior to treatment initiation in females of reproductive potential). Monitor for signs/symptoms of colitis, diarrhea, endocrinopathies, hepatitis, hypophysitis, infection, infusion reactions, pneumonitis, and ocular toxicity.

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. Females of reproductive potential should use effective contraception during therapy and for at least 5 months after the last atezolizumab dose. Verify pregnancy status prior to treatment initiation in females of reproductive potential.

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, bone 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 urinary tract infection (hematuria, burning or painful urination, polyuria, fever, lower abdominal pain, or pelvic pain), 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 kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), 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), signs of thyroid, pituitary, or adrenal gland problems (mood changes, behavioral 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 nervous system problems (mood changes, behavioral changes, confusion, fever, numbness or tingling in hands or feet, neck rigidity, sensitivity to light, or severe muscle weakness), signs of infection, signs of low sodium (headache, difficulty focusing, memory impairment, confusion, weakness, seizures, or change in balance), angina, tachycardia, abnormal heartbeat, shortness of breath, swelling of arms or legs, severe loss of strength and energy, bruising, bleeding, muscle pain, muscle weakness, 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.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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