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Guide
Drug Safety-related Labeling Changes (SrLC) Database
| ANDA | Abbreviated New Drug Application |
| BLA | Biologics License Application |
| CDER | Center for Drug Evaluation and Research |
| MG | Medication Guide |
| NDA | New Drug Application |
| PCI | Patient Counseling Information |
| PI | Patient Information |
| PLR | Physician Labeling Rule |
| PLLR | Pregnancy and Lactation Labeling Rule |
| Italics | For the most part, italics indicate an FDA comment such as:
Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section. |
| Underlines | Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text. |
Sections
| BW | Box Warning |
| WP | Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format) |
| AR | Adverse Reactions (in pre-PLR format, this may be a subheading under precautions). |
| DI | Drug Interactions (in pre-PLR format, this may be a subheading under precautions). |
| USP | Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format. |
| PCI/PI/MG | Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events. |
Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.
Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.
TECENTRIQ (BLA-761034)
(ATEZOLIZUMAB)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
04/22/2024 (SUPPL-53)
5 Warnings and Precautions
5.1 Severe and Fatal Immune-Mediated Adverse Reactions
Additions and/or revisions underlined:
…
Other (Hematologic/Immune): Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection, other transplant (including corneal graft) rejection.
05/12/2023 (SUPPL-49)
6 Adverse Reactions
6.2 Postmarketing ExperienceNew subsection added:
The following adverse reactions have been identified during post-approval use of TECENTRIQ. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Cardiac: pericarditis, pericardial effusion, cardiac tamponade
12/09/2022 (SUPPL-47)
6 Adverse Reactions
6.1 Clinical Trials ExperienceAdditions and/or revisions underlined:
…
Unresectable or Metastatic Alveolar Soft Part Sarcoma (ASPS)
The safety of TECENTRIQ was evaluated in 47 adult and 2 pediatric patients enrolled in Study ML39345 [see Clinical Studies (14.5)]. Adult patients received TECENTRIQ 1200 mg every
3 weeks and pediatric patients received 15 mg/kg up to a maximum 1200 mg every 3 weeks until disease progression or unacceptable toxicity. The median duration of exposure to TECENTRIQ was 8.9 months (1 to 40 months).
Serious adverse reactions occurred in 41% of patients receiving TECENTRIQ. The most frequent serious adverse reactions (>2%) were fatigue, pain in extremity, pulmonary hemorrhage, and pneumonia (4.1% each).
Dosage interruptions of TECENTRIQ due to an adverse reaction occurred in 35% of patients. The most common adverse reactions (greater than or equal to 3%) leading to dose interruptions were pneumonitis and pain in extremity (4.1% each).
Tables 20 and 21 summarize adverse reactions and laboratory abnormalities in Study ML39345.
Please refer to label to view Tables 20 and 21.
8 Use in Specific Populations
8.4 Pediatric UseAdditions and/or revisions underlined:
Alveolar Soft Part Sarcoma
The safety and effectiveness of TECENTRIQ for unresectable or metastatic ASPS have been established in pediatric patients aged 2 years and older. Use of TECENTRIQ for this indication is supported by evidence from an adequate and well controlled study of TECENTRIQ in adults and 2 adolescent pediatric patients (greater than or equal to 12 years of age) with ASPS with additional pharmacokinetic and safety data in pediatric patients 2 years to <17 years. These data suggest that atezolizumab exposure in pediatric patients aged 2 years and older is comparable with that of adults and is expected to result in similar safety and efficacy to that of adults [see Adverse Reactions (6.1), Pharmacokinetics (12.3), Clinical Studies (14.5)]. The course of unresectable or metastatic ASPS is sufficiently similar between pediatric patients 2 to 11 years old and that of adults and adolescent patients to allow extrapolation of efficacy and safety to pediatric patients 2 years and older.
The safety and effectiveness of TECENTRIQ for ASPS have not been established in pediatric patients younger than 2 years of age.
Solid Tumors and Lymphomas
The safety and effectiveness of TECENTRIQ in pediatric patients have not been established in non-small cell lung cancer, small-cell lung cancer, hepatocellular carcinoma, or melanoma.
The safety and effectiveness of TECENTRIQ were assessed, but not established in a single-arm, multi-center, multi-cohort trial (NCT02541604) in 60 pediatric patients aged 7 months to
<17 years with relapsed or progressive solid tumors and lymphomas. No new safety signals were observed in pediatric patients in this study.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDEAdditions and/or revisions underlined:
…
What is TECENTRIQ?
…
adults with a type of lung cancer called small cell lung cancer (SCLC). TECENTRIQ may be used with the chemotherapy medicines carboplatin and etoposide as your first treatment when your lung cancer
is a type called “extensive-stage SCLC,” which means that it has spread or grown.
adults with a type of liver cancer called hepatocellular carcinoma (HCC). TECENTRIQ may be used with the medicine bevacizumab when your liver cancer:
has spread or cannot be removed by surgery, and
you have not received other medicines by mouth or injection through your vein (IV) to treat your cancer.
adults with a type of skin cancer called melanoma. TECENTRIQ may be used with the medicines cobimetinib and vemurafenib when your melanoma:
has spread to other parts of the body or cannot be removed by surgery, and
has a certain type of abnormal “BRAF” gene. Your healthcare provider will perform a test to make sure this TECENTRIQ combination is right for you.
adults and children 2 years of age and older with a type of soft tissue tumor (cancer) called alveolar soft part sarcoma (ASPS). TECENTRIQ may be used when your sarcoma:
has spread to other parts of the body or cannot be removed by surgery. It is not known if TECENTRIQ is safe and effective when used:
in children younger than 2 years of age for the treatment of ASPS.
in children for the treatment of NSCLC, SCLC, HCC, or melanoma.
…
12/02/2022 (SUPPL-50)
6 Adverse Reactions
6.1 Clinical Trials ExperienceAdditions and/or revisions underlined:
… The data described in WARNINGS AND PRECAUTIONS reflect exposure to TECENTRIQ as a single-agent in 2616 patients in two randomized, active-controlled studies (POPLAR, OAK) and three open-label, single arm studies (PCD4989g, BIRCH, FIR) which enrolled 1636 patients with metastatic NSCLC, and 980 patients with other tumor types. TECENTRIQ was administered at a dose of 1200 mg intravenously …
Other
Withdrawal of the 1L metastatic urothelial carcinoma (mUC) accelerated approval indication for Tecentriq. This withdrawal affects many sections; please refer to label for complete information.
04/13/2021 (SUPPL-41)
8 Use in Specific Populations
8.5 Geriatric UseAdditions and/or revisions underlined
Of 2616 patients with metastatic urothelial carcinoma, metastatic NSCLC, and other tumor types treated with single agent TECENTRIQ in clinical studies, 49% were 65 years and over and 15% were 75 years and over.
Of 2421 patients with NSCLC and SCLC treated with TECENTRIQ in combination with other antineoplastic drugs in clinical studies, 48% were 65 years and over and 10% were 75 years and over.
No overall differences in safety or effectiveness were observed between patients aged 65 years or older and younger patients.
