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Tecentriq

Generic Name: atezolizumab
Dosage Form: injection, solution

Indications and Usage for Tecentriq

Tecentriq (atezolizumab) is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who:

  • Have disease progression during or following platinum-containing chemotherapy
  • Have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials [see Clinical Studies (14.1)].

Tecentriq Dosage and Administration

Recommended Dosing

The recommended dose of Tecentriq is 1200 mg administered as an intravenous infusion over 60 minutes every 3 weeks until disease progression or unacceptable toxicity. If the first infusion is tolerated, all subsequent infusions may be delivered over 30 minutes. Do not administer Tecentriq as an intravenous push or bolus.

Dose Modifications

No dose reductions of Tecentriq are recommended.

Withhold Tecentriq for any of the following:

Tecentriq may be resumed in patients whose adverse reactions recover to Grade 0–1.

Permanently discontinue Tecentriq for any of the following:

Preparation and Administration

Preparation

Visually inspect drug product for particulate matter and discoloration prior to administration whenever solution and container permit. Tecentriq is a colorless to slightly yellow solution. Discard the vial if the solution is cloudy, discolored, or visible particles are observed. Do not shake the vial.

Prepare the solution for infusion as follows:

  • Withdraw 20 mL of Tecentriq from the vial.
  • Dilute into a 250 mL polyvinyl chloride (PVC), polyethylene (PE), or polyolefin (PO) infusion bag containing 0.9% Sodium Chloride Injection, USP.
  • Dilute with 0.9% Sodium Chloride Injection only.
  • Mix diluted solution by gentle inversion. Do not shake.
  • Discard partially used or empty vials of Tecentriq.

Storage of Infusion Solution

This product does not contain a preservative.

Administer immediately once prepared. If diluted Tecentriq infusion solution is not used immediately, it can be stored either:

  • At room temperature for no more than 6 hours from the time of preparation. This includes room temperature storage of the infusion in the infusion bag and time for administration for infusion.
  • Under refrigeration at 2°C–8°C (36°F–46°F) for no more than 24 hours.

Do not freeze.

Do not shake.

Administration

Administer the initial infusion over 60 minutes through an intravenous line with or without a sterile, non-pyrogenic, low-protein binding in-line filter (pore size of 0.2–0.22 micron). If the first infusion is tolerated, all subsequent infusions may be delivered over 30 minutes.

Do not co-administer other drugs through the same intravenous line.

Dosage Forms and Strengths

Injection: 1200 mg/20 mL (60 mg/mL) colorless to slightly yellow solution in a single-dose vial.

Contraindications

None.

Warnings and 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 Tecentriq. 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 Tecentriq, 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. Tecentriq 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).

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 Tecentriq until resolution for Grade 2 pneumonitis. Permanently discontinue Tecentriq for Grade 3 or 4 pneumonitis [see Dosage and Administration (2.2)].

Immune-Related Hepatitis

Immune-mediated hepatitis, defined as requiring use of corticosteroids and with no clear alternate etiology, occurred in patients receiving Tecentriq. Liver test abnormalities occurred in patients who received Tecentriq. 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, Tecentriq was temporarily interrupted in four patients; none of these patients developed recurrence of hepatitis after resuming Tecentriq.

Monitor patients for signs and symptoms of hepatitis. Monitor AST, ALT, and bilirubin prior to and periodically during treatment with Tecentriq. 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 Tecentriq for Grade 2 and permanently discontinue Tecentriq for Grade 3 or 4 immune-mediated hepatitis [see Dosage and Administration (2.2) and Adverse Reactions (6.1)].

Immune-Related Colitis

Immune-mediated colitis or diarrhea, defined as requiring use of corticosteroids and with no clear alternate etiology, occurred in patients receiving Tecentriq. 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.

Monitor patients for signs and symptoms of diarrhea or colitis. Withhold treatment with Tecentriq 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 Tecentriq 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 Tecentriq 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 Tecentriq for Grade 4 diarrhea or colitis [see Dosage and Administration (2.2) and Adverse Reactions (6.1)].

Immune-Related Endocrinopathies

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

Hypophysitis

Hypophysitis occurred in 0.2% (1/523) of patients with urothelial cancer receiving Tecentriq. Monitor for signs and symptoms of hypophysitis. Administer corticosteroids and hormone replacement as clinically indicated. Withhold Tecentriq for Grade 2 or Grade 3 and permanently discontinue for Grade 4 hypophysitis [see Dosage and Administration (2.2) and Adverse Reactions (6.1)].

