Imfinzi
(durvalumab)Dosage & Administration
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Imfinzi Prescribing Information
Non-Small Cell Lung Cancer
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- IMFINZI in combination with platinum-containing chemotherapy as neoadjuvant treatment, followed by IMFINZI continued as a single agent as adjuvant treatment after surgery, is indicated for the treatment of adult patients with resectable (tumors ≥ 4 cm and/or node positive) non-small cell lung cancer (NSCLC) and no known epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements.
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- IMFINZI, as a single agent, is indicated for the treatment of adult patients with unresectable Stage III NSCLC whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy (cCRT).
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- IMFINZI, in combination with tremelimumab-actl and platinum-based chemotherapy, is indicated for the treatment of adult patients with metastatic NSCLC with no sensitizing EGFR mutations or ALK genomic tumor aberrations.
Small Cell Lung Cancer
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- IMFINZI, as a single agent, is indicated for the treatment of adult patients with limited-stage small cell lung cancer (LS-SCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy (cCRT).
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- IMFINZI, in combination with etoposide and either carboplatin or cisplatin, is indicated for the first-line treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC).
Biliary Tract Cancers
IMFINZI, in combination with gemcitabine and cisplatin, is indicated for the treatment of adult patients with locally advanced or metastatic biliary tract cancer (BTC).
Hepatocellular Carcinoma
IMFINZI, in combination with tremelimumab-actl, is indicated for the treatment of adult patients with unresectable hepatocellular carcinoma (uHCC).
1.5 Endometrial Cancer
IMFINZI, in combination with carboplatin and paclitaxel followed by IMFINZI as a single agent, is indicated for the treatment of adult patients with primary advanced or recurrent endometrial cancer that is mismatch repair deficient (dMMR) as determined by an FDA-approved test [see Dosage and Administration (2.1)].
1.6 Bladder Cancer
IMFINZI in combination with gemcitabine and cisplatin as neoadjuvant treatment, followed by single agent IMFINZI as adjuvant treatment following radical cystectomy, is indicated for the treatment of adult patients with muscle invasive bladder cancer (MIBC).
2.1 Patient Selection
Advanced or Recurrent dMMR Endometrial Cancer
Select patients for treatment based on the presence of dMMR in tumor specimens [see Clinical Studies (14.5)].
Information on FDA-approved tests for the detection of dMMR status in endometrial cancer is available at https://www.fda.gov/companiondiagnostics.
Recommended Dosage
The recommended dosages for IMFINZI as a single agent and IMFINZI in combination with other therapeutic agents are presented in Table 1. The recommended dosage schedule and regimens for IMFINZI for the treatment of metastatic NSCLC are provided in Tables 2 and 3 [see Indications and Usage (1.1)].
Administer IMFINZI as an intravenous infusion after dilution as recommended [ see Dosage and Administration (2.3)].
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Indication | Recommended IMFINZI Dosage | Duration of Therapy |
Neoadjuvant and Adjuvant Treatment of Resectable NSCLC | Patients with a body weight of ≥ 30 kg: Neoadjuvant: IMFINZI 1,500 mg in combination with chemotherapy * every 3 weeks for up to 4 cycles prior to surgery Adjuvant: IMFINZI 1,500 mg as a single agent every 4 weeks for up to 12 cycles after surgery. Patients with a body weight of < 30 kg: Neoadjuvant: IMFINZI 20 mg/kg every 3 weeks in combination with chemotherapy * for up to 4 cycles prior to surgery. Adjuvant: IMFINZI 20 mg/kg every 4 weeks for up to 12 cycles as a single agent after surgery. | Until disease progression that precludes definitive surgery, recurrence, unacceptable toxicity, or a maximum of 12 cycles after surgery |
Unresectable Stage III NSCLC | Following concurrent platinum-based chemotherapy and radiation therapy: Patients with a body weight of ≥ 30 kg: 10 mg/kg every 2 weeks or 1,500 mg every 4 weeks Patients with a body weight of < 30 kg: 10 mg/kg every 2 weeks | Until disease progression, unacceptable toxicity, or a maximum of 12 months |
Limited Stage SCLC | Following concurrent platinum-based chemotherapy and radiation therapy: Patients with a body weight of ≥ 30 kg: 1,500 mg every 4 weeks Patients with a body weight of < 30 kg: 20 mg/kg every 4 weeks | Until disease progression, unacceptable toxicity, or a maximum of 24 months |
Extensive Stage SCLC | Patients with a body weight of ≥ 30 kg: 1,500 mg in combination with chemotherapy * every 3 weeks (21 days) for 4 cycles, followed by 1,500 mg every 4 weeks as a single agent Patients with a body weight of < 30 kg: 20 mg/kg in combination with chemotherapy * every 3 weeks (21 days) for 4 cycles, followed by 10 mg/kg every 2 weeks as a single agent | Until disease progression or until unacceptable toxicity |
BTC | Patients with a body weight of ≥ 30 kg: 1,500 mg in combination with chemotherapy * every 3 weeks (21 days) up to 8 cycles followed by 1,500 mg every 4 weeks as a single agent Patients with a body weight of < 30 kg: 20 mg/kg in combination with chemotherapy * every 3 weeks (21 days) up to 8 cycles followed by 20 mg/kg every 4 weeks as a single agent | Until disease progression or until unacceptable toxicity |