12/18/2020 (SUPPL-31)
5 Warnings and Precautions
5.4 Increased Mortality in Patients with Metastatic TNBC when TECENTRIQ is Used with Paclitaxel(Newly added subsection)
In a randomized trial in patients with metastatic TNBC, an increase in the risk of death was observed in patients treated with TECENTRIQ plus paclitaxel compared with placebo and paclitaxel in the PD-L1-positive population. The efficacy of TECENTRIQ in combination with paclitaxel in patients with unresectable locally advanced or metastatic TNBC has not been demonstrated [see Indications and Usage (1.3) and Clinical Studies (14.4)].
Do not substitute paclitaxel protein-bound with paclitaxel in combination with TECENTRIQ in clinical practice for metastatic TNBC outside of controlled trials.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE(Additions and/or revisions underlined)
…
a type of breast cancer called triple-negative breast cancer (TNBC). TECENTRIQ may be used with the medicine paclitaxel protein-bound when your breast cancer:
has spread or cannot be removed by surgery, and
- your cancer tests positive for “PD-L1”.
TECENTRIQ is not for use with the medicine paclitaxel (a different medicine than paclitaxel protein-bound) in TNBC when your breast cancer has spread or cannot be removed by surgery.
…
12/18/2020 (SUPPL-32)
5 Warnings and Precautions
5.4 Increased Mortality in Patients with Metastatic TNBC when TECENTRIQ is Used with Paclitaxel(Newly added subsection)
In a randomized trial in patients with metastatic TNBC, an increase in the risk of death was observed in patients treated with TECENTRIQ plus paclitaxel compared with placebo and paclitaxel in the PD-L1-positive population. The efficacy of TECENTRIQ in combination with paclitaxel in patients with unresectable locally advanced or metastatic TNBC has not been demonstrated [see Indications and Usage (1.3) and Clinical Studies (14.4)].
Do not substitute paclitaxel protein-bound with paclitaxel in combination with TECENTRIQ in clinical practice for metastatic TNBC outside of controlled trials.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE(Additions and/or revisions underlined)
…
a type of breast cancer called triple-negative breast cancer (TNBC). TECENTRIQ may be used with the medicine paclitaxel protein-bound when your breast cancer:
has spread or cannot be removed by surgery, and
- your cancer tests positive for “PD-L1”.
TECENTRIQ is not for use with the medicine paclitaxel (a different medicine than paclitaxel protein-bound) in TNBC when your breast cancer has spread or cannot be removed by surgery.
…
11/10/2020 (SUPPL-20)
5 Warnings and Precautions
5.1 Severe and Fatal Immune-Mediated Adverse Reactions(Subsection title revised)
(Extensive changes; please refer to label)
(Newly added subsection)
Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/PD-L1 blocking antibody. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1/PD-L1 blockage and allogeneic HSCT.
Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefits versus risks of treatment with a PD-1/PD-L1 blocking antibody prior to or after an allogeneic HSCT.
6 Adverse Reactions
(Additions and/or revisions underlined)
The following clinically significant adverse reactions are described elsewhere in the labeling:
Severe and Fatal Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1)]
Infusion-Related Reactions [see Warnings and Precautions (5.2)]
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE(Extensive changes; please refer to label)
(Additions and/or revisions underlined)
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Immune-Mediated Adverse Reactions
Inform patients of the risk of immune-mediated 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)].
Colitis: Advise patients to contact their healthcare provider immediately for diarrhea, blood or mucus in stools, or severe abdominal pain [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 (5.1)].
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 [see Warnings and Precautions (5.1)].
Nephritis: Advise patients to contact their healthcare provider immediately for pelvic pain, frequent urination, or unusual swelling. [see Warnings and Precautions (5.1)].
Dermatologic Adverse Reactions: Advise patients to contact their healthcare provider immediately for generalized rash, skin eruption, or painful skin and mucous membrane lesions [see Warnings and Precautions (5.1)].
- Other Immune-Mediated Adverse Reactions: Advise patients to contact their healthcare provider immediately for signs or symptoms of other potential immune-mediated adverse reactions [see Warnings and Precautions (5.1)].
Infusion-Related Reactions
Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion-related reactions [see Warnings and Precautions (5.2)].
Complications of Allogeneic HSCT after PD-1/PD-L1 inhibitors
Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefits versus risks of treatment with a PD-1/PD-L1 blocking antibody prior to or after an allogeneic HSCT [see Warnings and Precautions (5.3)].
Embryo-Fetal Toxicity
Advise females of reproductive potential that TECENTRIQ can cause harm to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.4), Use in Specific Populations (8.1, 8.3)].
Advise 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 (8.3)].
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)].
09/30/2020 (SUPPL-29)
8 Use in Specific Populations
8.4 Pediatric Use(Additions and/or revisions underlined)
The safety and effectiveness of TECENTRIQ have not been established in pediatric patients.
The safety and antitumor activity of TECENTRIQ were assessed but not established in a single- arm, multi-center, multi-cohort trial (NCT02541604) in 60 pediatric patients aged 7 months to <17 years with relapsed or progressive solid tumors and lymphomas. No new safety signals were observed in pediatric patients in this study.
In pediatric patients who received TECENTRIQ 15 mg/kg with a maximum dose of 1200 mg every 3 weeks, the steady-state exposure (AUC) of atezolizumab in pediatric patients aged 12 years or older was comparable to that in adult patients who received TECENTRIQ 1200 mg every 3 weeks, while the exposure trended lower in pediatric patients less than 12 years old.
07/30/2020 (SUPPL-28)
5 Warnings and Precautions
5.1 Immune-Mediated Pneumonitis
Newly added information to the bottom of the subsection:
In a clinical study enrolling 230 patients with unresectable or metastatic BRAF V600 mutation- positive melanoma who received TECENTRIQ in combination with cobimetinib and vemurafenib [see Adverse Reactions (6.1)], immune-mediated pneumonitis occurred in 13% of patients, including Grades 3-4 in 1.3% of patients.
5.2 Immune-Mediated Hepatitis
Newly added information to the bottom of the subsection:
In a clinical study enrolling 230 patients with unresectable or metastatic BRAF V600 mutation- positive melanoma who received TECENTRIQ in combination with cobimetinib and vemurafenib [see Adverse Reactions (6.1)], immune-mediated hepatitis occurred in 53% of patients, including Grades 3-4 in 22%, and Grade 5 in <1% of patients.
5.3 Immune-Mediated Colitis
Newly added information to the bottom of the subsection:
In a clinical study enrolling 230 patients with unresectable or metastatic BRAF V600 mutation- positive melanoma who received TECENTRIQ in combination with cobimetinib and vemurafenib [see Adverse Reactions (6.1)], diarrhea or colitis occurred in 50% of patients, including Grades 3-4 in 3% of patients.
5.4 Immune-Mediated Endocrinopathies
Additions and/or revisions underlined:
In clinical studies enrolling 2616 patients who received TECENTRIQ as a single-agent [see Adverse Reactions (6.1)], hypothyroidism occurred in 4.6% of patients, and 3.8% of patients required the use of hormone replacement therapy. Hyperthyroidism occurred in 1.6% of patients. One patient experienced acute thyroiditis.
In a clinical study enrolling 230 patients with unresectable or metastatic BRAF V600 mutation- positive melanoma who received TECENTRIQ in combination with cobimetinib and vemurafenib [see Adverse Reactions (6.1)], hypothyroidism occurred in 26% of patients.
