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  • CLASSES

    Antineoplastic Monoclonal Antibodies

    DEA CLASS

    Rx

    DESCRIPTION

    Humanized monoclonal antibody that binds to and blocks programmed death-ligand 1
    Used for locally advanced or metastatic urothelial carcinoma and platinum-resistant metastatic non-small cell lung cancer
    Immune-mediated reactions have been reported; treatment may need to be withheld or permanently discontinued

    COMMON BRAND NAMES

    Tecentriq

    HOW SUPPLIED

    Tecentriq Intravenous Inj Sol: 1mL, 60mg

    DOSAGE & INDICATIONS

    For the treatment of locally advanced or metastatic urothelial carcinoma, including bladder cancer and other urinary system cancers.
    For the treatment of locally advanced or metastatic urothelial carcinoma, including bladder cancer and other urinary system cancers, in patients who progress during or following any platinum-containing chemotherapy.
    Intravenous dosage
    Adults

    1,200 mg IV over 60 minutes every 3 weeks until disease progression or unacceptable toxicity. If the first infusion is tolerated, all subsequent infusions may be infused over 30 minutes. In a multicenter, open-label clinical trial, atezolizumab was administered to patients with locally advanced or metastatic urothelial cancer (n = 310); 19% of patients had progression following platinum-containing neoadjuvant or adjuvant therapy, while 41% had received 2 or more systemic regimens for metastatic disease. After a median follow-up of 32.9 months, the objective response rate (ORR) was 14.8% (95% CI, 11.1% to 19.3%) and the median duration of response was 27.7 months (range, 2.1+ months to 33.4+ months). In a subgroup analysis, those with less than 5% PD-L1 expression in tumor-infiltrating immune cells (ICs) had an ORR of 9.5% and a median duration of 20.9 months; the ORR was 26% and median duration 29.7 months in those with 5% or more PD-L1 expression in ICs.

    For the treatment of locally advanced or metastatic urothelial carcinoma, including bladder cancer and other urinary system cancers, in patients who progress within 12 months of neoadjuvant or adjuvant chemotherapy.
    Intravenous dosage
    Adults

    1,200 mg IV over 60 minutes every 3 weeks until disease progression or unacceptable toxicity. If the first infusion is tolerated, all subsequent infusions may be infused over 30 minutes. In a multicenter, open-label clinical trial, atezolizumab was administered to patients with locally advanced or metastatic urothelial cancer (n = 310); 19% of patients had progression following platinum-containing neoadjuvant or adjuvant therapy, while 41% had received 2 or more systemic regimens for metastatic disease. After a median follow-up of 32.9 months, the objective response rate (ORR) was 14.8% (95% CI, 11.1% to 19.3%) and the median duration of response was 27.7 months (range, 2.1+ months to 33.4+ months). In a subgroup analysis, those with less than 5% PD-L1 expression in tumor-infiltrating immune cells (ICs) had an ORR of 9.5% and a median duration of 20.9 months; the ORR was 26% and median duration 29.7 months in those with 5% or more PD-L1 expression in ICs.

    For the treatment of locally advanced or metastatic urothelial carcinoma, including bladder cancer and other urinary system cancers, in patients whose tumors express PD-L1 (5% or more) as determined by an FDA-approved test and are ineligible for cisplatin-containing chemotherapy or in patients who are not eligible for any platinum-containing chemotherapy, regardless of PD-L1 status.
    NOTE: Select cisplatin-ineligible patients based on the PD-L1 expression on tumor-infiltrating immune cells. Information on FDA-approved tests for the determination of PD-L1 expression in locally advanced or metastatic urothelial carcinoma is available at: http://www.fda.gov/CompanionDiagnostics.
    Intravenous dosage
    Adults

    1,200 mg IV over 60 minutes every 3 weeks until disease progression or unacceptable toxicity. If the first infusion is tolerated, all subsequent infusions may be infused over 30 minutes. Atezolizumab was administered to patients with locally advanced or metastatic urothelial carcinoma who were ineligible for cisplatin-containing chemotherapy (n = 119). After a median follow-up of 14.4 months, the objective response rate (ORR) was 23.5% (95% CI, 16.2% to 32.2%) and the median duration of response had not been reached (range, 3.7 months to 16.6+ months); 6.7% of patients experienced a complete response (CR), while a partial response (PR) was achieved in 16.8%. In a subgroup analysis, patients with less than 5% PD-L1 expression in tumor-infiltrating immune cells (ICs) (n = 87) had an ORR of 21.8% (CR, 6.9%; PR, 14.9%), while the ORR was 28.1% (CR, 6.3%; PR, 21.9%) in those with 5% or more PD-L1 expression in ICs; the median duration of response was not reached in either group. In an ongoing multicenter, randomized trial in previously untreated patients with metastatic urothelial carcinoma who are eligible for platinum-containing chemotherapy (IMvigor130), patients with PD-L1 expression of less than 5% had decreased survival with atezolizumab monotherapy compared to those who received platinum-based chemotherapy; the monotherapy arm of this trial was closed to accrual for patients with low PD-L1 expression upon the recommendation of the independent Data Monitoring Committee.