Thyroid Disorders

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.

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.

Monitor thyroid function prior to and periodically during treatment with Tecentriq. Asymptomatic patients with abnormal thyroid function tests can receive Tecentriq. For symptomatic hypothyroidism, withhold Tecentriq and initiate thyroid hormone replacement as needed. Manage isolated hypothyroidism with replacement therapy and without corticosteroids. For symptomatic hyperthyroidism, withhold Tecentriq and initiate an anti-thyroid drug as needed. Resume treatment with Tecentriq when symptoms of hypothyroidism or hyperthyroidism are controlled and thyroid function is improving [see Dosage and Administration (2.2) and Adverse Reactions (6.1)].

Adrenal Insufficiency

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.

For symptomatic adrenal insufficiency, withhold Tecentriq 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 Tecentriq 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 [see Dosage and Administration (2.2) and Adverse Reactions (6.1)].

Diabetes Mellitus

New onset diabetes with ketoacidosis has occurred in patients receiving Tecentriq. Diabetes mellitus without an alternative etiology occurred in one (0.2%) patient with urothelial carcinoma.

Initiate treatment with insulin for type 1 diabetes mellitus. For ≥ Grade 3 hyperglycemia (fasting glucose >250–500 mg/dL), withhold Tecentriq. Resume treatment with Tecentriq when metabolic control is achieved on insulin replacement therapy [see Dosage and Administration (2.2) and Adverse Reactions (6.1)].

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 Tecentriq.

Meningitis / Encephalitis

Monitor patients for clinical signs and symptoms of meningitis or encephalitis. Permanently discontinue Tecentriq 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 [see Dosage and Administration (2.2) and Adverse Reactions (6.1)].

Motor and Sensory Neuropathy

Monitor patients for symptoms of motor and sensory neuropathy. Permanently discontinue Tecentriq 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 [see Dosage and Administration (2.2) and Adverse Reactions (6.1)].

Pancreatitis

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 Tecentriq 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 Tecentriq 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 Tecentriq for Grade 4 or any grade of recurrent pancreatitis [see Dosage and Administration (2.2) and Adverse Reactions (6.1)].

Infection

Severe infections, including sepsis, herpes encephalitis, and mycobacterial infection leading to retroperitoneal hemorrhage occurred in patients receiving Tecentriq. Across clinical trials, infections occurred in 38.4% (759/1978) of patients. In 523 patients with urothelial carcinoma who received Tecentriq, 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.

In a randomized trial in patients with non-small cell lung cancer, infections were more common in patients treated with Tecentriq (42%) compared with those treated with docetaxel (33%). Grade 3 or 4 infections occurred in 9.2% of patients treated with Tecentriq compared with 2.2% in patients treated with docetaxel. One patient (0.7%) treated with Tecentriq 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 Tecentriq.

Monitor patients for signs and symptoms of infection and treat with antibiotics for suspected or confirmed bacterial infections. Withhold Tecentriq for ≥ Grade 3 infection [see Dosage and Administration (2.2) and Adverse Reactions (6.1)].

Infusion-Related Reactions

Severe infusion reactions have occurred in patients in clinical trials of Tecentriq. 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 Tecentriq in patients with Grade 3 or 4 infusion reactions [see Dosage and Administration (2.2) and Adverse Reactions (6.1)].

Embryo-Fetal Toxicity

Based on its mechanism of action, Tecentriq 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 Tecentriq and for at least 5 months after the last dose [see Use in Specific Populations (8.1, 8.3)].

Adverse Reactions

The following adverse reactions are discussed in greater detail in other sections of the label:

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described in Table 1 reflects exposure to Tecentriq in Cohort 2 of Study 1. This cohort enrolled 310 patients in a single arm trial with locally advanced or metastatic urothelial carcinoma who had disease progression during or following at least one platinum-containing chemotherapy regimen or who had disease progression within 12 months of treatment with a platinum-containing neoadjuvant or adjuvant chemotherapy regimen [see Clinical Studies (14.1)]. Patients received 1200 mg of Tecentriq intravenously every 3 weeks until unacceptable toxicity or either radiographic or clinical progression. The median duration of exposure was 12.3 weeks (range: 0.1, 46 weeks).

