Drug Safety-related Labeling Changes (SrLC)
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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.
IMFINZI (BLA-761069)
(DURVALUMAB)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
12/04/2024 (SUPPL-49)
08/15/2024 (SUPPL-43)
07/24/2024 (SUPPL-47)
06/14/2024 (SUPPL-45)
04/22/2024 (SUPPL-48)
12/20/2023 (SUPPL-44)
06/16/2023 (SUPPL-42)
11/10/2022 (SUPPL-33)
10/21/2022 (SUPPL-36)
09/02/2022 (SUPPL-35)
05/11/2022 (SUPPL-32)
07/15/2021 (SUPPL-28)
11/18/2020 (SUPPL-23)
11/18/2020 (SUPPL-24)
11/18/2020 (SUPPL-25)
11/10/2020 (SUPPL-12)
06/05/2020 (SUPPL-20)
03/27/2020 (SUPPL-18)
5 Warnings and Precautions
5.1 Immune-Mediated Pneumonitis(additions
underlined)
…
The frequency and severity of immune-mediated pneumonitis were similar whether IMFINZI was given as a single agent in patients with various cancers or in combination with chemotherapy in patients with ES-SCLC.
…
6 Adverse Reactions
6.1 Clinical Trials Experience(additions and revisions, please refer to label for complete information)
(additions and revisions underlined)
…
Of 2280 patients who received IMFINZI 10 mg/kg every 2 weeks or 20 mg/kg every 4 weeks as a single- agent, 69 patients (3%) tested positive for treatment-emergent anti-drug antibodies (ADA) and 12 (0.5%) tested positive for neutralizing antibodies. The development of ADA against durvalumab appears to have no clinically relevant effect on its pharmacokinetics or safety.
Of 201 patients in the CASPIAN study who received IMFINZI 1500 mg every 3 weeks in combination with chemotherapy for four doses followed by IMFINZI 1500 mg every 4 weeks no patients tested positive for treatment-emergent ADA.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE(additions underlined)
…
What is IMFINZI?
IMFINZI is a prescription medicine used to treat adults with:
…
a type of lung cancer called small cell lung cancer (SCLC). IMFINZI may be used with the chemotherapy medicines etoposide and carboplatin or cisplatin as your first treatment when your SCLC:
has spread within your lungs or to other parts of the body, (extensive-stage small cell lung cancer, or ES-SCLC).
…
What are the possible side effects of IMFINZI?
IMFINZI can cause serious side effects, including:
…
The most common side effects of IMFINZI when used with other anticancer medicines in people with ES-SCLC include:
nausea
feeling tired or weak
hair loss
07/19/2019 (SUPPL-13)
02/16/2018 (SUPPL-2)
5 Warnings and Precautions
5.1 Immune-Mediated Pneumonitis(subsection revised, additions underlined)
IMFINZI can cause immune-mediated pneumonitis, defined as requiring use of corticosteroids. Fatal cases have been reported.
Monitor patients for signs and symptoms of pneumonitis. Evaluate patients with suspected pneumonitis with radiographic imaging. Administer corticosteroids, prednisone 1 to 2 mg per kg per day or equivalent for moderate (Grade 2) pneumonitis or prednisone 1 to 4 mg per kg per day or equivalent for more severe (Grade 3-4) pneumonitis, followed by taper. Interrupt or permanently discontinue IMFINZI based on the severity.
In clinical studies enrolling 1889 patients with various cancers who received IMFINZI, pneumonitis occurred in 5% of patients, including Grade 3 (0.8%), Grade 4 (< 0.1%) and Grade 5 (0.3%).immune-mediated pneumonitis. The median time to onset was 1.8 months (range: 1 day to 13.9 months) and the median time to resolution was 4.9 months (range: 0 days to 13.7 months).
Pneumonitis led to discontinuation of IMFINZI
in 1.5% of the 1889 patients. Pneumonitis resolved in 54% of patients. Systemic
corticosteroids were required in 3.5% of the 1889 patients, with 2.5% requiring
high-dose corticosteroids (prednisone greater than or equal to 40 mg per day or equivalent) and 0.1%
requiring infliximab.
The incidence of pneumonitis (including radiation pneumonitis) was higher in patients in the PACIFIC study who completed treatment with definitive chemoradiation within 42 days prior to initiation of IMFINZI (34%) compared to patients in other clinical studies (2.3%) in which radiation therapy was generally not administered immediately prior to initiation of IMFINZI.
In the PACIFIC study, the incidence of Grade 3 pneumonitis was 3.4% and of Grade 5 pneumonitis was 1.1% in the IMFINZI arm. The median time to onset of pneumonitis was 1.8 months and the median duration was 2.1 months (range: 3 days to 18.7 months). Pneumonitis led to discontinuation of IMFINZI in 6% of patients. Pneumonitis resolved in 47% of patients experiencing pneumonitis. Systemic corticosteroids were required in 21% of patients, with 12% requiring high-dose corticosteroids and 0.1% requiring infliximab.