uHCC | Patients with a body weight of ≥ 30 kg:
Patients with a body weight of < 30 kg:
| After Cycle 1 of combination therapy, administer IMFINZI as a single agent every 4 weeks until disease progression or unacceptable toxicity |
dMMR endometrial cancer | Patients with a body weight of ≥ 30 kg: IMFINZI 1,120 mg in combination with carboplatin and paclitaxel * every 3 weeks (21 days) for 6 cycles, followed by IMFINZI 1,500 mg every 4 weeks as a single agent Patients with a body weight of < 30 kg: IMFINZI 15 mg/kg in combination with carboplatin and paclitaxel * every 3 weeks (21 days) for 6 cycles, followed by IMFINZI 20 mg/kg every 4 weeks as a single agent | Until disease progression or unacceptable toxicity |
Neoadjuvant and Adjuvant Treatment of MIBC | Patients with a body weight of ≥30 kg: Neoadjuvant: 1,500 mg in combination with gemcitabine and cisplatin † every 3 weeks for 4 cycles prior to surgery Adjuvant: IMFINZI 1,500 mg as a single agent every 4 weeks for up to 8 cycles after surgery Patients with a body weight of < 30 kg: Neoadjuvant: 20 mg/kg in combination with gemcitabine and cisplatin † every 3 weeks for 4 cycles prior to surgery Adjuvant: IMFINZI 20 mg/kg as a single agent every 4 weeks for up to 8 cycles after surgery | |
IMFINZI in Combination with Tremelimumab-actl and Platinum-Based Chemotherapy
The recommended dosage schedule and regimens for IMFINZI for the treatment of metastatic NSCLC are provided in Tables 2 and 3.
Weigh patients prior to each infusion.
Calculate the appropriate dose using Table 3 below based on the patient’s weight and tumor histology.
| Week * † | |||||||||||||||||||||||||
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| 0 | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 | 14 | 15 | 16 | 17 | 18 | 19 | 20 | 21 | 22 | 23 | 24 | |
| Cycle: | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | |||||||||||||||||
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IMFINZI * ‡ | X | X | X | X | X | X | X | X | |||||||||||||||||
Tremelimumab-actl ‡ § | X | X | X | X | X | ||||||||||||||||||||
Chemotherapy | X | X | X | X | X ¶ | X ¶ | X ¶ | X ¶ | |||||||||||||||||
| Tumor Histology | Patient Weight | IMFINZI Dosage | Tremelimumab-actl Dosage * | Platinum-based Chemotherapy Regimen * |
|---|---|---|---|---|
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Non-Squamous | ≥ 30 kg | 1,500 mg | 75 mg |
OR
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< 30 kg | 20 mg/kg | 1 mg/kg | ||
Squamous | ≥ 30 kg | 1,500 mg | 75 mg |
OR
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< 30 kg | 20 mg/kg | 1 mg/kg | ||
Dosage Modifications for Adverse Reactions
No dose reduction for IMFINZI is recommended. In general, withhold IMFINZI for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue IMFINZI for life-threatening (Grade 4) immune-mediated adverse reactions, recurrent severe (Grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating corticosteroids.
Dosage modifications for IMFINZI or IMFINZI in combination with tremelimumab-actl or chemotherapy for adverse reactions that require management different from these general guidelines are summarized in Table 4.
| Adverse Reaction | Severity * | Dosage Modification |
|---|---|---|
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| Grade 2 | Withhold † |
Grade 3 or 4 | Permanently discontinue | |
| Grade 2 | Withhold † |
Grade 3 | Withhold † or permanently discontinue ‡ | |
Grade 4 | Permanently discontinue | |
| Any grade | Permanently discontinue |
| ALT or AST increases to more than 3 and up to 8 times the ULN or total bilirubin increases to more than 1.5 and up to 3 times ULN | Withhold † |
ALT or AST increases to more than 8 times ULN or total bilirubin increases to more than 3 times the ULN | Permanently discontinue | |
| AST or ALT is more than 1 and up to 3 times ULN at baseline and increases to more than 5 and up to 10 times ULN or AST or ALT is more than 3 and up to 5 times ULN at baseline and increases to more than 8 and up to 10 times ULN | Withhold † |
AST or ALT increases to more than 10 times ULN or total bilirubin increases to more than 3 times ULN | Permanently discontinue | |
| Grade 3 or 4 | Withhold until clinically stable or permanently discontinue depending on severity |
| Grade 2 or 3 increased blood creatinine | Withhold † |
Grade 4 increased blood creatinine | Permanently discontinue | |
| Suspected SJS, TEN, or DRESS | Withhold † |
Confirmed SJS, TEN, or DRESS | Permanently discontinue | |
| Grade 2, 3, or 4 | Permanently discontinue |
| Grade 2 | Withhold † |
Grade 3 or 4 | Permanently discontinue | |
Other Adverse Reactions | ||
| Grade 1 or 2 | Interrupt or slow the rate of infusion |
Grade 3 or 4 | Permanently discontinue | |
ALT = alanine aminotransferase, AST = aspartate aminotransferase, DRESS = Drug Rash with Eosinophilia and Systemic Symptoms, SJS = Stevens Johnson Syndrome, TEN = toxic epidermal necrolysis, ULN = upper limit normal. | ||
Preparation and Administration
Preparation
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- Visually inspect drug product for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard the vial if the solution is cloudy, discolored, or visible particles are observed.