The most common adverse reactions (≥ 20%) were fatigue (52%), decreased appetite (26%), nausea (25%), urinary tract infection (22%), pyrexia (21%), and constipation (21%). The most common Grade 3–4 adverse reactions (≥ 2%) were urinary tract infection, anemia, fatigue, dehydration, intestinal obstruction, urinary obstruction, hematuria, dyspnea, acute kidney injury, abdominal pain, venous thromboembolism, sepsis, and pneumonia.

Three patients (0.9%) who were treated with Tecentriq experienced either sepsis, pneumonitis, or intestinal obstruction which led to death. Tecentriq was discontinued for adverse reactions in 3.2% (10/310) of the 310 patients. Sepsis led to discontinuation in 0.6% (2/310) of patients. Adverse reactions leading to interruption of Tecentriq occurred in 27% of patients; the most common (> 1%) were liver enzyme increase, urinary tract infection, diarrhea, fatigue, confusional state, urinary obstruction, pyrexia, dyspnea, venous thromboembolism, and pneumonitis. Serious adverse reactions occurred in 45% of patients. The most frequent serious adverse reactions (> 2%) were urinary tract infection, hematuria, acute kidney injury, intestinal obstruction, pyrexia, venous thromboembolism, urinary obstruction, pneumonia, dyspnea, abdominal pain, sepsis, and confusional state.

Table 1 summarizes the adverse reactions that occurred in ≥ 10% of patients while Table 2 summarizes Grade 3–4 selected laboratory abnormalities that occurred in ≥ 1% of patients treated with Tecentriq in Cohort 2 of Study 1.

Table 1: All Grade Adverse Reactions in ≥ 10% of Patients with Urothelial Carcinoma in Study 1
Tecentriq
N = 310
Adverse Reaction All Grades
(%)
Grades 3 – 4
(%)
All Adverse Reactions 96 50
Gastrointestinal Disorders
Nausea 25 2
Constipation 21 0.3
Diarrhea 18 1
Abdominal pain 17 4
Vomiting 17 1
General Disorders and Administration
Fatigue 52 6
Pyrexia 21 1
Peripheral edema 18 1
Infections and Infestations
Urinary tract infection 22 9
Metabolism and Nutrition Disorders
Decreased appetite 26 1
Musculoskeletal and Connective Tissue Disorders
Back/Neck pain 15 2
Arthralgia 14 1
Renal and urinary disorders
Hematuria 14 3
Respiratory, Thoracic, and Mediastinal Disorders
Dyspnea 16 4
Cough 14 0.3
Skin and Subcutaneous Tissue Disorders
Rash 15 0.3
Pruritus 13 0.3
Table 2: Grade 3–4 Laboratory Abnormalities in Patients with Urothelial Carcinoma in Study 1 in ≥ 1% of Patients
Laboratory Test Grades 3–4
(%)
Lymphopenia 10
Hyponatremia 10
Anemia 8
Hyperglycemia 5
Increased Alkaline phosphatase 4
Increased Creatinine 3
Increased ALT 2
Increased AST 2
Hypoalbuminemia 1

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. Among 275 patients in Study 1, 114 patients (41.5%) tested positive for treatment-emergent (treatment-induced or treatment-enhanced) anti-therapeutic antibodies (ATA) at one or more post-dose time points. In Study 1, the presence of ATAs did not appear to have a clinically significant impact on pharmacokinetics, safety or efficacy.

Immunogenicity assay results are highly dependent on several factors, including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of incidence of ATAs to Tecentriq with the incidence of antibodies to other products may be misleading.

USE IN SPECIFIC POPULATIONS

Pregnancy

Risk Summary

Based on its mechanism of action, Tecentriq can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on the use of Tecentriq 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 [see Data]. 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.

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.

Data

Animal Data

Animal reproduction studies have not been conducted with Tecentriq 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 Tecentriq 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.

Lactation

Risk Summary

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 Tecentriq, advise a lactating woman not to breastfeed during treatment and for at least 5 months after the last dose.

Females and Males of Reproductive Potential

Contraception

Females

Based on its mechanism of action, Tecentriq can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with Tecentriq and for at least 5 months following the last dose.

Infertility

Females

Based on animal studies, Tecentriq may impair fertility in females of reproductive potential while receiving treatment [see Nonclinical Toxicology (13.1)].