    For the treatment of metastatic non-small cell lung cancer (NSCLC), with disease progression on or after platinum-containing chemotherapy, and after progression on FDA-approved EGFR- or ALK-targeted therapy if applicable.
    Intravenous dosage
    Adults

    1,200 mg IV over 60 minutes on day 1, every 3 weeks until disease progression or unacceptable toxicity. If the first infusion is tolerated, subsequent doses may be given over 30 minutes. In clinical trials, atezolizumab could be continued beyond disease progression, as long as clinical benefit was evident. In a multicenter, randomized, open-label phase 2 clinical trial, second-line treatment of platinum-resistant NSCLC with atezolizumab significantly improved overall survival compared with docetaxel (12.6 months vs. 9.7 months); progression-free survival (PFS) and objective response rate (ORR) were not significantly different. In a pre-planned subgroup analysis, the benefit of atezolizumab was greater in patients with 1% or more PD-L1 expressing tumor cells or tumor-infiltrating cells. Atezolizumab was better tolerated than docetaxel.

    MAXIMUM DOSAGE

    Adults

    1,200 mg IV every 3 weeks.

    Geriatric

    1,200 mg IV every 3 weeks.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Baseline 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.
    Treatment-Related Hepatotoxicity
    AST/ALT 3 to 8 times the upper limit of normal (ULN) or total bilirubin 1.5 to 3 times ULN (grade 2): Hold atezolizumab therapy and initiate therapy with prednisone 1 to 2 mg/kg per day (or equivalent), followed by steroid taper. Resume therapy at the original dose when the AST or ALT recover to grade 1 or less and the corticosteroid dose is prednisone 10 mg per day (or equivalent) or less. Dosage adjustments of atezolizumab are not recommended. Permanently discontinue atezolizumab if resolution to grade 1 or less does not occur within 12 weeks, if steroids are unable to be tapered to less than or equal to prednisone 10 mg per day (or equivalent) within 12 weeks, or for recurrent grade 3 or 4 hepatotoxicity.
    AST/ALT more than 8 times ULN or total bilirubin more than 3 times ULN (grade 3 or higher): Permanently discontinue atezolizumab and initiate therapy with prednisone 1 to 2 mg/kg per day (or equivalent) followed by steroid taper.

    Renal Impairment

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

    ADMINISTRATION

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Administer the first dose intravenously, with or without a sterile, non-pyrogenic, low-protein binding in-line filter (0.2 to 0.22 micron), over 60 minutes. If tolerated, all subsequent infusions may be infused over 30 minutes.
    Interrupt or slow administration for grade 2 infusion-related reactions; the infusion may resume when symptoms have resolved to grade 0 or 1.
    Permanently discontinue atezolizumab for grade 3 or 4 infusion-related reactions.
    Do not administer atezolizumab as an IV push or bolus.
    Do not infuse through the same IV line with other drugs.
     
    Dilution
    Withdraw 20 mL (1,200 mg) atezolizumab from the vial and dilute into a polyvinyl chloride (PVC), polyethylene (PE), or polyolefin (PO) infusion bag containing 250 mL of 0.9% Sodium Chloride Injection. Mix by gentle inversion; do not shake.
    Store diluted solution at room temperature for no more than 6 hours (including infusion time), or under refrigeration (2 to 8 degrees C; 36 to 46 degrees F) for no more than 24 hours from the time of preparation.

    STORAGE

    Tecentriq :
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Do not freeze
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)
    - Store in original container

    CONTRAINDICATIONS / PRECAUTIONS

    Pneumonitis, pulmonary disease

    Use atezolizumab with caution in patients with pre-existing pulmonary disease. Immune-mediated pneumonitis or interstitial lung disease, including fatalities, has been reported with atezolizumab therapy. Monitor patients for signs and symptoms of pneumonitis (e.g., new or worsening cough, chest pain, shortness of breath); if suspected, confirm with radiographic imaging. Therapy may need to be temporarily withheld or permanently discontinued. Corticosteroids should be administered in patients who develop grade 2 or greater immune-mediated pneumonitis.