In clinical studies enrolling 2421 patients with NSCLC and SCLC who received TECENTRIQ in combination with platinum-based chemotherapy [see Adverse Reactions (6.1)], hypothyroidism occurred in 11% of patients …
In a clinical study enrolling 230 patients with unresectable or metastatic BRAF V600 mutation- positive melanoma who received TECENTRIQ in combination with cobimetinib and vemurafenib [see Adverse Reactions (6.1)], hyperthyroidism occurred in 19% of patients, including Grades 3-4 in 0.9% of patients.
5.6 Infections
Newly added information to the bottom of the subsection:
In a clinical study enrolling 230 patients with unresectable or metastatic BRAF V600 mutation- positive melanoma who received TECENTRIQ in combination with cobimetinib and vemurafenib [see Adverse Reactions (6.1)], infections occurred in 60% of patients, including Grade 3-4 in 9%, and Grade 5 in 1.7% of patients. The most common infection was upper respiratory tract infection.
6 Adverse Reactions
6.1 Clinical Trials Experience
Additions and/or revisions underlined:
… In addition, the data reflect exposure to TECENTRIQ in combination with other antineoplastic drugs in 2421 patients with NSCLC (N = 2223) or SCLC (N = 198) enrolled in five randomized, active-controlled trials, including IMpower150, IMpower130 and IMpower133 …
The data also reflect exposure to TECENTRIQ administered in combination with cobimetinib and vemurafenib in 230 patients enrolled in IMspire150. Among the 230 patients, 62% were exposed to TECENTRIQ for longer than 6 months and 42% were exposed to TECENTRIQ for longer than 12 months.
Following Table 19: Laboratory Abnormalities Worsening from Baseline Occurring in
greater than or equal to20% of Patients with HCC Receiving TECENTRIQ in IMbrave150, the following information is newly added:
Melanoma
The safety of TECENTRIQ, administered with cobimetinib and vemurafenib was evaluated in
IMspire150, a double-blind, randomized (1:1), placebo-controlled study conducted in patients
with previously untreated BRAF V600 mutation-positive metastatic or unresectable melanoma
[see Clinical Studies (14.5)]. Patients received TECENTRIQ with cobimetinib and vemurafenib
(N=230) or placebo with cobimetinib and vemurafenib (n=281).
Among the 230 patients who received TECENTRIQ administered with cobimetinib and
vemurafenib, the median duration of exposure to TECENTRIQ was 9.2 months (range: 0-30
months) to cobimetinib was 10.0 months (range: 1-31 months) and to vemurafenib was 9.8
months (range: 1-31 months).
Fatal adverse reactions occurred in 3% of patients in the TECENTRIQ plus cobimetinib and
vemurafenib arm. Adverse reactions leading to death were hepatic failure, fulminant hepatitis,
sepsis, septic shock, pneumonia, and cardiac arrest.
Serious adverse reactions occurred in 45% of patients in the TECENTRIQ plus cobimetinib and
vemurafenib arm. The most frequent (greater than or equal to 2%) serious adverse reactions were hepatotoxicity (7%),
pyrexia (6%), pneumonia (4.3%), malignant neoplasms (2.2%), and acute kidney injury (2.2%).
Adverse reactions leading to discontinuation of TECENTRIQ occurred in 21% of patients in the
TECENTRIQ plus cobimetinib and vemurafenib arm. The most frequent (greater than or equal to 2%) adverse
reactions leading to TECENTRIQ discontinuation were increased ALT (2.2%) and pneumonitis
(2.6%).
Adverse reactions leading to interruption of TECENTRIQ occurred in 68% of patients in the
TECENTRIQ plus cobimetinib and vemurafenib arm. The most frequent (greater than or equal to 2%) adverse
reactions leading to TECENTRIQ interruption were pyrexia (14%), increased ALT (13%),
hyperthyroidism (10%), increased AST (10%), increased lipase (9%), increased amylase (7%),
pneumonitis (5%), increased CPK (4.3%), diarrhea (3.5%), pneumonia (3.5%), asthenia (3%),
rash (3%), influenza (3%), arthralgia (2.6%), fatigue (2.2%), dyspnea (2.2%), cough (2.2%),
peripheral edema (2.2%), uveitis (2.2%), bronchitis (2.2%), hypothyroidism (2.2%), and
respiratory tract infection (2.2%).
Tables 20 and 21 summarizes the incidence of adverse reactions and laboratory abnormalities in
Study IMspire150.
Table 20: Adverse Reactions Occurring in greater than or equal to10% of Patients on the TECENTRIQ plus Cobimetinib and Vemurafenib Arm or the Placebo plus Cobimetinib and Vemurafenib Arm and at a Higher Incidence (Between Arm Difference of greater than or equal to 5% All Grades or greater than or equal to 2% Grades 3-4 TECENTRIQ in IMspire150) Newly added table; please refer to label for complete information.
Clinically important adverse reactions in < 10% of patients who received TECENTRIQ plus
cobimetinib and vemurafenib were:
Cardiac Disorders: Arrhythmias, ejection fraction decreased, electrocardiogram QT prolonged
Eye Disorders: Uveitis
Gastrointestinal disorders: Pancreatitis
Infections and infestations: Pneumonia, urinary tract infection
Metabolism and nutrition disorders: Hyperglycemia
Nervous system Disorders: Dizziness, dysgeusia, syncope
Respiratory, thoracic and mediastinal disorders: Dyspnea, oropharyngeal pain
Skin and Subcutaneous Tissue Disorders: Vitiligo
Table 21: Laboratory Abnormalities Worsening from Baseline Occurring in greater than or equal to 20% of Patients Receiving TECENTRIQ plus Cobimetinib and Vemurafenib Arm or the Placebo plus Cobimetinib and Vemurafenib Arm and at a Higher Incidence (Between Arm Difference of greater than or equal to 5% All Grades or greater than or equal to 2% Grades 3-4) in IMspire150 Newly added table; please refer to label for complete information.
6.2 Immunogenicity
Newly added information at the bottom of the subsection:
Among 218 ADA-evaluable patients with melanoma who received TECENTRIQ in combination
with cobimetinib and vemurafenib in IMspire150, 13% (n=29) tested positive for treatment emergent
ADA at one or more post-dose time points. Patients who tested positive for treatment emergent
ADA had decreased systemic atezolizumab exposure [see Clinical Pharmacology
(12.3)]. There are insufficient numbers of patients with positive ADA to determine whether ADA
alters the efficacy or incidence or severity of adverse reactions.
8 Use in Specific Populations
8.5 Geriatric UseAdditions and/or revisions underlined:
Of 3040 patients with urothelial carcinoma, lung cancer, triple-negative breast cancer,
hepatocellular carcinoma, and melanoma who were treated with TECENTRIQ in clinical studies,
43% were 65 years and over and 12% were 75 years and over. No overall differences in safety or
effectiveness were observed between patients aged 65 years or older and younger patients.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDEWhat is TECENTRIQ?
TECENTRIQ is a prescription medicine used to treat adults with:
Newly added information (underlined) following a type of liver canner called hepatocellular carcinoma (HCC):
a type of skin cancer called melanoma. TECENTRIQ may be used with the medicines cobimetinib and vemurafenib when your melanoma:
has spread to other parts of the body or cannot be removed by surgery, and
has a certain type of abnormal “BRAF” gene. Your healthcare provider will perform a test to make sure this TECENTRIQ combination is right for you.