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- Do not shake the vial.
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- Withdraw the required volume from the vial(s) of IMFINZI and transfer into an intravenous bag containing 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. Mix diluted solution by gentle inversion. Do not shake the solution. The final concentration of the diluted solution should be between 1 mg/mL and 15 mg/mL.
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- Discard partially used or empty vials of IMFINZI.
Storage of Infusion Solution
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- IMFINZI does not contain a preservative.
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- Administer infusion solution immediately once prepared. If the infusion solution is not administered immediately and needs to be stored, the time from preparation until the completion of the infusion should not exceed:
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- 28 days in a refrigerator at 2°C to 8°C (36°F to 46°F)
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- 8 hours at room temperature up to 25°C (77°F)
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- Do not freeze.
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- Do not shake.
Administration
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- Administer infusion solution intravenously over 60 minutes through an intravenous line containing a sterile, low-protein binding 0.2 or 0.22 micron in-line filter.
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- Use separate infusion bags and filters for each drug product.
IMFINZI in Combination with Other Products
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- Administer all intravenous all drug products as separate infusions.
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- Do not co-administer other intravenous drugs through the same infusion line.
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- For platinum-based chemotherapy, refer to Prescribing Information for administration information.
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- For pemetrexed therapy, refer to Prescribing Information for administration information.
Combination Regimens: Order of Infusions
IMFINZI in Combination with Tremelimumab-actl
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- Infuse tremelimumab-actl first, followed by IMFINZI on the same day of dosing.
IMFINZI in Combination with Tremelimumab-actl and Platinum-Based Chemotherapy
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- Infuse tremelimumab-actl first, followed by IMFINZI and then platinum-based chemotherapy on the day of dosing.
IMFINZI in Combination with Tremelimumab-actl and Pemetrexed Therapy
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- Infuse tremelimumab-actl first, followed by IMFINZI and then pemetrexed therapy on the day of dosing.
IMFINZI in Combination with Chemotherapy
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- Infuse IMFINZI first and then chemotherapy on the same day of dosing.
Combination Regimens: Infusion Instructions
IMFINZI in Combination with Tremelimumab-actl
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- Administer tremelimumab-actl over 60 minutes followed by a 60 minute observation period. Then administer IMFINZI as a separate intravenous infusion over 60 minutes.
IMFINZI in Combination with Tremelimumab-actl and Platinum-Based Chemotherapy/ Pemetrexed Therapy
Cycle 1
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- Infuse tremelimumab-actl over 60 minutes. One to two hours after completion of tremelimumab-actl infusion, infuse IMFINZI over 60 minutes. One to two hours after completion of IMFINZI infusion, administer platinum-based chemotherapy.
Subsequent Cycles
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- If there are no infusion reactions during cycle 1, subsequent cycles of IMFINZI can be given immediately after tremelimumab-actl. The time between the end of the IMFINZI infusion and the start of chemotherapy can be reduced to 30 minutes.
Injection: 120 mg/2.4 mL (50 mg/mL) and 500 mg/10 mL (50 mg/mL) clear to opalescent, colorless to slightly yellow solution in a single-dose vial.
Pregnancy
Risk Summary
Based on findings from animal studies and its mechanism of action, IMFINZI can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on the use of IMFINZI in pregnant women.
In animal reproduction studies, administration of durvalumab to pregnant cynomolgus monkeys from the confirmation of pregnancy through delivery at exposure levels approximately 6 to 20 times higher than those observed at the clinical dose of 10 mg/kg based on area under the curve (AUC), resulted in an increase in premature delivery, fetal loss, and premature neonatal death (see Data). Human immunoglobulin G1 (IgG1) is known to cross the placental barrier; therefore, durvalumab has the potential to be transmitted from the mother to the developing fetus. Apprise pregnant women 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
As reported in the literature, the PD-1/PD-L1 pathway plays a central role in preserving pregnancy by maintaining maternal immune tolerance to the fetus. In mouse allogeneic pregnancy models, disruption of PD-L1 signaling was shown to result in an increase in fetal loss. The effects of durvalumab on prenatal and postnatal development were evaluated in reproduction studies in cynomolgus monkeys. Durvalumab was administered from the confirmation of pregnancy through delivery at exposure levels approximately 6 to 20 times higher than those observed at a clinical dose of 10 mg/kg (based on AUC). Administration of durvalumab resulted in premature delivery, fetal loss (abortion and stillbirth), and increase in neonatal deaths. Durvalumab was detected in infant serum on postpartum Day 1, indicating the presence of placental transfer of durvalumab. Based on its mechanism of action, fetal exposure to durvalumab may increase the risk of developing immune-mediated disorders or altering the normal immune response and immune-mediated disorders have been reported in PD-1 knockout mice.