    Hepatic disease, hepatitis

    Use atezolizumab with caution in patients with baseline moderate to severe hepatic disease, as it has not been studied in this patient population; no initial dose adjustment is necessary for patients with mild hepatic impairment. Immune-mediated hepatitis requiring the use of corticosteroids has occurred in patients treated with atezolizumab. Monitor patients for signs and symptoms of hepatitis, including monitoring liver function tests (LFTs), prior to beginning treatment with atezolizumab, periodically during therapy, and after discontinuation of atezolizumab. An interruption or discontinuation of therapy may be necessary, along with treatment with high-dose corticosteroids.

    Autoimmune disease

    Atezolizumab treatment has been associated with serious and sometimes fatal immune-mediated toxicities. Cautious use of atezolizumab may be warranted in patients with a history of autoimmune disease or who are receiving systemic immunostimulatory agents or immunosuppressive therapy, as these patients were excluded from clinical trials.

    Colitis, diarrhea

    Atezolizumab treatment can result in severe and fatal immune-mediated colitis or diarrhea requiring the use of corticosteroids. Monitor patients for signs and symptoms of enterocolitis (diarrhea, abdominal pain, and mucus or blood in stool) and bowel perforation (peritoneal signs and ileus). In symptomatic patients, rule out infectious etiologies and consider endoscopic evaluation for persistent or severe symptoms; an interruption or discontinuation of therapy may be necessary, along with high-dose corticosteroids. Cautious use of atezolizumab in patients with inflammatory bowel disease such as ulcerative colitis or Crohn's disease may be warranted; patients with a history of autoimmune disease were excluded from clinical trials.

    Adrenal insufficiency, hyperthyroidism, hypophysitis, hypopituitarism, hypothyroidism, thyroid disease

    Atezolizumab can result in severe and life-threatening immune-mediated endocrinopathies, including hypophysitis and thyroid disorders. An interruption or discontinuation of therapy along with initiation of corticosteroid treatment may be necessary. Begin appropriate hormone replacement therapy as clinically indicated. Assess patients for signs and symptoms of endocrinopathy such as hypophysitis, hypopituitarism, adrenal insufficiency (including adrenal crisis), hyperthyroidism, and hypothyroidism; presentation may include fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, hypotension, or other nonspecific symptoms. Evaluate thyroid function tests at baseline and periodically during treatment. Cautious use of atezolizumab may be warranted for patients with pre-existing thyroid disease or Addison's disease; patients with a history of autoimmune disease were excluded from clinical trials.

    Diabetes mellitus, diabetic ketoacidosis

    Type 1 diabetes mellitus, including diabetic ketoacidosis, can occur in patients treated with atezolizumab. Initiate treatment with insulin as clinically indicated. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Cautious use of atezolizumab may be necessary in patients with pre-existing diabetes mellitus; patients with a history of autoimmune disease were excluded from clinical trials.

    Immune-mediated reactions

    Atezolizumab can cause severe and fatal immune-mediated reactions that may involve any organ system. These immune-mediated reactions usually occur during treatment, but can also occur after discontinuation of atezolizumab therapy. If an immune-mediated reaction occurs, an interruption or discontinuation of therapy may be necessary, along with treatment with high-dose corticosteroids.

    Pancreatitis

    Immune-mediated pancreatitis has been reported with atezolizumab treatment across clinical trials. Monitor patients for signs and symptoms of pancreatitis, including amylase and lipase levels. An interruption or discontinuation of therapy may be necessary, as well as treatment with corticosteroids.

    Infection

    Severe infection, including fatal cases, have occurred in patients treated with atezolizumab across clinical trials. The most common severe infections were urinary tract infections and pneumonia. Monitor patients for signs and symptoms of infection and treat with antibiotic or antiviral therapy as appropriate. Hold atezolizumab therapy for grade 3 or higher infections and resume once clinically stable.

    Infusion-related reactions

    Severe or life-threatening infusion-related reactions have occurred during administration of atezolizumab in clinical trials. Monitor for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion for mild to moderate reactions; consider premedication with subsequent doses of atezolizumab. Permanently discontinue atezolizumab for grade 3 or 4 infusion-related reactions.

    Myocarditis

    Myocarditis has been reported in patients treated with atezolizumab in clinical trials. Myocarditis may be immune-related, as has occurred with other similar-in-class drugs. Monitor patients for signs and symptoms of myocarditis. If myocarditis develops, consider treatment with systemic corticosteroids; an interruption or discontinuation of therapy may be necessary.