How will I receive TECENTRIQ?
For treatment of a type of skin cancer called melanoma, your healthcare provider will also prescribe you cobimetinib and vemurafenib. Take cobimetinib and vemurafenib exactly as your healthcare provider tells you.
What are the possible side effects of TECENTRIQ?
TECENTRIQ can cause serious side effects, including:
• See “What is the most important information I should know about TECENTRIQ?”
The most common side effects of TECENTRIQ when used in melanoma with cobimetinib and vemurafenib include:
skin rash
joint, muscle, or bone pain
feeling tired or weak
liver injury
fever
nausea
itching
swelling of legs or arms
mouth swelling (sometimes with sores)
low thyroid hormone levels
sunburn or sun sensitivity
05/29/2020 (SUPPL-25)
6 Adverse Reactions
6.1 Clinical Trials ExperienceTable 17: Laboratory Abnormalities Worsening from Baseline Occurring in greater than or equal to 20% of Patients with SCLC Receiving TECENTRIQ in IMpower133
Newly added information:
Hepatocellular Carcinoma (HCC)
The safety of TECENTRIQ in combination with bevacizumab was evaluated in IMbrave150, a multicenter, international, randomized, open-label trial in patients with locally advanced or metastatic or unresectable hepatocelullar carcinoma who have not received prior systemic treatment [see Clinical Studies (14.5)]. Patients received 1,200 mg of TECENTRIQ intravenously followed by 15 mg/kg bevacizumab (n=329) every 3 weeks, or 400 mg of sorafenib (n=156) given orally twice daily, until disease progression or unacceptable toxicity. The median duration of exposure to TECENTRIQ was 7.4 months (range: 0-16 months) and to bevacizumab was 6.9 months (range: 0-16 months). Fatal adverse reactions occurred in 4.6% of patients in the TECENTRIQ and bevacizumab arm. The most common adverse reactions leading to death were gastrointestinal and esophageal varices hemorrhage (1.2%) and infections (1.2%).
Serious adverse reactions occurred in 38% of patients in the TECENTRIQ and bevacizumab arm. The most frequent serious adverse reactions (greater than or equal to 2%) were gastrointestinal hemorrhage (7%), infections (6%), and pyrexia (2.1%).
Adverse reactions leading to discontinuation of TECENTRIQ occurred in 9% of patients in the TECENTRIQ and bevacizumab arm. The most common adverse reactions leading to TECENTRIQ discontinuation were hemorrhages (1.2%), including gastrointestinal, subarachnoid, and pulmonary hemorrhages; increased transaminases or bilirubin (1.2%); infusion-related reaction/cytokine release syndrome (0.9%); and autoimmune hepatitis (0.6%).
Adverse reactions leading to interruption of TECENTRIQ occurred in 41% of patients in the TECENTRIQ and bevacizumab arm; the most common (greater than or equal to 2%) were liver function laboratory abnormalities including increased transaminases, bilirubin, or alkaline phosphatate (8%); infections (6%); gastrointestinal hemorrhages (3.6%); thrombocytopenia/decreased platelet count (3.6%); hyperthyroidism (2.7%); and pyrexia (2.1%).
Immune-related adverse reactions requiring systemic corticosteroid therapy occurred in 12% of patients in the TECENTRIQ and bevacizumab arm.
Tables 18 and 19 summarize adverse reactions and laboratory abnormalities, respectively, in patients who received TECENTRIQ and bevacizumab in IMbrave150.
Newly added tables; please refer to label for complete information.
Table 18: Adverse Reactions Occurring in greater than or equal to 10% of Patients with HCC Receiving TECENTRIQ in IMbrave150
Table 19: Laboratory Abnormalities Worsening from Baseline Occurring in greater than or equal to 20% of Patients with HCC Receiving TECENTRIQ in IMbrave150
Newly added information:
Among 315 ADA-evaluable patients with HCC who received TECENTRIQ and bevacizumab in IMbrave150, 28% (n=88) tested positive for treatment-emergent ADA at one or more post-dose time points and 66% (58/88) of these 88 patients tested ADA-positive prior to receiving the third dose of TECENTRIQ. The ability of these binding ADA to neutralize atezolizumab is unknown. Patients who tested positive for treatment-emergent ADA had lower systemic atezolizumab exposure as compared to patients who were ADA-negative [see Clinical Pharmacology (12.3)]. Exploratory analyses showed that the subset of patients who were ADA-positive by week 6 (20%; 58/288) appeared to have less efficacy (effect on overall survival) as compared to patients who tested negative for treatment-emergent ADA by week 6; [see Clinical Studies (14.5)]. The presence of ADA did not have a clinically significant effect on the incidence or severity of adverse reactions.
8 Use in Specific Populations
8.5 Geriatric UseAdditions and/or revisions underlined:
Of 2810 patients with urothelial carcinoma, lung cancer, triple-negative breast cancer, and hepatocellular carcinoma who were treated with TECENTRIQ in clinical studies, 45% were 65 years and over and 12% were 75 years and over. No overall differences in safety or effectiveness were observed between patients aged 65 years or older and younger patients.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDEWhat is TECENTRIQ?
TECENTRIQ is a prescription medicine used to treat adults with:
Newly added information:
a type of liver cancer called hepatocellular carcinoma (HCC). TECENTRIQ may be used with the medicine bevacizumab when your liver cancer:
has spread or cannot be removed by surgery, and
you have not received other medicines by mouth or injection through your vein (IV) to treat your cancer.
How will I receive TECENTRIQ?
Newly added information:
The most common side effects of TECENTRIQ when used in hepatocellular carcinoma with bevacizumab include:
high blood pressure
feeling tired or weak
too much protein in the urine
05/18/2020 (SUPPL-27)
6 Adverse Reactions
6.1 Clinical Trials Experience(Extensive changes; please refer to label)
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE(Additions and/or revisions underlined)
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What is TECENTRIQ?
TECENTRIQ is a prescription medicine used to treat adults with:
a type of bladder and urinary tract cancer called urothelial carcinoma. TECENTRIQ may be used when your bladder cancer has spread or cannot be removed by surgery, and if you have any one of the following conditions:
you are not able to take chemotherapy that contains a medicine called cisplatin, and your cancer tests positive for “PD-L1”, or
you are not able to take chemotherapy that contains any platinum regardless of “PD-L1” status, or
you have tried chemotherapy that contains platinum, and it did not work or is no longer working.
a type of lung cancer called non-small cell lung cancer (NSCLC).
TECENTRIQ may be used alone as your first treatment when your lung cancer:
has spread or grown, and
your cancer tests positive for “high PD-L1”, and
your tumor does not have an abnormal “EGFR” or “ALK” gene.
TECENTRIQ may be used with the medicines bevacizumab, paclitaxel, and carboplatin as your first treatment when your lung cancer:
has spread or grown, and
is a type called “non-squamous NSCLC”, and
your tumor does not have an abnormal “EGFR” or “ALK” gene.
