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Atezolizumab

Class: Antineoplastic Agents
Brands: Tecentriq

Introduction

Atezolizumab is an antineoplastic agent.1

Uses for Atezolizumab

Atezolizumab has the following uses:

Atezolizumab is a programmed death-ligand 1 (PD-L1) blocking antibody indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who had disease progression during or following platinum-containing chemotherapy or had disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.1

This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.1

Atezolizumab Dosage and Administration

General

Atezolizumab is available in the following dosage form(s) and strength(s):

Injection: 1200 mg/20 mL (60 mg/mL) solution in a single-dose vial.1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

  • Administer 1200 mg as an intravenous infusion over 60 minutes every 3 weeks.1

  • Dilute prior to intravenous infusion.1

Cautions for Atezolizumab

Contraindications

None.1

Warnings/Precautions

Immune-related Pneumonitis

Immune-mediated pneumonitis or interstitial lung disease, defined as requiring use of corticosteroids and with no clear alternate etiology, occurred in patients receiving atezolizumab. Across clinical trials, 2.6% (51/1978) of patients developed pneumonitis. Fatal pneumonitis occurred in two patients. In 523 patients with urothelial carcinoma who received atezolizumab, pneumonitis occurred in 6 (1.1%) patients. Of these patients, there was one patient with fatal pneumonitis, one patient with grade 3, three patients with grade 2, and one patient with grade 1 pneumonitis. Atezolizumab was held in all cases and five patients were treated with corticosteroids. Pneumonitis resolved in three patients. The median time to onset was 2.6 months (range: 15 days to 4.2 months). The median duration was 15 days (range: 6 days to 3.1+ months).1

Monitor patients for signs with radiographic imaging and symptoms of pneumonitis. Administer steroids at a dose of 1 to 2 mg/kg/day prednisone equivalents for grade 2 or greater pneumonitis, followed by corticosteroid taper. Withhold atezolizumab until resolution for grade 2 pneumonitis. Permanently discontinue atezolizumab for grade 3 or 4 pneumonitis.1

Immune-related Hepatitis

Immune-mediated hepatitis, defined as requiring use of corticosteroids and with no clear alternate etiology, occurred in patients receiving atezolizumab. Liver test abnormalities occurred in patients who received atezolizumab. Across clinical trials (n=1978), grade 3 or 4 elevation occurred in ALT (2.5%), AST (2.3%), and total bilirubin (1.6%). In patients with urothelial carcinoma (n=523), grade 3 or 4 elevation occurred in ALT (2.5%), AST (2.5%), and total bilirubin (2.1%). Immune-mediated hepatitis occurred in 1.3% of patients. Of these cases, one patient died from hepatitis, five patients had grade 3, and one patient had grade 2 hepatitis. The median time to onset was 1.1 months (range: 0.4 to 7.7 months). Of the seven patients with immune-mediated hepatitis, atezolizumab was temporarily interrupted in four patients; none of these patients developed recurrence of hepatitis after resuming atezolizumab.1

Monitor patients for signs and symptoms of hepatitis. Monitor AST, ALT, and bilirubin prior to and periodically during treatment with atezolizumab. Administer corticosteroids at a dose of 1-2 mg/kg/day prednisone equivalents for grade 2 or greater transaminase elevations, with or without concomitant elevation in total bilirubin, followed by corticosteroid taper. Withhold atezolizumab for grade 2 and permanently discontinue atezolizumab for grade 3 or 4 immune-mediated hepatitis.1

Immune-related Colitis

Immune-mediated colitis or diarrhea, defined as requiring use of corticosteroids and with no clear alternate etiology, occurred in patients receiving atezolizumab. Across clinical trials, colitis or diarrhea occurred in 19.7% (389/1978) of all patients and in 18.7% (98/523) of patients with urothelial carcinoma. Ten patients (1.9%) developed grade 3 or 4 diarrhea. Four patients (0.8%) had immune-mediated colitis or diarrhea with a median time to onset of 1.7 months (range: 1.1 to 3.1 months). Immune-mediated colitis resolved with corticosteroid administration in three of these patients, while the other patient died without resolution of colitis in the setting of diarrhea-associated renal failure.1