Lactation
Risk Summary
There are no data on the presence of durvalumab in human milk, its effects on the breastfed child, or the effects on milk production. Maternal IgG is known to be present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed child to IMFINZI are unknown. Durvalumab was present in the milk of lactating cynomolgus monkeys and was associated with premature neonatal death (see Data).
Because of the potential for adverse reactions in a breastfed child, advise women not to breastfeed during treatment with IMFINZI and for 3 months after the last dose. Refer to the Prescribing Information for the agents administered in combination with IMFINZI for recommended duration to not breastfeed, as appropriate.
Data
In lactating cynomolgus monkeys, durvalumab was present in breast milk at about 0.15% of maternal serum concentrations after administration of durvalumab from the confirmation of pregnancy through delivery at exposure levels approximately 6 to 20 times higher than those observed at the recommended clinical dose of 10 mg/kg (based on AUC). Administration of durvalumab resulted in premature neonatal death.
Females and Males of Reproductive Potential
Pregnancy testing
Verify pregnancy status of females of reproductive potential prior to initiating treatment with IMFINZI.
Contraception
Females
IMFINZI 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 IMFINZI and for 3 months following the last dose of IMFINZI. Refer to the Prescribing Information for the agents administered in combination with IMFINZI for recommended contraception duration, as appropriate.
Pediatric Use
The safety and effectiveness of IMFINZI have not been established in pediatric patients. Safety and efficacy were assessed but not established in a multi-center, open-label study (NCT03837899) in 45 pediatric patients aged 1 to < 17 years with advanced solid tumors. All 45 patients received at least a single dose of IMFINZI, and 41 patients received IMFINZI in combination with tremelimumab-actl. No new safety signals were observed in pediatric patients in this study.
Durvalumab systemic exposure in pediatric patients weighing ≥ 35 kg was within the range of values previously observed in adults given the same weight-based dose, whereas the systemic exposure in pediatric patients weighing < 35 kg was lower than that observed in adults.
Geriatric Use
Of the 401 patients with resectable NSCLC treated with IMFINZI in combination with chemotherapy in the AEGEAN study, 209 (52%) patients were 65 years or older and 49 (12%) patients were 75 years or older. There were no overall clinically meaningful differences in safety or efficacy between patients ≥ 65 years of age and younger patients.
Of the 476 patients with unresectable, Stage III NSCLC 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.
Of the 330 patients with metastatic NSCLC treated with IMFINZI in combination with tremelimumab-actl and platinum-based chemotherapy, 143 (43%) patients were 65 years or older and 35 (11%) patients were 75 years or older. There were no clinically meaningful differences in safety or efficacy between patients 65 years or older and younger patients.
Of the 262 patients with LS-SCLC treated with IMFINZI, 103 (39%) patients were 65 years or older and 15 (6%) patients were 75 years or older. There were no clinically meaningful differences in safety and efficacy between patients 65 years or older and younger patients.
Of the 265 patients with ES-SCLC treated with IMFINZI in combination with chemotherapy 101 (38%) patients were 65 years or older and 19 (7.2%) patients were 75 years or older. There were no clinically meaningful differences in safety or efficacy between patients 65 years or older and younger patients.
Of the 338 patients with BTC treated with IMFINZI in combination with chemotherapy in the TOPAZ-1 study, 158 (47%) patients were 65 years or older and 38 (11%) patients were 75 years or older. No overall differences in safety or effectiveness of IMFINZI have been observed between patients 65 years of age and older and younger adult patients.
Of the 393 patients with uHCC treated with IMFINZI in combination with tremelimumab-actl, 50% of patients were 65 years of age or older and 13% of patients were 75 years of age or older. No overall differences in safety or effectiveness of IMFINZI have been observed between patients 65 years of age and older and younger adult patients.
Of the 235 patients with endometrial cancer treated with IMFINZI with carboplatin and paclitaxel, 49% of patients were 65 years of age or older and 12% of patients were 75 years of age or older. No overall differences in safety or effectiveness of IMFINZI have been observed between patients 65 years of age and older and younger adult patients.
Of the 530 patients with MIBC treated with IMFINZI in combination with gemcitabine and cisplatin in the NIAGARA study, 272 (51%) patients were 65 years or older, and 57 (11%) patients were 75 years or older. No overall differences in safety or effectiveness of IMFINZI have been observed between patients 65 years of age and older and younger adult patients.
None.
Immune-Mediated Adverse Reactions
IMFINZI is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death-receptor 1 (PD-1) or the PD-ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Important immune-mediated adverse reactions listed under Warnings and Precautions may not include all possible severe and fatal immune-mediated reactions.
The incidence and severity of immune-mediated adverse reactions were similar when IMFINZI was administered as a single agent or in combination with chemotherapy or in combination with tremelimumab-actl and platinum-based chemotherapy, unless otherwise noted.
Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. Immune-mediated adverse reactions can occur at any time after starting treatment with a PD 1/PD L1 blocking antibody. While immune-mediated adverse reactions usually manifest during treatment with PD-1/PD-L1 blocking antibodies, immune-mediated adverse reactions can also manifest after discontinuation of PD-1/PD-L1 blocking antibodies.
Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of PD-1/PD-L1 blocking antibodies. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.