(subsection revised, additions underlined)
IMFINZI can cause 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 IMFINZI, including clinical chemistry monitoring. Administer corticosteroids, prednisone 1 to 2 mg per kg per day or equivalent, followed by taper for Grade 2 or higher elevations of ALT, AST, and/or total bilirubin.
Interrupt or permanently discontinue IMFINZI based on the severity.
In clinical studies enrolling 1889 patients with various cancers who received IMFINZI, hepatitis occurred in 12% of patients, including Grade 3 (4.4%), Grade 4 (0.4%) and Grade 5 (0.2%) immune-mediated hepatitis. The median time to onset was 1.2 months (range: 1 day to
13.6 months). Hepatitis led to discontinuation of IMFINZI in 0.7% of the 1889 patients. Hepatitis resolved in 49% of patients. Systemic corticosteroids were required in 2.7% of patients, with 1.7% requiring high-dose corticosteroids and 0.1% requiring mycophenolate
(subsection revised, additions underlined)
IMFINZI can cause immune-mediated colitis, defined as requiring use of corticosteroids.
Monitor patients for signs and symptoms of diarrhea or colitis. Administer corticosteroids, prednisone 1 to 2 mg per kg per day or equivalent, for moderate (Grade 2) or more severe (Grade 3-4) colitis, followed by taper. Interrupt or permanently discontinue IMFINZI based on the severity.
In clinical studies enrolling
1889 patients with various cancers who received IMFINZI, diarrhea or colitis occurred in 18% of patients, including Grade 3
(1%) and Grade 4 (0.1%) immune-mediated colitis. The median time to onset was
1.4 months (range: 1 day to 14 months). Diarrhea or colitis lead to
discontinuation of IMFINZI in 0.4% of the 1889 patients. Diarrhea or colitis
resolved in 78% of the patients. Systemic corticosteroids were required in 1.9%
of patients, with 1%requiring high-dose corticosteroids and 0.1% requiring
other immunosuppressants (e.g., infliximab, mycophenolate).
(subsection revised, additions underlined)
IMFINZI can cause immune-mediated endocrinopathies, including thyroid disorders, adrenal insufficiency, type 1 diabetes mellitus and hypophysitis/hypopituitarism.
Thyroid Disorders: Monitor thyroid function prior to and periodically during treatment with IMFINZI. Initiate hormone replacement therapy or medical management of hyperthyroidism as clinically indicated.
Continue IMFINZI for hypothyroidism and interrupt for hyperthyroidism based on the severity.
In clinical studies enrolling 1889 patients who received IMFINZI , hypothyroidism occurred in 11% of patients and hyperthyroidism occurred in 7% of patients. Thyroiditis occurred in 0.9% of patients, including Grade 3 (< 0.1%) thyroiditis. Hypothyroidism was preceded by thyroiditis or hyperthyroidism in 25% of patients.
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 per kg per day or equivalent, followed by corticosteroid taper and hormone replacement as clinically indicated. Interrupt IMFINZI based on the severity.
In clinical studies enrolling 1889 patients who received IMFINZI, adrenal insufficiency occurred in 0.7% of patients, including Grade 3 (< 0.1%) adrenal insufficiency. Systemic corticosteroids were required in 0.4% of patients, including 0.1% of patients 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 IMFINZI based on the severity.
In clinical studies enrolling 1889 patients who received IMFINZI, type 1 diabetes mellitusoccurred in
< 0.1 % of patients. The median time to onset was 1.4 months.
For Grade 2 or higher hypophysitis, initiate prednisone 1 to 2 mg per kg per day or equivalent, followed by corticosteroid taper and hormone replacement therapy as clinically indicated. Interrupt IMFINZI based on the severity
Hypopituitarism leading to adrenal insufficiency and diabetes insipidus occurred in0.1% of 1889 patients who received IMFINZI in clinical studies.
(new subsection
added)
IMFINZI can cause immune-mediated
nephritis defined as evidence of renal dysfunction, requirement for
corticosteroids. Fatal cases have occurred.
Monitor patients for abnormal renal function tests prior to and periodically during treatment with IMFINZI. Initiate prednisone 1 to 2 mg per kg per day or equivalent, for moderate (Grade 2) or severe (Grade 3-4) nephritis, followed by taper. Interrupt or permanently discontinue IMFINZI based on the severity.
In clinical studies enrolling 1889 patients with various cancers who received IMFINZI , nephritis (reported as any of the following increased creatinine or urea, acute kidney injury, renal failure, decreased glomerular filtration rate, tubulointerstitial nephritis, decreased creatinine clearance, glomerulonephritis, and nephritis) occurred in 6.3% of patients including Grade 3 (1.1%), Grade 4 (0.2%) and Grade 5 (0.1%) immune-mediated nephritis. The median time to onset was 2 months (range: 1 day to 14.2 months). IMFINZI was discontinued in 0.3% of the 1889 patients. Nephritis resolved in 50% of patients. Systemic corticosteroids were required in 0.6% of patients, with 0.4% receiving high-dose corticosteroids.
(new subsection added)
IMFINZI can cause
immune-mediated rash; bullous dermatitis, Stevens Johnson Syndrome (SJS)/toxic
epidermal necrolysis (TEN) have occurred with other products in this class.