Pediatric Use

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

Geriatric Use

Of the 310 patients with urothelial carcinoma treated with Tecentriq 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.

Renal Impairment

Based on a population pharmacokinetic analysis, no dose adjustment of Tecentriq is recommended for patients with renal impairment [see Clinical Pharmacology (12.3)].

Hepatic Impairment

Based on a population pharmacokinetic analysis, no dose adjustment of Tecentriq is recommended for patients with mild hepatic impairment. Tecentriq has not been studied in patients with moderate or severe hepatic impairment [see Clinical Pharmacology (12.3)].

Overdosage

There is no information on overdose with Tecentriq.

Tecentriq Description

Atezolizumab is an Fc-engineered, humanized, monoclonal antibody that binds to PD-L1 and blocks interactions with the PD-1 and B7.1 receptors. Atezolizumab is a non-glycosylated IgG1 kappa immunoglobulin that has a calculated molecular mass of 145 kDa.

Tecentriq injection for intravenous infusion is a sterile, preservative-free, colorless to slightly yellow solution in single-dose vials. Each mL of Tecentriq contains 60 mg of atezolizumab and is formulated in glacial acetic acid (16.5 mg), L-histidine (62 mg), sucrose (821.6 mg), polysorbate 20 (8 mg), pH 5.8.

Tecentriq - Clinical Pharmacology

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.

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.

Pharmacokinetics

Patients' exposures to atezolizumab increased dose proportionally over the dose range of 1 mg/kg to 20 mg/kg, including the fixed dose 1200 mg administered every 3 weeks. Based on a population analysis that included 472 patients in the dose range, the typical population clearance was 0.20 L/day, volume of distribution at steady state was 6.9 L, and the terminal half-life was 27 days. The population PK analysis suggests steady state is obtained after 6 to 9 weeks (2 to 3 cycles) of repeated dosing. The systemic accumulation in area under the curve (AUC), maximum concentration (Cmax) and trough concentration (Cmin) was 1.91, 1.46 and 2.75-fold, respectively.

Specific Populations: Age (21–89 years), body weight, gender, positive anti-therapeutic antibody (ATA) status, albumin levels, tumor burden, region or race, mild or moderate renal impairment (estimated glomerular filtration rate (eGFR) 30 to 89 mL/min/1.73 m2), mild hepatic impairment (bilirubin ≤ ULN and AST > ULN or bilirubin < 1.0 to 1.5 × ULN and any AST), level of PD-L1 expression, or ECOG status had no clinically significant effect on the systemic exposure of atezolizumab.

The effect of severe renal impairment (eGFR 15 to 29 mL/min/1.73 m2) or moderate or severe hepatic impairment (bilirubin > ULN and AST > ULN or bilirubin ≥ 1.0 to 1.5 × ULN and any AST) on the pharmacokinetics of atezolizumab is unknown.

Drug Interaction Studies

The drug interaction potential of atezolizumab is unknown.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

No studies have been performed to test the potential of atezolizumab for carcinogenicity or genotoxicity.

Animal fertility studies have not been conducted with atezolizumab; however, an assessment of the male and female reproductive organs was included in a 26-week, repeat-dose toxicity study in cynomolgus monkeys. Weekly administration of atezolizumab to female monkeys at the highest dose tested caused an irregular menstrual cycle pattern and a lack of newly formed corpora lutea in the ovaries. This effect occurred at an estimated AUC approximately 6 times the AUC in patients receiving the recommended dose and was reversible. There was no effect on the male monkey reproductive organs.

Animal Toxicology and/or Pharmacology

In animal models, inhibition of PD-L1/PD-1 signaling increased the severity of some infections and enhanced inflammatory responses. M. tuberculosis-infected PD-1 knockout mice exhibit markedly decreased survival compared with wild-type controls, which correlated with increased bacterial proliferation and inflammatory responses in these animals. PD-L1 and PD-1 knockout mice and mice receiving PD-L1 blocking antibody have also shown decreased survival following infection with lymphocytic choriomeningitis virus.