Monitor patients for signs and symptoms of diarrhea or colitis. Withhold treatment with atezolizumab for grade 2 diarrhea or colitis. If symptoms persist for longer than 5 days or recur, administer 1–2 mg/kg prednisone or equivalent per day. Withhold treatment with atezolizumab for grade 3 diarrhea or colitis. Treat with IV methylprednisolone 1–2 mg/kg per day and convert to oral steroids once the patient has improved. For both grade 2 and grade 3 diarrhea or colitis, when symptoms improve to grade 0 or grade 1, taper steroids over ≥ 1 month. Resume treatment with atezolizumab if the event improves to grade 0 or 1 within 12 weeks and corticosteroids have been reduced to the equivalent of ≤ 10 mg oral prednisone per day. Permanently discontinue atezolizumab for grade 4 diarrhea or colitis.1

Immune-related Endocrinopathies

Immune-related thyroid disorders, adrenal insufficiency, hypophysitis, and type 1 diabetes mellitus, including diabetic ketoacidosis, have occurred in patients receiving atezolizumab. Monitor patients for clinical signs and symptoms of endocrinopathies.1

Hypophysitis occurred in 0.2% (1/523) of patients with urothelial cancer receiving atezolizumab. Monitor for signs and symptoms of hypophysitis. Administer corticosteroids and hormone replacement as clinically indicated. Withhold atezolizumab for grade 2 or grade 3 and permanently discontinue for grade 4 hypophysitis. 1

Thyroid function was assessed routinely only at baseline and the end of the study. Across clinical trials, hypothyroidism occurred in 3.9% (77/1978) of patients and in 2.5% (13/523) of patients with urothelial carcinoma. One patient had grade 3 and twelve patients had grade 1–2 hypothyroidism. The median time to first onset was 5.4 months (range: 21 days to 11.3 months). Thyroid stimulating hormone (TSH) was elevated and above the patient's baseline in 16% (21/131) of patients with a follow-up measurement.1

Hyperthyroidism occurred in 1.0% (20/1978) of patients across clinical trials and in 0.6% (3/523) of patients with urothelial carcinoma. Of the three urothelial carcinoma patients, one patient had grade 2 and two patients had grade 1 hyperthyroidism. The median time to onset was 3.2 months (range: 1.4 to 5.8 months). TSH was decreased and below the patient's baseline in 3.8% (5/131) of patients with a follow-up measurement.1 Monitor thyroid function prior to and periodically during treatment with atezolizumab. Asymptomatic patients with abnormal thyroid function tests can receive atezolizumab. For symptomatic hypothyroidism, withhold atezolizumab and initiate thyroid hormone replacement as needed. Manage isolated hypothyroidism with replacement therapy and without corticosteroids. For symptomatic hyperthyroidism, withhold atezolizumab and initiate an anti-thyroid drug as needed. Resume treatment with atezolizumab when symptoms of hypothyroidism or hyperthyroidism are controlled and thyroid function is improving. 1

Adrenal insufficiency occurred in 0.4% (7/1978) of patients across clinical trials, including two patients with grade 3, four patients with grade 2, and one patient with grade 1. Adrenal insufficiency resolved in two patients. 1 For symptomatic adrenal insufficiency, withhold atezolizumab and administer methylprednisolone 1–2 mg/kg per day IV followed by oral prednisone 1–2 mg/kg per day or equivalent once symptoms improve. Start steroid taper when symptoms improve to ≤ grade 1 and taper steroids over ≥ 1 month. Resume treatment with atezolizumab if the event improves to ≤ grade 1 within 12 weeks and corticosteroids have been reduced to the equivalent of ≤ 10 mg oral prednisone per day and the patient is stable on replacement therapy, if required. 1

New onset diabetes with ketoacidosis has occurred in patients receiving atezolizumab. Diabetes mellitus without an alternative etiology occurred in one (0.2%) patient with urothelial carcinoma.1 Initiate treatment with insulin for type 1 diabetes mellitus. For ≥ grade 3 hyperglycemia (fasting glucose >250–500 mg/dL), withhold atezolizumab. Resume treatment with atezolizumab when metabolic control is achieved on insulin replacement therapy.1

Other Immune-related Adverse Reactions

Other immune-related adverse reactions including meningoencephalitis, myasthenic syndrome/myasthenia gravis, Guillain-Barré, ocular inflammatory toxicity, and pancreatitis, including increases in serum amylase and lipase levels, have occurred in ≤ 1.0% of patients treated with atezolizumab.1

Monitor patients for clinical signs and symptoms of meningitis or encephalitis. Permanently discontinue atezolizumab for any grade of meningitis or encephalitis. Treat with IV steroids (1–2 mg/kg/day methylprednisolone or equivalent) and convert to oral steroids (prednisone 60 mg/day or equivalent) once the patient has improved. When symptoms improve to ≤ grade 1, taper steroids over ≥ 1 month.1