    Uveitis

    Immune-mediated ocular toxicity has been reported with atezolizumab therapy; monitor patients for signs or symptoms of blurred vision and reduced visual acuity. Consider a diagnosis of Vogt-Koyanagi-Harada-like syndrome if uveitis occurs in combination with other immune-mediated adverse reactions; this syndrome has been reported with other products in this class. Patients with Vogt-Koyanagi-Harada-like syndrome may require treatment with systemic steroids to reduce the risk of permanent vision loss.

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during treatment and for at least 5 months after the last dose. Although there are no adequately controlled studies in pregnant animals or humans, atezolizumab can cause fetal harm or death, including increased stillbirths and abortion, when administered during pregnancy based on its mechanism of action. A central function of the PD-L1/PD-1 pathway is to preserve pregnancy by maintaining a maternal immune tolerance of the fetus. Animal studies have shown that inhibition of the PD-L1/PD-1 pathway can lead to increased risk of immune-related rejection of a developing fetus, leading to fetal death. In mouse models, blocking the PD-1 pathway resulted in increased fetal loss. There were no fetal malformations identified in literature reports; however, fetal exposure to atezolizumab may increase the risk of developing immune-related disorders or altering the normal immune response.

    Contraception requirements, infertility, pregnancy testing, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during atezolizumab treatment. Atezolizumab can increase the risk of fetal loss, or may result in altered immune responses in surviving fetuses, if taken by the mother during pregnancy. Females should avoid pregnancy and use effective contraception during treatment with atezolizumab and for at least 5 months after the last dose. Females of reproductive potential should undergo pregnancy testing prior to initiation of atezolizumab. Women who become pregnant while receiving atezolizumab should be apprised of the potential hazard to the fetus. In addition, atezolizumab caused irregular menstrual cycles and lack of newly formed corpora lutea in the ovaries of female monkeys; there was no effect on male reproductive organs. Atezolizumab treatment may result in impaired fertility or infertility in females of reproductive potential.

    Breast-feeding

    Due to the potential for serious adverse reactions in nursing infants from atezolizumab, advise women to discontinue breast-feeding during treatment and for 5 months after the final dose. It is not known whether atezolizumab is present in human milk. Many drugs are excreted in human milk including antibodies.

    ADVERSE REACTIONS

    Severe

    hyponatremia / Delayed / 7.0-15.0
    lymphopenia / Delayed / 7.0-14.0
    infection / Delayed / 9.2-11.5
    hyperglycemia / Delayed / 5.0-10.0
    anemia / Delayed / 3.0-8.0
    fatigue / Early / 4.0-8.0
    diarrhea / Early / 0-5.0
    hypophosphatemia / Delayed / 4.0-5.0
    elevated hepatic enzymes / Delayed / 2.0-4.0
    hypoalbuminemia / Delayed / 1.0-4.0
    abdominal pain / Early / 0.8-4.0
    hyperbilirubinemia / Delayed / 0-3.0
    hepatitis / Delayed / 0-3.0
    anorexia / Delayed / 0-3.0
    back pain / Delayed / 0-3.0
    hematuria / Delayed / 0-3.0
    hypermagnesemia / Delayed / 0-3.0
    hypokalemia / Delayed / 2.0-3.0
    constipation / Delayed / 0.3-2.0
    nausea / Early / 0-2.0
    peripheral edema / Delayed / 1.0-2.0
    colitis / Delayed / 1.4-1.4
    myalgia / Early / 0-1.3
    vomiting / Early / 0-1.0
    hemolytic anemia / Delayed / 0-1.0
    Guillain-Barre syndrome / Delayed / 0-1.0
    pancreatitis / Delayed / 0-1.0
    Vogt-Koyanagi-Harada syndrome / Delayed / 0-1.0
    uveitis / Delayed / 0-1.0
    fever / Early / 0-1.0
    Stevens-Johnson syndrome / Delayed / 0-1.0
    toxic epidermal necrolysis / Delayed / 0-1.0
    rash / Early / 0-1.0
    erythema multiforme / Delayed / 0-1.0
    nephrotic syndrome / Delayed / 0-1.0
    hypomagnesemia / Delayed / 0-1.0
    myocarditis / Delayed / 0-1.0
    rhabdomyolysis / Delayed / 0-1.0
    vasculitis / Delayed / 0-1.0
    pruritus / Rapid / 0-0.8
    infusion-related reactions / Rapid / 0-0.2
    pleural effusion / Delayed / 1.0
    GI obstruction / Delayed / 2.0
    dehydration / Delayed / 2.0
    renal failure (unspecified) / Delayed / 2.0
    thromboembolism / Delayed / 1.0
    hypotension / Rapid / 2.0
    diabetic ketoacidosis / Delayed / Incidence not known
    pulmonary embolism / Delayed / Incidence not known