Clinical Studies

Urothelial Carcinoma

Tecentriq was investigated in Study 1, a multicenter, open-label, two-cohort trial that included patients with locally advanced or metastatic urothelial carcinoma. In Cohort 2 of Study 1, 310 patients with locally advanced or metastatic urothelial carcinoma who had disease progression during or following a platinum-containing chemotherapy regimen or who had disease progression within 12 months of treatment with a platinum-containing neoadjuvant or adjuvant chemotherapy regimen were treated with Tecentriq. This study excluded patients who had: a history of autoimmune disease, active or corticosteroid-dependent brain metastases, administration of a live, attenuated vaccine within 28 days prior to enrollment, or administration of systemic immunostimulatory agents or systemic immunosuppressive medications. Patients received an intravenous infusion of 1200 mg of Tecentriq every 3 weeks until unacceptable toxicity or either radiographic or clinical progression. Tumor response assessments were conducted every 9 weeks for the first 54 weeks and every 12 weeks thereafter. Major efficacy outcome measures included confirmed objective response rate (ORR) as assessed by independent review facility (IRF) using Response Evaluation Criteria in Solid Tumors (RECIST v1.1) and duration of response (DoR).

In this cohort, the median age was 66 years, 78% were male, 91% patients were Caucasian. Twenty-six percent had non-bladder urothelial carcinoma and 78% of patients had visceral metastases. Sixty-two percent of patients had an ECOG score of 1 and 35% of patients had a baseline creatinine clearance of < 60 mL/min. Nineteen percent of patients had disease progression following prior platinum-containing neoadjuvant or adjuvant chemotherapy. Forty-one percent of patients had received ≥ 2 prior systemic regimens in the metastatic setting. Seventy-three percent of patients received prior cisplatin, 26% had prior carboplatin, and 1% were treated with other platinum-based regimens.

Tumor specimens were evaluated prospectively using the Ventana PD-L1 (SP142) Assay at a central laboratory, and the results were used to define subgroups for pre-specified analyses. Of the 310 patients, 32% were classified as having PD-L1 expression of ≥ 5% (defined as PD-L1 stained tumor-infiltrating immune cells [ICs] covering ≥ 5% of the tumor area). The remaining, 68% of patients, were classified as having PD-L1 expression of <5% (PD-L1 stained tumor-infiltrating ICs covering < 5% of the tumor area).

Confirmed ORR in all patients and the two PD-L1 subgroups are summarized in Table 3. The median follow-up time for this cohort was 14.4 months. In 59 patients with disease progression following neoadjuvant or adjuvant therapy, the ORR was 22.0% (95% CI: 12.3%, 34.7%).

Table 3: Summary of Efficacy from Cohort 2 of Study 1
All Patients PD-L1 Expression Subgroups
N=310 PD-L1 Expression of < 5% in ICs*
(N=210)
PD-L1 Expression of ≥ 5% in ICs*
(N=100)
NR = Not reached
*
PD-L1 expression in tumor-infiltrating immune cells (ICs)
Denotes a censored value
Number of IRF-assessed Confirmed Responders 46 20 26
ORR % (95% CI) 14.8% (11.1, 19.3) 9.5% (5.9, 14.3) 26.0% (17.7, 35.7)
Complete Response (CR) (%) 5.5% 2.4% 12.0%
Partial Response (PR) (%) 9.4% 7.1% 14.0%
Median DoR, months (range) NR
(2.1, 13.8)
12.7
(2.1, 12.7)
NR
(4.2, 13.8)

How Supplied/Storage and Handling

Tecentriq injection is a sterile, preservative-free, and colorless to slightly yellow solution for intravenous infusion supplied as a carton containing one 1200 mg/20 mL single-dose vial (NDC 50242-917-01).

Storage: Store vials under refrigeration at 2°C to 8°C (36°F to 46°F) in original carton to protect from light. Do not freeze. Do not shake.

Patient Counseling Information

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

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

  • Pneumonitis: Advise patients to contact their healthcare provider immediately for any new or worsening cough, chest pain, or shortness of breath [see Warnings and Precautions (5.1)].
  • 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 [see Warnings and Precautions (5.2)].
  • Colitis: Advise patients to contact their healthcare provider immediately for diarrhea or severe abdominal pain [see Warnings and Precautions (5.3)].
  • 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 [see Warnings and Precautions (5.4)]
  • 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 [see Warnings and Precautions (5.5)].
  • Ocular Inflammatory Toxicity: Advise patients to contact their healthcare provider immediately for signs or symptoms of ocular inflammatory toxicity [see Warnings and Precautions (5.5)].
  • Pancreatitis: Advise patients to contact their healthcare provider immediately for signs and symptoms of pancreatitis [see Warnings and Precautions (5.5)].
  • Infection: Advise patients to contact their healthcare provider immediately for signs or symptoms of infection [see Warnings and Precautions (5.6)].
  • Infusion-Related Reactions: Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion-related reactions [see Warnings and Precautions (5.7)].
  • Rash: Advise patients to contact their healthcare provider immediately for signs or symptoms of rash [see Dosage and Administration (2.2)].