Monitor patients for symptoms of motor and sensory neuropathy. Permanently discontinue atezolizumab for any grade of myasthenic syndrome/myasthenia gravis or Guillain-Barré syndrome. Institute medical intervention as appropriate. Consider initiation of systemic corticosteroids at a dose of 1–2 mg/kg/day prednisone.1

Symptomatic pancreatitis without an alternative etiology occurred in 0.1% (2/1978) of patients across clinical trials. Monitor patients for signs and symptoms of acute pancreatitis. Withhold atezolizumab for ≥ grade 3 serum amylase or lipase levels (> 2.0 ULN), or grade 2 or 3 pancreatitis. Treat with 1–2 mg/kg IV methylprednisolone or equivalent per day. Once symptoms improve, follow with 1–2 mg/kg of oral prednisone or equivalent per day. Resume treatment with atezolizumab if serum amylase and lipase levels improve to ≤ grade 1 within 12 weeks, symptoms of pancreatitis have resolved, and corticosteroids have been reduced to ≤ 10 mg oral prednisone or equivalent per day. Permanently discontinue atezolizumab for grade 4 or any grade of recurrent pancreatitis. 1

Infection

Severe infections, including sepsis, herpes encephalitis, and mycobacterial infection leading to retroperitoneal hemorrhage occurred in patients receiving atezolizumab. Across clinical trials, infections occurred in 38.4% (759/1978) of patients. In 523 patients with urothelial carcinoma who received atezolizumab, infection occurred in 197 (37.7%) patients. Grade 3 or 4 infection occurred in 60 (11.5%) patients, while three patients died due to infections. Urinary tract infections were the most common cause of grade 3 or higher infection, occurring in 37 (7.1%) patients.1

In a randomized trial in patients with non-small cell lung cancer, infections were more common in patients treated with atezolizumab (42%) compared with those treated with docetaxel (33%). Grade 3 or 4 infections occurred in 9.2% of patients treated with atezolizumab compared with 2.2% in patients treated with docetaxel. One patient (0.7%) treated with atezolizumab died due to infection, compared to two patients (1.5%) treated with docetaxel. Pneumonia was the most common cause of grade 3 or higher infection, occurring in 6.3% of patients treated with atezolizumab.1

Monitor patients for signs and symptoms of infection and treat with antibiotics for suspected or confirmed bacterial infections. Withhold atezolizumab for ≥ grade 3 infection.1

Infusion-related Reactions

Severe infusion reactions have occurred in patients in clinical trials of atezolizumab. Infusion-related reactions occurred in 1.3% (25/1978) of patients across clinical trials and in 1.7% (9/523) of patients with urothelial carcinoma. Interrupt or slow the rate of infusion in patients with mild or moderate infusion reactions. Permanently discontinue atezolizumab in patients with grade 3 or 4 infusion reactions. 1

Embryo-fetal Toxicity

Based on its mechanism of action, atezolizumab can cause fetal harm when administered to a pregnant woman. Animal studies have demonstrated that inhibition of the PD-L1/PD-1 pathway can lead to increased risk of immune-related rejection of the developing fetus resulting in fetal death. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with atezolizumab and for at least 5 months after the last dose.1

Specific Populations

Pregnancy

Based on its mechanism of action, atezolizumab can cause fetal harm when administered to a pregnant woman. There are no available data on the use of atezolizumab in pregnant women. Animal studies have demonstrated that inhibition of the PD-L1/PD-1 pathway can lead to increased risk of immune-related rejection of the developing fetus resulting in fetal death. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential risk to a fetus.1 In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.1

Animal reproduction studies have not been conducted with atezolizumab to evaluate its effect on reproduction and fetal development. A literature-based assessment of the effects on reproduction demonstrated that a central function of the PD-L1/PD-1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to a fetus. Blockage of PD-L1 signaling has been shown in murine models of pregnancy to disrupt tolerance to a fetus and to result in an increase in fetal loss; therefore, potential risks of administering atezolizumab during pregnancy include increased rates of abortion or stillbirth. As reported in the literature, there were no malformations related to the blockade of PD-L1/PD-1 signaling in the offspring of these animals; however, immune-mediated disorders occurred in PD-1 and PD-L1 knockout mice. Based on its mechanism of action, fetal exposure to atezolizumab may increase the risk of developing immune-mediated disorders or altering the normal immune response.1