    Moderate

    antibody formation / Delayed / 30.0-48.0
    hyperthyroidism / Delayed / 0-1.6
    encephalopathy / Delayed / 0-1.0
    meningitis / Delayed / 0-1.0
    paresis / Delayed / 0-1.0
    myasthenia / Delayed / 0-1.0
    hyperamylasemia / Delayed / 0-1.0
    iritis / Delayed / 0-1.0
    bullous rash / Early / 0-1.0
    hypophysitis / Delayed / 0-0.1
    diabetes mellitus / Delayed / 0-0.1
    confusion / Early / 2.0
    chest pain (unspecified) / Early / Incidence not known
    cystitis / Delayed / Incidence not known
    edema / Delayed / Incidence not known

    Mild

    arthralgia / Delayed / 11.5-13.0
    purpura / Delayed / 0-1.0
    asthenia / Delayed / Incidence not known
    malaise / Early / Incidence not known
    lethargy / Early / Incidence not known
    maculopapular rash / Early / Incidence not known
    acneiform rash / Delayed / Incidence not known

    DRUG INTERACTIONS

    There are no drug interactions associated with Atezolizumab products.

    PREGNANCY AND LACTATION

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during treatment and for at least 5 months after the last dose. Although there are no adequately controlled studies in pregnant animals or humans, atezolizumab can cause fetal harm or death, including increased stillbirths and abortion, when administered during pregnancy based on its mechanism of action. A central function of the PD-L1/PD-1 pathway is to preserve pregnancy by maintaining a maternal immune tolerance of the fetus. Animal studies have shown that inhibition of the PD-L1/PD-1 pathway can lead to increased risk of immune-related rejection of a developing fetus, leading to fetal death. In mouse models, blocking the PD-1 pathway resulted in increased fetal loss. There were no fetal malformations identified in literature reports; however, fetal exposure to atezolizumab may increase the risk of developing immune-related disorders or altering the normal immune response.

    Due to the potential for serious adverse reactions in nursing infants from atezolizumab, advise women to discontinue breast-feeding during treatment and for 5 months after the final dose. It is not known whether atezolizumab is present in human milk. Many drugs are excreted in human milk including antibodies.

    MECHANISM OF ACTION

    Atezolizumab is an Fc-engineered, humanized, non-glycosylated IgG1 kappa monoclonal antibody that inhibits programmed death ligand 1 (PD-L1) interactions with the PD-1 and B7.1 receptors. PD-L1 may be expressed on tumor cells and/or tumor-infiltrating immune cells, and can contribute to inhibition of the anti-tumor immune response in the tumor microenvironment; PD-1 and B7.1 receptors are found on T-cells and antigen-presenting cells. The PD-1 pathway regulates the balance between T-cell activation and protection of healthy tissues from immune-mediated damage. In cancer, the PD-1 pathway is thought to play an important role in the interaction of tumor cells with the host immune response. Binding of PD-L1 to the PD-1 and B7.1 receptors suppresses cytotoxic T-cell activity, T-cell proliferation, and cytokine production; PD-L1 expression in a tumor cell may provide adaptive immune resistance and lead to poor outcomes. Atezolizumab binds to PD-L1 and prevents its interaction with both PD-1 and B7.1 receptors, releasing the PD-L1/PD-1 mediated inhibition of an anti-tumor immune response without inducing antibody-dependent cellular cytotoxicity. In syngeneic mouse tumor models, blocking PD-L1 activity resulted in decreased tumor growth.

    PHARMACOKINETICS

    Atezolizumab is administered intravenously. Exposure to atezolizumab increases in a dose proportional manner over a range of 1 mg/kg to 20 mg/kg, including the recommended fixed dose of 1,200 mg. Clearance was 0.2 L/day (CV, 29%) and volume of distribution (Vd) at steady-state was 6.9 L. Atezolizumab clearance was found to decrease over time, with a mean maximal reduction (% coefficient of variation; CV%) from baseline value of approximately 17.1% (CV%, 41%); however, this was not considered statistically relevant. The terminal half-life was 27 days, with steady-state reached after 6 to 9 weeks of repeated dosing (2 to 3 cycles).
     
    Affected cytochrome (CYP) 450 isoenzymes: None.

    Intravenous Route

    The systemic accumulation ratio at steady-state in AUC, Cmax, and Cmin was 1.9-, 1.5-, and 2.8-fold, respectively.