Embryo-Fetal Toxicity

Advise female patients that Tecentriq 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 Tecentriq [see Use in Specific Populations (8.1, 8.3)].

Lactation

Advise female patients not to breastfeed while taking Tecentriq and for at least 5 months after the last dose [see Use in Specific Populations (8.2)].

Tecentriq™ [atezolizumab]

Manufactured by:
Genentech, Inc.
A Member of the Roche Group
1 DNA Way
South San Francisco, CA 94080-4990

Tecentriq is a trademark of Genentech, Inc.
© 2016 Genentech, Inc.

U.S. License No. 1048

MEDICATION GUIDE
Tecentriq™ (te-SEN-trik)
(atezolizumab)
injection
What is the most important information I should know about Tecentriq?
Tecentriq is a medicine that may treat your bladder cancer by working with your immune system. Tecentriq can cause your immune system to attack normal organs and tissues in many areas of your body and can affect the way they work. These problems can sometimes become serious or life-threatening and can lead to death.
Call or see your healthcare provider right away if you get any symptoms of the following problems or these symptoms get worse:
Lung problems (pneumonitis). Signs and symptoms of pneumonitis may include:
  • new or worsening cough
  • shortness of breath
  • chest pain
Liver problems (hepatitis). Signs and symptoms of hepatitis may include:
  • yellowing of your skin or the whites of your eyes
  • severe nausea or vomiting
  • pain on the right side of your stomach area (abdomen)
  • drowsiness
  • dark urine (tea colored)
  • bleeding or bruising more easily than normal
  • feeling less hungry than usual
Intestinal problems (colitis). Signs and symptoms of colitis may include:
  • diarrhea (loose stools) or more bowel movements than usual
  • blood in your stools or dark, tarry, sticky stools
  • severe stomach area (abdomen) pain or tenderness
Hormone gland problems (especially the pituitary, thyroid, adrenal glands, and pancreas). Signs and symptoms that your hormone glands are not working properly may include:
  • headaches that will not go away or unusual headaches
  • extreme tiredness
  • weight gain or weight loss
  • dizziness or fainting
  • feeling more hungry or thirsty than usual
  • hair loss
  • feeling cold
  • constipation
  • your voice gets deeper
  • urinating more often than usual
  • nausea or vomiting
  • stomach area (abdomen) pain
  • changes in mood or behavior, such as decreased sex drive, irritability, or forgetfulness
Nervous system problems (neuropathy, meningoencephalitis). Signs of nervous system problems may include:
  • severe muscle weakness
  • numbness or tingling in hands or feet
  • fever
  • confusion
  • changes in mood or behavior
  • extreme sensitivity to light
  • neck stiffness
Inflammation of the eyes. Symptoms may include:
  • blurry vision, double vision, or other vision problems
  • eye pain or redness
Severe infections. Symptoms of infection may include:
  • fever
  • cough
  • frequent urination
  • flu-like symptoms
  • pain when urinating
Severe infusion reactions. Signs and symptoms of infusion reactions may include:
  • chills or shaking
  • itching or rash
  • flushing
  • shortness of breath or wheezing
  • dizziness
  • fever
  • feeling like passing out
  • back or neck pain
  • facial swelling
Getting medical treatment right away may help keep these problems from becoming more serious.
Your healthcare provider will check you for these problems during your treatment with Tecentriq. Your healthcare provider may treat you with corticosteroid or hormone replacement medicines. Your healthcare provider may delay or completely stop treatment with Tecentriq if you have severe side effects.
What is Tecentriq?
Tecentriq is a prescription medicine used to treat:
  • a type of bladder cancer called urothelial carcinoma. Tecentriq may be used when your bladder cancer has spread or cannot be removed by surgery (advanced urothelial carcinoma) and,
  • you have tried chemotherapy that contains platinum, and it did not work or is no longer working.
It is not known if Tecentriq is safe and effective in children.
Before you receive Tecentriq, tell your healthcare provider about all of your medical conditions, including if you:
  • have immune system problems such as Crohn's disease, ulcerative colitis, or lupus
  • have had an organ transplant
  • have lung or breathing problems
  • have liver problems
  • have a condition that affects your nervous system, such as Myasthenia Gravis or Guillain-Barré syndrome
  • are being treated for an infection
  • are pregnant or plan to become pregnant. Tecentriq can harm your unborn baby. If you are able to become pregnant, you should use an effective method of birth control during your treatment and for at least 5 months after the last dose of Tecentriq.
  • are breastfeeding or plan to breastfeed. It is not known if Tecentriq passes into your breast milk. Do not breastfeed during treatment and for at least 5 months after the last dose of Tecentriq.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
How will I receive Tecentriq?
  • Your healthcare provider will give you Tecentriq into your vein through an intravenous (IV) line over 30 to 60 minutes.
  • Tecentriq is usually given every 3 weeks.
  • Your healthcare provider will decide how many treatments you need.
  • Your healthcare provider will test your blood to check you for certain side effects.
    If you miss any appointments, call your healthcare provider as soon as possible to reschedule your appointment.
What are the possible side effects of Tecentriq?
Tecentriq can cause serious side effects, including:
The most common side effects of Tecentriq include:
  • feeling tired
  • decreased appetite
  • nausea
  • urinary tract infection
  • fever
  • constipation
These are not all the possible side effects of Tecentriq. Ask your healthcare provider or pharmacist for more information.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
General information about the safe and effective use of Tecentriq.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. If you would like more information about Tecentriq, talk with your healthcare provider. You can ask your healthcare provider for information about Tecentriq that is written for health professionals.
What are the ingredients in Tecentriq?
Active ingredient: atezolizumab
Inactive ingredients: glacial acetic acid, L-histidine, sucrose, polysorbate 20
Manufactured by: Genentech, Inc., A Member of the Roche Group, 1 DNA Way, South San Francisco, CA 94080 USA
U.S. License No. 1048 Tecentriq is a trademark of Genentech, Inc.
For more information, call 1-844-832-3687 or go to www.Tecentriq.com.
This Medication Guide has been approved by the U.S. Food and Drug Administration. Issued: 05/2016