Lactation

There is no information regarding the presence of atezolizumab in human milk, the effects on the breastfed infant, or the effects on milk production. As human IgG is excreted in human milk, the potential for absorption and harm to the infant is unknown. Because of the potential for serious adverse reactions in breastfed infants from atezolizumab, advise a lactating woman not to breastfeed during treatment and for at least 5 months after the last dose.1

Females and Males of Reproductive Potential

Based on its mechanism of action, atezolizumab can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with atezolizumab and for at least 5 months following the last dose.1

Based on animal studies, atezolizumab may impair fertility in females of reproductive potential while receiving treatment.1

Pediatric Use

The safety and effectiveness of atezolizumab have not been established in pediatric patients.1

Geriatric Use

Of the 310 patients with urothelial carcinoma treated with atezolizumab in Study 1, 59% were 65 years or older. No overall differences in safety or efficacy were observed between patients ≥ 65 years of age and younger patients.1

Renal Impairment

Based on a population pharmacokinetic analysis, no dose adjustment of atezolizumab is recommended for patients with renal impairment.1

Hepatic Impairment

Based on a population pharmacokinetic analysis, no dose adjustment of atezolizumab is recommended for patients with mild hepatic impairment. Atezolizumab has not been studied in patients with moderate or severe hepatic impairment.1

Common Adverse Effects

Most common adverse reactions (≥ 20% of patients) included: fatigue, decreased appetite, nausea, urinary tract infection, pyrexia, and constipation.1

Actions

Mechanism of Action

PD-L1 may be expressed on tumor cells and/or tumor-infiltrating immune cells and can contribute to the inhibition of the anti-tumor immune response in the tumor microenvironment. Binding of PD-L1 to the PD-1 and B7.1 receptors found on T cells and antigen presenting cells suppresses cytotoxic T-cell activity, T-cell proliferation and cytokine production. 1

Atezolizumab is a monoclonal antibody that binds to PD-L1 and blocks its interactions with both PD-1 and B7.1 receptors. This releases the PD-L1/PD-1 mediated inhibition of the immune response, including activation of the anti-tumor immune response without inducing antibody-dependent cellular cytotoxicity. In syngeneic mouse tumor models, blocking PD-L1 activity resulted in decreased tumor growth. 1

Advice to Patients

Advise the patient to read the FDA-approved patient labeling (Medication Guide).1

Advise female patients that atezolizumab can cause fetal harm. Instruct females of reproductive potential to use effective contraception during treatment and for at least 5 months after the last dose of atezolizumab.1

Advise female patients not to breastfeed while taking atezolizumab and for at least 5 months after the last dose.1

Inform patients of the risk of immune-related adverse reactions that may require corticosteroid treatment and interruption or discontinuation of atezolizumab, including: 1

  • Pneumonitis: Advise patients to contact their healthcare provider immediately for any new or worsening cough, chest pain, or shortness of breath.1

  • Hepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, pain on the right side of abdomen, lethargy, or easy bruising or bleeding.1

  • Colitis: Advise patients to contact their healthcare provider immediately for diarrhea or severe abdominal pain.1

  • Endocrinopathies: Advise patients to contact their healthcare provider immediately for signs or symptoms of hypophysitis, hyperthyroidism, hypothyroidism, adrenal insufficiency, or type 1 diabetes mellitus, including diabetic ketoacidosis.1

  • Meningoencephalitis, Myasthenic Syndrome/Myasthenia Gravis, and Guillain-Barré Syndrome: Advise patients to contact their healthcare provider immediately for signs or symptoms of meningitis, myasthenic syndrome/myasthenia gravis, or Guillain-Barré syndrome.1

  • Ocular Inflammatory Toxicity: Advise patients to contact their healthcare provider immediately for signs or symptoms of ocular inflammatory toxicity.1

  • Pancreatitis: Advise patients to contact their healthcare provider immediately for signs and symptoms of pancreatitis.1

  • Infection: Advise patients to contact their healthcare provider immediately for signs or symptoms of infection.1

  • Infusion-Related Reactions: Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion-related reactions.1

  • Rash: Advise patients to contact their healthcare provider immediately for signs or symptoms of rash.1

Additional Information

AHFS First Release. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Atezolizumab

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, Solution

1200 mg /20 mL

Tecentriq

Genentech Inc.

AHFS DI Essentials. © Copyright, 2016, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

Last reviewed: September 08, 2016
Date modified: October 12, 2016
Date published: September 08, 2016

References

1. Genentech, Inc. TECENTRIQ (atezolizumab) INTRAVENOUS prescribing information. 2016 May.

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