Monitor for signs and symptoms of rash. Initiate prednisone 1 to 2 mg per kg per day or equivalent, for moderate (Grade 2) rash or dermatitis lasting for more than 1 week or severe (Grade 3-4) rash or dermatitis followed by taper. Interrupt or permanently discontinue IMFINZI based on the severity.
In clinical studies enrolling 1889 patients with various cancers who received IMFINZI, 26% of patients developed rash or dermatitis and 0.4% of the patients developed vitiligo. Rash or dermatitis led to discontinuation of IMFINZI in 0.1% of the 1889 patients. Rash resolved in 62% of patients. Systemic corticosteroids were required in 2.0% of patients, including high-dose corticosteroids in 1% of patients.
(subsection revised, additions underlined)
IMFINZI 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 IMFINZI, immune-mediated adverse reactions can also manifest after discontinuation of IMFINZI.
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 4 mg per kg per day or
equivalent, followed by taper. Interrupt or permanently discontinue IMFINZI,
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.
following clinically significant, immune-mediated adverse reactions occurred at an incidence of less than 1% each in 1889 patients who received IMFINZI: aseptic meningitis, hemolytic anemia, immune thrombocytopenic purpura, myocarditis, myositis, and ocular inflammatory toxicity, including uveitis and keratitis. The following clinically significant, immune-mediated adverse reactions have been reported with other products in this class: bullous dermatitis, Stevens Johnson Syndrome (SJS)/toxic epidermal necrolysis (TEN), pancreatitis, systemic inflammatory response syndrome, rhabdomyolysis, myasthenia gravis, histiocytic necrotizing lymphadenitis, demyelination, vasculitis, hemolytic anemia, iritis, encephalitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barré syndrome and Vogt-Koyanagi-Harada syndrome.
(subsection revised, additions underlined)
IMFINZI can cause serious infections, including fatal
cases.
Monitor patients for signs and symptoms of infection. For Grade 3 or higher infections, withhold IMFINZI and resume once clinically stable
In clinical studies enrolling 1889 patients with various cancers who received IMFINZI, infections occurred in 43% of patients, including Grade 3 (8%), Grade 4 (1.9%), and Grade 5 (1.0%). In the urothelial carcinoma cohort in Study 1108 the most common Grade 3 or higher infection was urinary tract infections which occurred in 4% of patients. In the PACIFIC study the most common Grade 3 or higher infection was pneumonia, which occurred in 5% of patients. The overall incidence of infections in IMFINZI-treated patients (56%) in the PACIFIC study was higher compared to patients in other studies (38%) in which radiation therapy was generally not administered immediately prior to initiation of IMFINZI.
(subsection revised, additions underlined)
IMFINZI 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 IMFINZI based on the severity. For Grade 1 or 2 infusion-related reactions, consider using pre-medications with subsequent doses.
In clinical studies enrolling 1889 patients with various cancers, infusion related reactions occurred in 2.2% of patients, including Grade 3 (0.3%).
6 Adverse Reactions
(additions underlined)…
Immune-Mediated Nephritis
Immune-Mediated Dermatologic Reactions
…
(extensive additions and revisions, please refer to label)
(additions and revisions underlined)
…
Due to the limitations in assay performance, the incidence of antibody development in patients receiving IMFINZI may be underestimated. Of 1570 patients who were treated with IMFINZI 10 mg/kg every 2 weeks and evaluable for the presence of anti-drug antibodies (ADAs), 45 (2.9%) patients tested positive for treatment-emergent ADAs. The development of treatment-emergent ADA against durvalumab appears to have no clinically relevant effect on its pharmacokinetic profile. There are insufficient numbers of patients with ADA to determine whether ADA alters the safety or efficacy of durvalumab.
8 Use in Specific Populations
8.3 Females and Males of Reproductive Potential(additions underlined)
Contraception
Females
Based on its mechanism of action and data from animal studies, IMFINZI can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with IMFINZI and for at least 3 months following the last dose of IMFINZI.
(additions and underlined)
Of the 182 patients treated with IMFINZI in patients with urothelial carcinoma, 112 patients were 65 years or older and 34 patients were 75 years or older. The overall response rate in patients 65 years or older was 15% (17/112) and was 12% (4/34) in patients 75 years or older. Grade 3 or 4 adverse reactions occurred in 38% (42/112) of patients 65 years or older and 35% (12/34) of patients 75 years or older.
Of the 476 patients treated with IMFINZI in the PACIFIC study, 45% were 65 years or older, while 7.6% were 75 years or older. No overall differences in safety or effectiveness were observed between patients 65 years or older and younger patients. The PACIFIC study did not include sufficient numbers of patients aged 75 years and over to determine whether they respond differently from younger patients.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION(additions underlined)
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Inform patients of the risk of immune-mediated adverse reactions that may require corticosteroid treatment and interruption or discontinuation of IMFINZI, including:
…
Nephritis: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis.
Dermatological Reactions: Advise patients to contact their healthcare provider immediately signs or symptoms of severe dermatological reactions.
…