Withhold or permanently discontinue IMFINZI depending on severity [see Dosage and Administration (2.3)]. In general, if IMFINZI requires interruption or discontinuation, administer systemic corticosteroid therapy (1 mg to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy.
Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.
Immune-Mediated Pneumonitis
IMFINZI can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation.
IMFINZI as a Single Agent
In Patients Who Did Not Receive Recent Prior Radiation
In patients who received IMFINZI on clinical studies in which radiation therapy was generally not administered immediately prior to initiation of IMFINZI, the incidence of immune-mediated pneumonitis was 2.4% (34/1414), including fatal (< 0.1%), and Grade 3-4 (0.4%) adverse reactions. Events resolved in 19 of the 34 patients and resulted in permanent discontinuation in 5 patients. Systemic corticosteroids were required in 19 patients (19/34) with pneumonitis who did not receive chemoradiation prior to initiation of IMFINZI.
The frequency and severity of immune-mediated pneumonitis in patients who did not receive definitive chemoradiation prior to IMFINZI were similar whether IMFINZI was given as a single agent in patients with various cancers in a pooled data set or in patients with ES-SCLC or BTC when given in combination with chemotherapy.
In Patients Who Received Recent Prior Radiation
The incidence of pneumonitis (including radiation pneumonitis) in patients with unresectable Stage III NSCLC following definitive chemoradiation within 42 days prior to initiation of IMFINZI in PACIFIC was 18.3% (87/475) in patients receiving IMFINZI and 12.8% (30/234) in patients receiving placebo. Of the patients who received IMFINZI (475), 1.1% had a fatal adverse reaction and 2.7% had Grade 3 adverse reactions. Events resolved in 50 of the 87 (57%) patients and resulted in permanent discontinuation in 27 of the 87 (31%) patients. Systemic corticosteroids were required in 64 patients (64/87) with pneumonitis who had received chemoradiation prior to initiation of IMFINZI, while 2 patients required use of infliximab with high-dose steroids.
The incidence of pneumonitis (including radiation pneumonitis) in patients with LS-SCLC following chemoradiation within 42 days prior to initiation of IMFINZI in ADRIATIC was 14% (37/262) in patients receiving IMFINZI and 6% (16/265) in patients receiving placebo. Of the patients who received IMFINZI (262), 0.4% had a fatal adverse reaction and 2.7% had Grade 3 adverse reactions. Events resolved in 19 of the 37 (51%) patients and resulted in permanent discontinuation in 18 of the 37 (49%) patients. Systemic corticosteroids were required in all patients, while 1 patient required use of infliximab with high-dose steroids.
IMFINZI with Tremelimumab-actl
Immune-mediated pneumonitis occurred in 1.3% (5/388) of patients receiving IMFINZI in combination with tremelimumab-actl, including fatal (0.3%) and Grade 3 (0.2%) adverse reactions. Events resolved in 3 of the 5 patients and resulted in permanent discontinuation in 1 patient. Systemic corticosteroids were required in all patients; of these, 4 patients required high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). One patient (1/5) required other immunosuppressants.
IMFINZI with Tremelimumab-actl and Platinum-Based Chemotherapy
Immune-mediated pneumonitis occurred in 3.5% (21/596) of patients receiving IMFINZI in combination with tremelimumab-actl and platinum-based chemotherapy, including fatal (0.5%), and Grade 3 (1%) adverse reactions. Events resolved in 11 of the 21 patients and resulted in permanent discontinuation in 7 patients. Systemic corticosteroids were required in all patients with immune-mediated pneumonitis, while 1 patient (1/21) required other immunosuppressants.
Immune-Mediated Colitis
IMFINZI can cause immune-mediated colitis that is frequently associated with diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies.
IMFINZI as a Single Agent
Immune-mediated colitis occurred in 2% (37/1889) of patients receiving IMFINZI, including Grade 4 (< 0.1%) and Grade 3 (0.4%) adverse reactions. Events resolved in 27 of the 37 patients and resulted in permanent discontinuation in 8 patients. Systemic corticosteroids were required in all patients with immune-mediated colitis, while 2 patients (2/37) required other immunosuppressants (e.g., infliximab, mycophenolate).
IMFINZI with Tremelimumab-actl
Immune-mediated colitis or diarrhea occurred in 6% (23/388) of patients receiving IMFINZI in combination with tremelimumab-actl, including Grade 3 (3.6%) adverse reactions. Events resolved in 22 of the 23 patients and resulted in permanent discontinuation in 5 patients. All patients received systemic corticosteroids, and 20 of the 23 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Three patients also received other immunosuppressants.
Intestinal perforation has been observed in other studies of IMFINZI in combination with tremelimumab-actl.
IMFINZI with Tremelimumab-actl and Platinum-Based Chemotherapy
Immune-mediated colitis occurred in 6.5% (39/596) of patients receiving IMFINZI in combination with tremelimumab-actl including fatal (0.2%) and Grade 3 (2.5%) adverse reactions. Events resolved in 33 of 39 patients and resulted in permanent discontinuation in 11 patients. Systemic corticosteroids were required in all patients with immune-mediated colitis, while 4 patients (4/39) required other corticosteroids.
Intestinal perforation and large intestine perforation were reported in 0.1% of patients receiving IMFINZI in combination with tremelimumab-actl.