TECENTRIQ may be used with the medicines paclitaxel protein-bound and carboplatin as your first treatment when your lung cancer:
has spread or grown, and
is a type called “non-squamous NSCLC”, and
your tumor does not have an abnormal “EGFR” or “ALK” gene.
TECENTRIQ may also be used alone when your lung cancer:
has spread or grown, and
you have tried chemotherapy that contains platinum, and it did not work or is no longer working.
if your tumor has an abnormal “EGFR” or “ALK” gene, you should have also tried an FDA-approved therapy for tumors with these abnormal genes, and it did not work or is no longer working.
a type of breast cancer called triple-negative breast cancer (TNBC). TECENTRIQ may be used with the medicine paclitaxel protein-bound when your breast cancer:
has spread or cannot be removed by surgery, and
your cancer tests positive for “PD-L1”.
a type of lung cancer called small cell lung cancer (SCLC). TECENTRIQ may be used with the chemotherapy medicines carboplatin and etoposide as your first treatment when your lung cancer
- is a type called “extensive-stage SCLC,” which means that it has spread or grown.
It is not known if TECENTRIQ is safe and effective in children.
…
12/04/2019 (SUPPL-21)
6 Adverse Reactions
6.1 Clinical Trials Experience(extensive additions and revisions, please refer to label)
05/06/2019 (SUPPL-13)
5 Warnings and Precautions
5.7 Infusion-Related Reactions(Additions and/or revisions are underlined)
TECENTRIQ can cause severe or life-threatening infusion-related reactions. Monitor for signs and symptoms of infusion-related reactions. Interrupt, slow the rate of, or permanently discontinue TECENTRIQ based on the severity. For Grade 1 or 2 infusion-related reactions, consider using pre-medications with subsequent doses.
In clinical studies enrolling 2616 patients with various cancers who received TECENTRIQ as a single-agent, infusion-related reactions occurred in 1.3% of patients, including Grade 3 (0.2%). The frequency and severity of infusion-related reactions were similar whether TECENTRIQ was given as a single-agent in patients with various cancers, in combination with other antineoplastic drugs in NSCLC and SCLC, and across the recommended dose range (840 mg Q2W to 1680 mg Q4W).
05/06/2019 (SUPPL-14)
5 Warnings and Precautions
5.7 Infusion-Related Reactions(Additions and/or revisions are underlined)
TECENTRIQ can cause severe or life-threatening infusion-related reactions. Monitor for signs and symptoms of infusion-related reactions. Interrupt, slow the rate of, or permanently discontinue TECENTRIQ based on the severity. For Grade 1 or 2 infusion-related reactions, consider using pre-medications with subsequent doses.
In clinical studies enrolling 2616 patients with various cancers who received TECENTRIQ as a single-agent, infusion-related reactions occurred in 1.3% of patients, including Grade 3 (0.2%). The frequency and severity of infusion-related reactions were similar whether TECENTRIQ was given as a single-agent in patients with various cancers, in combination with other antineoplastic drugs in NSCLC and SCLC, and across the recommended dose range (840 mg Q2W to 1680 mg Q4W).
03/08/2019 (SUPPL-18)
6 Adverse Reactions
6.1 Clinical Trials Experience(extensive additions, please refer to label)
(subsection revised, additions and revisions underlined)
As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay.
Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other atezolizumab products may be misleading.
…
Among 434 patients with TNBC in IMpassion130, 13% tested positive for treatment-emergent ADA at one or more post-dose time points. Among 178 patients in PD-L1 positive subgroup with TNBC in IMpassion130, 12% tested positive for treatment-emergent ADA at one or more post-dose time points. Patients who tested positive for treatment-emergent ADA had decreased systemic atezolizumab exposure. There are insufficient numbers of patients in the PD-L1 positive subgroup with ADA to determine whether ADA alters the efficacy of atezolizumab. The presence of ADA did not have a clinically significant effect on the incidence or severity of adverse reactions.
8 Use in Specific Populations
8.5 Geriatric Use(additions underlined)
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Of the 452 patients with TNBC treated with TECENTRIQ in combination with paclitaxel protein-bound in IMpassion130, 23% were 65 years or older. No overall differences in safety or efficacy were observed between patients greater than or equal to 65 years of age and younger patients.
12/06/2018 (SUPPL-9)
5 Warnings and Precautions
5.1 Immune-Mediated Pneumonitis(additions underlined)
…
In clinical studies enrolling 2616 patients with various cancers who received TECENTRIQ as a single agent, pneumonitis occurred in 2.5% of patients, including Grade 3 (0.6%), Grade 4 (0.1%), and Grade 5 (< 0.1%) immune-mediated pneumonitis.
…
The incidence of pneumonitis in 793 TECENTRIQ-treated patients in IMpower150 was 4.5%, including Grade 3-4 (1.8%) events. Systemic corticosteroids were required in 4% of patients, including 2.8% who received high-dose corticosteroids (prednisone greater than or equal to 40 mg per day or equivalent) for a median duration of 3 days (1 day to 43 days) followed by a corticosteroid taper.
(additions underlined)
...
The incidence of hepatitis in 793 TECENTRIQ-treated patients in IMpower150 was 12.1%, including Grade 3-4 (4.0%) events. Systemic corticosteroids were required in 3.8% of the patients, with 2.6% requiring high-dose corticosteroids for a median duration of 7 days (1 day to 68 days) followed by a corticosteroid taper.
(additions underlined)
…
In clinical studies enrolling 2616 patients with various cancers who received TECENTRIQ as a single agent, diarrhea or colitis occurred in 20%, including Grade 3 (1.4%) events. The median time to onset of diarrhea or colitis was 1.5 months (1 day to 41 months). Diarrhea and colitis resolved in 85% of the patients. Diarrhea or colitis led to discontinuation of TECENTRIQ in 0.2% of 2616 patients. Systemic corticosteroids were required in 1.1% of patients and high-dose corticosteroids was required in 0.4% patients with a median duration of 3 days (1 day to 11 days) followed by a corticosteroid taper.
The incidence of diarrhea or colitis in 793 TECENTRIQ-treated patients in IMpower150 was 27%, including Grade 3-4 (4.3%) events. Systemic corticosteroids were required in 4.5% of patients and high-dose corticosteroids was required in 3.2% patients with a median duration of 5 days (1 day to 103 days) followed by a corticosteroid taper.
(additions unserlined)
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The incidence of hypothyroidism in 793 TECENTRIQ-treated patients in IMpower150 was 11.3%, and 8.6% of patients required hormone replacement therapy. Hyperthyroidism occurred in 3.4% of patients and 0.1% experienced thyroiditis.
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In clinical studies enrolling 2616 patients who received TECENTRIQ as a single agent, adrenal insufficiency occurred in 0.4% of patients, including Grade 3 (< 0.1%) adrenal insufficiency.
Median time to onset was 5.7 months (3 days to 19 months). There was insufficient information to adequately characterize the median duration of adrenal insufficiency. Adrenal insufficiency resolved in 27% of patients. Systemic corticosteroids were required in 0.3% of 2616 patients, including 0.1% who required high-dose corticosteroids.
The incidence of adrenal insufficiency in 793 TECENTRIQ-treated patients in Study IMpower150 was 0.8%.