"Representative sample of labeling (see HOW SUPPLIED section for complete listing):"

PRINCIPAL DISPLAY PANEL - 20 mL Vial Carton

NDC 50242-917-01

Tecentriq ™
(atezolizumab)
Injection

1200 mg/20 mL
(60 mg/mL)

For Intravenous Infusion After Dilution
Single-Dose Vial
Discard Unused Portion

No preservative.

Attention Pharmacist: Dispense the
accompanying Medication Guide
to each patient.

Rx only

1 vial

Genentech

10168531

Tecentriq 
atezolizumab injection, solution
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:50242-917
Route of Administration INTRAVENOUS DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
atezolizumab (atezolizumab) atezolizumab 1200 mg  in 20 mL
Inactive Ingredients
Ingredient Name Strength
histidine 62 mg  in 20 mL
acetic acid 16.5 mg  in 20 mL
sucrose 821.6 mg  in 20 mL
polysorbate 20 8 mg  in 20 mL
water  
Packaging
# Item Code Package Description
1 NDC:50242-917-01 1 VIAL, SINGLE-USE in 1 CARTON
1 20 mL in 1 VIAL, SINGLE-USE
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
BLA BLA761034 05/18/2016
Labeler - Genentech, Inc. (080129000)
Establishment
Name Address ID/FEI Operations
Roche Diagnostics GmbH 315028860 MANUFACTURE(50242-917), ANALYSIS(50242-917), PACK(50242-917)
Establishment
Name Address ID/FEI Operations
F. Hoffmann-La Roche Ltd 485244961 ANALYSIS(50242-917), LABEL(50242-917)
Establishment
Name Address ID/FEI Operations
Genentech, Inc. (Hillsboro) 833220176 LABEL(50242-917)
Establishment
Name Address ID/FEI Operations
F. Hoffmann-La Roche Ltd 482242971 API MANUFACTURE(50242-917), ANALYSIS(50242-917)
Revised: 05/2016
 
Genentech, Inc.
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