Immune-Mediated Hepatitis
IMFINZI can cause immune-mediated hepatitis.
IMFINZI as a Single Agent
Immune-mediated hepatitis occurred in 2.8% (52/1889) of patients receiving IMFINZI, including fatal (0.2%), Grade 4 (0.3%) and Grade 3 (1.4%) adverse reactions. Events resolved in 21 of the 52 patients and resulted in permanent discontinuation of IMFINZI in 6 patients. Systemic corticosteroids were required in all patients with immune-mediated hepatitis, while 2 patients (2/52) required use of mycophenolate with high-dose steroids.
IMFINZI with Tremelimumab-actl
Immune-mediated hepatitis occurred in 7.5% (29/388) of patients receiving IMFINZI in combination with tremelimumab-actl, including fatal (0.8%), Grade 4 (0.3%), and Grade 3 (4.1%) adverse reactions. Events resolved in 12 of the 29 patients and resulted in permanent discontinuation in 9 patients. Systemic corticosteroids were required in all 29 patients and all 29 patients required high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Eight patients (8/29) required other immunosuppressants.
IMFINZI with Tremelimumab-actl and Platinum-Based Chemotherapy
Immune-mediated hepatitis occurred in 3.9% (23/596) of patients receiving IMFINZI in combination with tremelimumab-actl, including fatal (0.3%), Grade 4 (0.5%), and Grade 3 (2.0%) adverse reactions. Events resolved in 12 of the 23 patients and resulted in permanent discontinuation in 10 patients. Systemic corticosteroids were required in all patients with immune-mediated hepatitis, while 2 patients (2/23) required use of other immunosuppressants.
Immune-Mediated Endocrinopathies
Adrenal Insufficiency
IMFINZI can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold or permanently discontinue IMFINZI based on the severity [see Dosage and Administration (2.3)].
IMFINZI as a Single Agent
Immune-mediated adrenal insufficiency occurred in 0.5% (9/1889) of patients receiving IMFINZI, including Grade 3 (< 0.1%) adverse reactions. Events resolved in 1 of the 9 patients and did not lead to permanent discontinuation of IMFINZI in any patients. Systemic corticosteroids were required in all patients with adrenal insufficiency; of these, the majority remained on systemic corticosteroids.
IMFINZI with Tremelimumab-actl
Immune-mediated adrenal insufficiency occurred in 1.5% (6/388) of patients receiving IMFINZI in combination with tremelimumab-actl, including Grade 3 (0.3%) adverse reactions. Events resolved in 2 of the 6 patients. Systemic corticosteroids were required in all 6 patients, and of these, 1 patient required high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day).
IMFINZI with Tremelimumab-actl and Platinum-Based Chemotherapy
Immune-mediated adrenal insufficiency occurred in 2.2% (13/596) of patients receiving IMFINZI in combination with tremelimumab-actl, including Grade 3 (0.8%) adverse reactions. Events resolved in 2 of the 13 patients and resulted in permanent discontinuation in 1 patient. Systemic corticosteroids were required in all patients with adrenal insufficiency. One patient also required endocrine therapy.
Hypophysitis
IMFINZI can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field cuts. Hypophysitis can cause hypopituitarism. Initiate symptomatic treatment including hormone replacement as clinically indicated. Withhold or permanently discontinue IMFINZI depending on severity [see Dosage and Administration (2.3)].
IMFINZI as a Single Agent
Grade 3 hypophysitis/hypopituitarism occurred in < 0.1% (1/1889) of patients who received IMFINZI. Treatment with systemic corticosteroids was administered in this patient. The event did not lead to permanent discontinuation of IMFINZI.
IMFINZI with Tremelimumab-actl
Immune-mediated hypophysitis/hypopituitarism occurred in 1% (4/388) of patients receiving IMFINZI in combination with tremelimumab-actl. Events resolved in 2 of the 4 patients. Systemic corticosteroids were required in 3 patients, and of these, 1 patient received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Two patients also required endocrine therapy.
IMFINZI with Tremelimumab-actl and Platinum-Based Chemotherapy
Immune-mediated hypophysitis occurred in 1.3% (8/596) of patients receiving IMFINZI in combination with tremelimumab-actl, including Grade 3 (0.5%) adverse reactions. Events resulted in permanent discontinuation in 1 patient. Systemic corticosteroids were required in 6 patients with immune-mediated hypophysitis; of these, 2 of the 8 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Four patients also required endocrine therapy.
Thyroid Disorders
IMFINZI can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement therapy for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or discontinue IMFINZI based on the severity [see Dosage and Administration (2.3)].
Thyroiditis
IMFINZI as a Single Agent
Immune-mediated thyroiditis occurred in 0.5% (9/1889) of patients receiving IMFINZI, including Grade 3 (< 0.1%) adverse reactions. Events resolved in 4 of the 9 patients and resulted in permanent discontinuation in 1 patient. Systemic corticosteroids were required in 3 patients (3/9) with immune-mediated thyroiditis, while 8 patients (8/9) required endocrine therapy.