…
In clinical studies enrolling 2616 patients who received TECENTRIQ as a single agent, type 1 diabetes mellitus occurred in < 0.1% of patients. Insulin was required in one patient. The incidence of new onset diabetes mellitus in 698 TECENTRIQ-treated patients in Study IMpower150 was 0.1%
…
In clinical studies enrolling 2616 patients who received TECENTRIQ as a single agent, Grade 2 hypophysitis occurred in < 0.1% of patients.
The incidence of hypophysitis in 793 TECENTRIQ-treated patients in IMpower150 was 0.4%, including Grade 2 (0.1%) and Grade 3 (0.1%) events.
(additions underlined)
…
The incidence of infections in 793 TECENTRIQ-treated patients in IMpower150 was 50.1%, including Grade 3 (12%), Grade 4 (1.9%), and Grade 5 (0.4%). The most common Grade 3 or higher infection was pneumonia, occurring in 4.8% of patients.
(additions underlined)
…
In clinical studies enrolling 2616 patients with various cancers who received TECENTRIQ as a single agent, infusion-related reactions occurred in 1.3% of patients, including Grade 3 (0.2%). The incidence of infusion-related reactions in 793 TECENTRIQ-treated patients in IMpower150 was 3.8%, including Grade 3-4 (0.8%).
6 Adverse Reactions
6.1 Clinical Trials Experience(extensive additions, please refer to label)
(additions underlined)
…
Among 364 ADA-evaluable patients with NSCLC who received TECENTRIQ with bevacizumab, paclitaxel and carboplatin in IMpower150, (36% (n=132) tested positive for treatment-emergent ADA at one or more post-dose time points and 83% of these 132 patients tested ADA positive prior to receiving the second dose of atezolizumab. The ability of these binding ADA to neutralize atezolizumab is unknown. Patients who tested positive for treatment- emergent ADA had lower systemic atezolizumab exposure as compared to patients who were ADA negative. The presence of ADA did not increase the incidence or severity of adverse reactions.
…
8 Use in Specific Populations
8.5 Geriatric Use(subsection revised, additions and revisions underlined)
Of the 919 patients treated with TECENTRIQ as a single-agent in IMvigor210 (Cohort 2) and OAK, 50% were 65 years or older. Of the 400 patients randomized to TECENTRIQ in combination with bevacizumab, paclitaxel, and carboplatin in IMpower150, 46% were 65 years or older and 9% were 75 years or older. No overall differences in safety or efficacy were observed between patients 65 years or older and younger patients in IMvigor210 (Cohort 2), OAK, and IMpower150.
Of the 310 previously-treated Of the 119 cisplatin-ineligible patients with urothelial carcinoma treated with TECENTRIQ as a single-agent in IMvigor210 (Cohort 1), 83% were 65 years or older and 41% were 75 years or older. No overall differences in safety or efficacy were observed between these patients and younger patients.
04/30/2018 (SUPPL-3)
5 Warnings and Precautions
5.1 Immune-Mediated Pneumonitis(Additions and/or revisions are underlined)
TECENTRIQ can cause immune-mediated pneumonitis or interstitial lung disease, defined as requiring use of corticosteroids, including fatal cases. Monitor patients for signs and symptoms of pneumonitis. Evaluate patients with suspected pneumonitis with radiographic imaging.
Administer corticosteroids, prednisone 1–2 mg/kg/day or equivalents, followed by a taper for Grade 2 or higher pneumonitis. Withhold or permanently discontinue TECENTRIQ based on the severity.
In clinical studies enrolling 2616 patients with various cancers who received TECENTRIQ [see Adverse Reaction (6.1)], pneumonitis occurred in 2.5% of patients, including Grade 3 (0.6%), Grade 4 (0.1%), and Grade 5 (< 0.1%) immune-mediated pneumonitis.
The median time to onset of pneumonitis was 3.6 months (3 days to 20.5 months) and median duration of pneumonitis was 1.4 months (1 day to 15.1 months). Pneumonitis resolved in 67% of patients. Pneumonitis led to discontinuation of TECENTRIQ in 0.4% of the 2616 patients. Systemic corticosteroids were required in 1.5% of patients, including 0.8% who received high-dose corticosteroids (prednisone greater than or equal to 40 mg per day or equivalent) for a median duration of 4 days (1 day to 45 days) followed by a corticosteroid taper.
(Additions and/or revisions are underlined)
TECENTRIQ can cause liver test abnormalities and immune-mediated hepatitis, defined as requiring use of corticosteroids. Fatal cases have been reported. Monitor patients for signs and symptoms of hepatitis, during and after discontinuation of TECENTRIQ, including clinical chemistry monitoring. Administer corticosteroids, prednisone 1–2 mg/kg/day or equivalents, followed by a taper for Grade 2 or higher elevations of ALT, AST and/or total bilirubin. Interrupt or permanently discontinue TECENTRIQ based on the severity.
In clinical studies enrolling 2616 patients with various cancers who received TECENTRIQ , hepatitis occurred in 9% of patients, including Grade 3 (2.3%), Grade 4 (0.6%), and Grade 5 (< 0.1%). The median time to onset of hepatitis was 1.4 months (1 days to 25.8 months) and median duration was 24 days (1 day to 13 months). Hepatitis resolved in 71% of patients. Hepatitis led to discontinuation of TECENTRIQ in 0.4% of 2616 patients. Systemic corticosteroids was required in 2% of the patients, with 1.3% requiring high-dose corticosteroids for a median duration of 3 days (1 day to 35 days) followed by a corticosteroid taper.
(Additions and/or revisions are underlined)
TECENTRIQ can cause immune-mediated colitis or diarrhea, defined as requiring use of corticosteroids. Monitor patients for signs and symptoms of diarrhea or colitis. Withhold treatment with TECENTRIQ for Grade 2 or 3 diarrhea or colitis. If symptoms persist for longer than 5 days or recur, administer corticosteroids, prednisone 1–2 mg/kg/day or equivalents, followed by a taper for Grade 2 diarrhea or colitis. Interrupt or permanently discontinue TECENTRIQ based on the severity.
In clinical studies enrolling 2616 patients with various cancers who received TECENTRIQ, diarrhea or colitis occurred in 20%, including Grade 3 (1.4%) events. The median time to onset of diarrhea or colitis was 1.5 months (1 day to 41 months). Diarrhea and colitis resolved in 85% of the Inpatients. Diarrhea or colitis led to discontinuation of TECENTRIQ in 0.2% of 2616 patients. Systemic corticosteroids were required in 1.1% of patients and high-dose corticosteroids was required in 0.4% patients with a median duration of 3 days (1 day to 11 days).
(Subsection title has been revised; additions and/or revisions are underlined)
TECENTRIQ can cause immune-mediated endocrinopathies, including thyroid disorders, adrenal insufficiency, and type 1 diabetes mellitus, including diabetic ketoacidosis, and hypophysitis/hypopituitarism.
Thyroid Disorders: Monitor thyroid function prior to and periodically during treatment with TECENTRIQ. Initiate hormone replacement therapy or medical management of hyperthyroidism as clinically indicated. Continue TECENTRIQ for hypothyroidism and interrupt for hyperthyroidism based on the severity.