IMFINZI with Tremelimumab-actl
Immune-mediated thyroiditis occurred in 1.5% (6/388) of patients receiving IMFINZI in combination with tremelimumab-actl. Events resolved in 2 of the 6 patients. Systemic corticosteroids were required in 2 patients (2/6) with immune-mediated thyroiditis; of these, 1 patient required high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). All patients required other therapy including hormone replacement therapy, thiamazole, carbimazole, propylthiouracil, perchlorate, calcium channel blocker, or beta-blocker.
IMFINZI with Tremelimumab-actl and Platinum-Based Chemotherapy
Immune-mediated thyroiditis occurred in 1.2% (7/596) of patients receiving IMFINZI in combination with tremelimumab-actl. Events resolved in 2 of the 7 patients and one resulted in permanent discontinuation. Systemic corticosteroids were required in 2 patients (2/7) with immune-mediated thyroiditis, while all patients required endocrine therapy.
Hyperthyroidism
IMFINZI as a Single Agent
Immune-mediated hyperthyroidism occurred in 2.1% (39/1889) of patients receiving IMFINZI. Events resolved in 30 of the 39 patients and did not lead to permanent discontinuation of IMFINZI in any patients. Systemic corticosteroids were required in 9 patients (9/39) with immune-mediated hyperthyroidism, while 35 patients (35/39) required endocrine therapy.
IMFINZI with Tremelimumab-actl
Immune-mediated hyperthyroidism occurred in 4.6% (18/388) of patients receiving IMFINZI in combination with tremelimumab-actl, including Grade 3 (0.3%) adverse reactions. Events resolved in 15 of the 18 patients. Two patients (2/18) required high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Seventeen patients required other therapy (thiamazole, carbimazole, propylthiouracil, perchlorate, calcium channel blocker, or beta-blocker).
IMFINZI with Tremelimumab-actl and Platinum-Based Chemotherapy
Immune-mediated hyperthyroidism occurred in 5% (30/596) of patients receiving IMFINZI in combination with tremelimumab-actl, including Grade 3 (0.2%) adverse reactions. Events resolved in 21 of the 30 patients. Systemic corticosteroids were required in 5 patients (5/30) with immune-mediated hyperthyroidism, while 28 patients (28/30) required endocrine therapy.
Hypothyroidism
IMFINZI as a Single Agent
Immune-mediated hypothyroidism occurred in 8.3% (156/1889) of patients receiving IMFINZI, including Grade 3 (<0.1%) adverse reactions. Events resolved in 31 of the 156 patients and did not lead to permanent discontinuation of IMFINZI in any patients. Systemic corticosteroids were required in 11 patients (11/156) and the majority of patients (152/156) required long-term thyroid hormone replacement.
IMFINZI with Tremelimumab-actl
Immune-mediated hypothyroidism occurred in 11% (42/388) of patients receiving IMFINZI in combination with tremelimumab-actl. Events resolved in 5 of the 42 patients. One patient received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). All patients required other therapy (thiamazole, carbimazole, propylthiouracil, perchlorate, calcium channel blocker, or beta-blocker).
IMFINZI with Tremelimumab-actl and Platinum-Based Chemotherapy
Immune-mediated hypothyroidism occurred in 8.6% (51/596) of patients receiving IMFINZI in combination with tremelimumab-actl, including Grade 3 (0.5%) adverse reactions. Systemic corticosteroids were required in 2 patients (2/51) and all patients required endocrine therapy.
IMFINZI with Carboplatin and Paclitaxel
Immune-mediated hypothyroidism occurred in 14% (34/235) of patients receiving IMFINZI in combination with carboplatin and paclitaxel. Events resolved in 8 of the 34 patients. Endocrine therapy was required in 34 of the 34 patients.
Type 1 Diabetes Mellitus, which can present with diabetic ketoacidosis
Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold or permanently discontinue IMFINZI based on the severity [see Dosage and Administration (2.3)].
IMFINZI as a Single Agent
Grade 3 immune-mediated type 1 diabetes mellitus occurred in < 0.1% (1/1889) of patients receiving IMFINZI. This patient required long-term insulin therapy and IMFINZI was permanently discontinued. Two additional patients (0.1%, 2/1889) had events of hyperglycemia requiring insulin therapy that did not resolve at the time of reporting.
IMFINZI with Tremelimumab-actl
Two patients (0.5%, 2/388) had events of hyperglycemia requiring insulin therapy that had not resolved at last follow-up.
IMFINZI with Tremelimumab-actl and Platinum-Based Chemotherapy
Immune-mediated Type 1 diabetes mellitus occurred in 0.5% (3/596) of patients receiving IMFINZI in combination with tremelimumab-actl, including Grade 3 (0.3%) adverse reactions. All patients required endocrine therapy.
Immune-Mediated Nephritis with Renal Dysfunction
IMFINZI can cause immune-mediated nephritis.
IMFINZI as a Single Agent
Immune-mediated nephritis occurred in 0.5% (10/1889) of patients receiving IMFINZI, including Grade 3 (< 0.1%) adverse reactions. Events resolved in 5 of the 10 patients and resulted in permanent discontinuation in 3 patients. Systemic corticosteroids were required in all patients with immune-mediated nephritis.
IMFINZI with Tremelimumab-actl
Immune-mediated nephritis occurred in 1% (4/388) of patients receiving IMFINZI in combination with tremelimumab-actl, including Grade 3 (0.5%) adverse reactions. Events resolved in 3 of the 4 patients and resulted in permanent discontinuation in 2 patients. Systemic corticosteroids were required in all patients with immune-mediated nephritis; of these, 3 patients required high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day).
IMFINZI with Tremelimumab-actl and Platinum-Based Chemotherapy
Immune-mediated nephritis occurred in 0.7% (4/596) of patients receiving IMFINZI in combination with tremelimumab-actl, including Grade 3 (0.2%) adverse reactions. Events resolved in 1 of the 4 patients and resulted in permanent discontinuation in 3 patients. Systemic corticosteroids were required in all patients with immune-mediated nephritis.
Immune-Mediated Dermatology Reactions
IMFINZI can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens Johnson Syndrome (SJS), drug rash with eosinophilia and systemic symptoms (DRESS), and toxic epidermal necrolysis (TEN), has occurred with PD-1/L-1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. Withhold or permanently discontinue IMFINZI depending on severity [see Dosage and Administration (2.3)].
IMFINZI as a Single Agent
Immune-mediated rash or dermatitis occurred in 1.8% (34/1889) of patients receiving IMFINZI, including Grade 3 (0.4%) adverse reactions. Events resolved in 19 of the 34 patients and resulted in permanent discontinuation in 2 patients. Systemic corticosteroids were required in all patients with immune-mediated rash or dermatitis.
IMFINZI with Tremelimumab-actl
Immune-mediated rash or dermatitis occurred in 4.9% (19/388) of patients receiving IMFINZI in combination with tremelimumab-actl, including Grade 4 (0.3%) and Grade 3 (1.5%) adverse reactions. Events resolved in 13 of the 19 patients and resulted in permanent discontinuation in 2 patients. Systemic corticosteroids were required in all patients with immune-mediated rash or dermatitis; of these, 12 patients required high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). One patient received other immunosuppressants.
IMFINZI with Tremelimumab-actl and Platinum-Based Chemotherapy
Immune-mediated rash or dermatitis occurred in 7.2% (43/596) of patients receiving IMFINZI in combination with tremelimumab-actl, including Grade 3 (0.3%) adverse reactions. Events resolved in 32 of the 43 patients and resulted in permanent discontinuation in 2 patients. Systemic corticosteroids were required in all patients with immune-mediated rash or dermatitis.
Immune-Mediated Pancreatitis
IMFINZI in combination with tremelimumab-actl can cause immune-mediated pancreatitis.
IMFINZI with Tremelimumab-actl
Immune-mediated pancreatitis occurred in 2.3% (9/388) of patients receiving IMFINZI in combination with tremelimumab-actl, including Grade 4 (0.3%) and Grade 3 (1.5%) adverse reactions. Events resolved in 6 of the 9 patients. Systemic corticosteroids were required in all 9 patients, and of these 7 patients required high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day).
Other Immune-Mediated Adverse Reactions
The following clinically significant, immune-mediated adverse reactions occurred at an incidence of less than 1% each in patients who received IMFINZI or IMFINZI in combination with tremelimumab-actl, or were reported with the use of other PD-1/PD-L1 blocking antibodies.
Cardiac/vascular: Myocarditis, pericarditis, vasculitis.
Nervous system: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy.
Ocular: Uveitis, iritis, and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment to include blindness can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss.
Gastrointestinal: Pancreatitis including increases in serum amylase and lipase levels, gastritis, duodenitis.
Musculoskeletal and connective tissue disorders: Myositis/polymyositis, rhabdomyolysis and associated sequelae including renal failure, arthritis, polymyalgia rheumatic.
Endocrine: Hypoparathyroidism.
Other (hematologic/immune): Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenia, solid organ transplant rejection, other transplant (including corneal graft) rejection.
Infusion-Related Reactions
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 [see Dosage and Administration (2.3)]. For Grade 1 or 2 infusion-related reactions, consider using pre-medications with subsequent doses.
IMFINZI as a Single Agent
Infusion-related reactions occurred in 2.2% (42/1889) of patients receiving IMFINZI, including Grade 3 (0.3%) adverse reactions.
IMFINZI in Combination with Tremelimumab-actl
Infusion-related reactions occurred in 2.6% (10/388) of patients receiving IMFINZI in combination with tremelimumab-actl.
IMFINZI with Tremelimumab-actl and Platinum-Based Chemotherapy
Infusion-related reactions occurred in 2.9% (17/596) of patients receiving IMFINZI in combination with tremelimumab-actl, including Grade 3 (0.3%) adverse reactions.
Infusion-related reactions occurred in 2.2% (42/1889) of patients receiving IMFINZI, including Grade 3 (0.3%) adverse reactions.
Complications of Allogeneic HSCT after IMFINZI
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/L-1 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/L-1 blockade and allogeneic HSCT.
Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1/L-1 blocking antibody prior to or after an allogeneic HSCT.
Embryo-Fetal Toxicity
Based on its mechanism of action and data from animal studies, IMFINZI can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of durvalumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased premature delivery, fetal loss and premature neonatal death. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with IMFINZI and for 3 months after the last dose of IMFINZI [see Use in Specific Populations (8.1, 8.3)].