In clinical studies enrolling 2616 patients who received TECENTRIQ, hypothyroidism occurred in 4.6% of patients and 3.8% of patients required the use of hormone replacement therapy. Hyperthyroidism occurred in 1.6% of patients. One patient was noted to have acute thyroiditis.
Adrenal Insufficiency: Monitor patients for clinical signs and symptoms of adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate prednisone 1 to 2 mg/kg/day or equivalents, followed by a taper and hormone replacement as clinically indicated. Interrupt TECENTRIQ based on the severity.
In clinical studies enrolling 2616 patients who received TECENTRIQ, adrenal insufficiency occurred in 0.4% of patients, including Grade 3 (less than < 0.1%) adrenal insufficiency. Median time to onset was 5.7 months (3 days to 19 months). There was insufficient information to adequately characterize the median duration of adrenal insufficiency. Adrenal insufficiency resolved in 27% of patients. Systemic corticosteroids were required in 0.3% of 2616 patients, including 0.1% who required high-dose corticosteroids.
Type 1 Diabetes Mellitus Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Interrupt TECENTRIQ based on the severity.
In clinical studies enrolling 2616 patients who received TECENTRIQ type 1 diabetes mellitus occurred in < 0.1% of patients. Insulin was required in one patient.
Hypophysitis: For Grade 2 or higher hypophysitis, initiate prednisone 1?2 mg/kg/day or equivalents, followed by a taper and hormone replacement therapy as clinically indicated. Interrupt TECENTRIQ based on the severity.
In clinical studies enrolling 2616 patients who received TECENTRIQ, Grade 2 hypophysitis occurred in < 0.1% of patients.
(Subsection title has been revised; additions and/or revisions are underlined)
TECENTRIQ can cause severe and fatal immune-mediated adverse reactions. These immune- mediated reactions may involve any organ system. While immune-mediated reactions usually manifest during treatment with TECENTRIQ, immune-mediated adverse reactions can also manifest after discontinuation of TECENTRIQ.
For suspected Grade 2 immune-mediated adverse reactions, exclude other causes and initiate corticosteroids as clinically indicated. For severe (Grade 3 or 4) adverse reactions, administer corticosteroids, prednisone 1 to 2 mg/kg/day or equivalents, followed by a taper. Interrupt or permanently discontinue TECENTRIQ, based on the severity of the reaction.
If uveitis occurs in combination with other immune-mediated adverse reactions, evaluate for Vogt-Koyanagi-Harada syndrome, which has been observed with other products in this class and may require treatment with systemic steroids to reduce the risk of permanent vision loss.
The following clinically significant, immune-mediated adverse reactions occurred at an incidence of < 1% in 2616 patients who received TECENTRIQ or were reported in other products in this class.
Dermatologic: bullous dermatitis, pemphigoid, erythema multiforme, Stevens Johnson Syndrome (SJS)/toxic epidermal necrolysis (TEN).
Gastrointestinal: pancreatitis, including increases in serum amylase or lipase levels
General: systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis
Hematological: autoimmune hemolytic anemia, immune thrombocytopenic purpura.
Musculoskeletal: myositis, rhabdomyolysis.
Neurological: Guillain-Barre syndrome, myasthenia syndrome/myasthenia gravis, demyelination, immune-related meningoencephalitis, aseptic meningitis, encephalitis, facial and abducens nerve paresis, polymyalgia rheumatica, autoimmune neuropathy, and Vogt-Koyanagi- Harada syndrome.
Ophthalmological: uveitis, iritis. Renal: nephrotic syndrome, nephritis. Vascular:vasculitis
(Newly added subsection)
TECENTRIQ can cause severe infections including fatal cases. Monitor patients for signs and symptoms of infection. For Grade 3 or higher infections, withhold TECENTRIQ and resume once clinically stable
In clinical studies enrolling 2616 patients with various cancers who received TECENTRIQ, infections occurred in 42% of patients, including Grade 3 (8.7%), Grade 4 (1.5%), and Grade 5 (1%). In patients with urothelial carcinoma, the most common Grade 3 or higher infection was urinary tract infections, occurring in 6.5% of patients. In patients with NSCLC, the most common Grade 3 or higher infection was pneumonia, occurring in 3.8% of patients.
(Additions and/or revisions are underlined)
TECENTRIQ can cause severe or life-threatening infusion-related reactions. Monitor for signs and symptoms of infusion-related reactions. Interrupt, slow the rate of, or permanently discontinue TECENTRIQ based on the severity. For Grade 1 or 2 infusion-related reactions, consider using pre-medications with subsequent doses.
In clinical studies enrolling 2616 patients with various cancers who received TECENTRIQ, infusion-related reactions occurred in 1.3% of patients, including Grade 3 (0.2 %).
(Additions and/or revisions are underlined)
Based on its mechanism of action, TECENTRIQ can cause fetal harm when administered to a pregnant woman. 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.
Verify pregnancy status of females of reproductive potential prior to initiating TECENTRIQ. Advise females of reproductive potential 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.
6 Adverse Reactions
6.1 Clinical Trials Experience(Additions and/or revisions are underlined)
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 the Warnings and Precautions section reflect exposure to TECENTRIQ in 2616 patients in two randomized, active-controlled studies (POPLAR, OAK) and four open- label, single arm studies (PCD4989g, IMvigor210, BIRCH, FIR) which enrolled 524 patients with metastatic urothelial carcinoma, 1636 patients with metastatic NSCLC, and 456 patients with other tumor types. TECENTRIQ was administered at a dose of 1200 mg intravenously every 3 weeks in all studies except PCD4989g. Among the 2616 patients, 36% were exposed for longer than 6 months and 20% were exposed for longer than 12 months.
The data described in this section were obtained from one open-label, single arm, multiple cohort study (IMvigor210) and one randomized open-label, active-controlled study (OAK) in which TECENTRIQ was administered to 429 patients with locally advanced and metastatic urothelial carcinoma and 609 patients with metastatic NSCLC. In these trials, TECENTRIQ was administered at a dose of 1200 mg intravenously every 3 weeks.
Cisplatin-Ineligible Patients with Locally Advanced or Metastatic Urothelial Carcinoma
The safety of TECENTRIQ was evaluated in IMvigor 210 (Cohort 1), a multicenter, open-label, single-arm trial that included 119 patients with locally advanced or metastatic urothelial carcinoma who were ineligible for cisplatin-containing chemotherapy and were either previously untreated or had disease progression at least 12 months after neoadjuvant or adjuvant chemotherapy. Patients received TECENTRIQ 1200 mg intravenously every 3 weeks until either unacceptable toxicity or disease progression. The median duration of exposure was 15 weeks (0 to 87 weeks).
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(Table title and numbers have been revised; please refer to label)
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NSCLC
The safety of TECENTRIQ was evaluated in OAK, a multicenter, international, randomized, open-label trial in patients with metastatic NSCLC who progressed during or following a platinum-containing regimen, regardless of PD-L1 expression. A total of 609 patients received TECENTRIQ 1200 mg intravenously every 3 weeks weeks until unacceptable toxicity, radiographic progression, or clinical progression or docetaxel (n=578) 75 mg/m2 intravenously every 3 weeks until unacceptable toxicity or disease progression. The study excluded patients with active or prior autoimmune disease or with medical conditions that required systemic corticosteroids . The study population characteristics were: median age of 63 years (25 to 85 years), 46% age 65 years or older, 62% male, 71% White, 20% Asian, 68% former smoker, 16% current smoker, and 63% had ECOG performance status of 1. The median duration of exposure was 3.4 months (0 to 26 months) in TECENTRIQ-treated patients and 2.1 months (0 to 23 months) in docetaxel-treated patients.
The most common adverse reactions (? 20%) in patients receiving TECENTRIQ were fatigue (43.5%), decreased appetite (23.5%), dyspnea (22%), and cough (26.4%). The most common Grade 3?4 adverse reactions (greater thatn or equal to 2%) were dyspnea, pneumonia, fatigue, anemia, and pulmonary embolism.
TECENTRIQ was discontinued due to adverse reactions in 8% of patients. The most common adverse reactions leading to TECENTRIQ discontinuation were fatigue, infections and dyspnea. Fatal adverse reactions occurred in 1.6% of patients; these included pneumonia, sepsis, septic shock, dyspnea, pulmonary hemorrhage, sudden death, myocardial ischemia or renal failure.
Adverse reactions leading to interruption of TECENTRIQ occurred in 25% of patients; the most common (greater than 1%) were pneumonia, liver function test abnormality, back pain. Serious adverse reactions occurred in 33.5% of patients. The most frequent serious adverse reactions (greater than 1%) were pneumonia, sepsis, dyspnea, pleural effusion, pulmonary embolism, pyrexia and respiratory tract infection.
Table 6 summarizes adverse reactions that occurred in at least 10% of patients treated with TECENTRIQ. Table 7 summarizes selected laboratory abnormalities worsening from baseline that occurred in greater than or equal to 20% of patients treated with TECENTRIQ .
(Table 6 and 7 has been revised; please refer to label)
(Additions and/or revisions are underlined)
As with all therapeutic proteins, there is a potential for immunogenicity.
Among 565 patients with NSCLC in OAK, 30% tested positive for treatment-emergent anti-drug antibodies (ADA) at one or more post-dose time points. The median onset time to ADA formation was 3 weeks. The ability of these binding ADA to neutralize atezolizumab is unknown. Patients who tested positive for treatment-emergent ADA also had decreased systemic atezolizumab exposure. Exploratory analyses showed that the subset of patients who were ADA positive by week 4 (21%; 118/560) appeared to have less efficacy (effect on overall survival) as compared to patients who tested negative for treatment- emergent ADA by week 4. The presence of ADA did not have a clinically significant effect on the incidence or severity of adverse reactions.
Among 275 patients with urothelial carcinoma in IMvigor210 (Cohort 2), 42% tested positive for treatment-emergent ADA at one or more post-dose time points. Among 111 patients in IMvigor210 (Cohort 1), 48% tested positive for treatment-emergent ADA at one or more post- dose time points. StudyPatients who tested positive for treatment-emergent ADA also had decreased systemic atezolizumab exposures. The presence of ADA did not have a clinically significant effect on the incidence or severity of adverse reactions.
The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to atezolizumab in the studies described above with the incidence of antibodies in other studies or to other products may be misleading.
8 Use in Specific Populations
8.1 Pregnancy(Additions and/or revisions are underlined)
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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 Advise females of reproductive potential of the potential risk to a fetus.
…
(Additions and/or revisions are underlined)
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 women not to breastfeed during treatment and for at least 5 months after the last dose.
(Additions and/or revisions are underlined)
Pregnancy Testing
Verify pregnancy status in females of reproductive potential prior to initiating TECENTRIQ.
(Additions and/or revisions are underlined)
Of the 609 patients with NSCLC treated with TECENTRIQ in OAK, 45% were 65 years or older. No overall differences in safety or efficacy were observed between patients ? 65 years of age and younger patients.
Of the 310 previously-treated patients with urothelial carcinoma treated with TECENTRIQ in IMvigor210 (Cohort 2), 59% were 65 years or older. Of the 119 cisplatin-ineligible patients with urothelial carcinoma treated with TECENTRIQ in IMvigor210 (Cohort 1), 83% were 65 years or older and 41% were 75 years or older. …
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION(Additions and/or revisions are underlined)
Advise the patient to read the FDA-approved patient labeling (Medication Guide). Immune-mediated adverse reactions
Inform patients of the risk of immune-mediated 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.
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.
Colitis: Advise patients to contact their healthcare provider immediately for diarrhea, blood or mucous in stools, or severe abdominal pain.
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.
Other Immune-Mediated Adverse Reactions: Advise patients to contact their healthcare provider immediately for signs or symptoms of other potential immune-mediated adverse reactions.
Infections
Advise patients to contact their healthcare provider immediately for signs or symptoms of infection
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)].
Embryo-Fetal Toxicity
Advise females of reproductive potential that TECENTRIQ can cause harm to a fetus and to inform their healthcare provider of a known or suspected pregnancy.
Advise females of reproductive potential to use effective contraception during treatment and for at least 5 months after the last dose of TECENTRIQ.
…
(Additions and/or revisions are underlined)
What is the most important information I should know about TECENTRIQ?
TECENTRIQ is a medicine that may treat a type of cancer in the bladder and urinary tract or a type of lung cancer by working with your immune system. TECENTRIQ can cause your immune system to attack normal organs and tissues and can affect the way they work. These problems can sometimes become serious or life-threatening and can lead to death.
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Intestinal problems (colitis). Signs and symptoms of colitis may include:
diarrhea (loose stools) or more bowel movements than usual
blood or mucous in your stools or dark, tarry, sticky stools
severe stomach area (abdomen) pain or tenderness
Hormone gland problems (especially the thyroid, adrenal glands, pancreas, and pituitary).
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Problems in other organs. Signs and symptoms may include:
feeling cold
constipation
your voice gets deeper
…
skin blisters or peeling
chest pain, irregular heartbeat, shortness of breath or swelling of the ankles
Severe infections. Signs and symptoms of infection may include:
• fever
• cough
• frequent urination
• flu-like symptoms
• pain when urinating, frequent urination or back pain
….
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.
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Before you receive TECENTRIQ, tell your healthcare provider about all of your medical conditions, including if you:
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- are pregnant or plan to become pregnant. TECENTRIQ can harm your unborn baby. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with TECENTRIQ.
If you are able to become pregnant:
Your healthcare provider should do a pregnancy test before you start treatment with TECENTRIQ.
You should use an effective method of birth control during your treatment and for at least 5 months after the last dose of TECENTRIQ.
...
03/13/2018 (SUPPL-5)
5 Warnings and Precautions
5.5 Other Immune-Related Adverse ReactionsAdditions and/or revisions underlined:
… Guillain-Barré, ocular inflammatory toxicity, pancreatitis, including increases in serum amylase and lipase levels, and myocarditis have occurred in less than or equal to 1.0% of patients treated with TECENTRIQ.
Myocarditis
Monitor patients for signs and symptoms of myocarditis. Withhold TECENTRIQ for Grade 2 myocarditis. Permanently discontinue TECENTRIQ for Grade 3 or 4 myocarditis. Consider initiation of treatment with systemic corticosteroids.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATIONAdditions and/or revisions underlined:
Myocarditis: Advise patients to contact their healthcare provider immediately for signs and symptoms of myocarditis