Durvalumab

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# Overview
Durvalumab is a human immunoglobulin G1 kappa (IgG1) monoclonal antibody that is FDA approved for the treatment of locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy, or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.   Common adverse reactions include fatigue, musculoskeletal pain, constipation, decreased appetite, nausea, peripheral edema, and urinary tract infection, or cough, fatigue, pneumonitis/radiation pneumonitis, upper respiratory tract infections, dyspnea, and rash.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
- Durvalumab is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who:
- Have disease progression during or following platinum-containing chemotherapy.
- Have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
- This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
- Durvalumab is indicated for the treatment of patients with unresectable Stage III non-small cell lung cancer (NSCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy.
- The recommended dose of durvalumab is 10 mg/kg administered as an intravenous infusion over 60 minutes every 2 weeks, until disease progression or unacceptable toxicity.
- The recommended dose of durvalumab is 10 mg/kg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression, unacceptable toxicity, or a maximum of 12 months.
- No dose reductions are recommended. Withhold or discontinue durvalumab to manage adverse reactions as described in Table 1.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding durvalumab Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.

### NonGuideline-Supported Use
There is limited information regarding durvalumab Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Durvalumab FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding durvalumab Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.

### NonGuideline-Supported Use
There is limited information regarding durvalumab Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.

# Contraindications
- None.

# Warnings
- Durvalumab 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 durvalumab based on the severity.
- In clinical studies enrolling 1889 patients with various cancers who received durvalumab, 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 durvalumab 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  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 durvalumab (34%) compared to patients in other clinical studies (2.3%) in which radiation therapy was generally not administered immediately prior to initiation of durvalumab.
- In the PACIFIC study, the incidence of Grade 3 pneumonitis was 3.4% and of Grade 5 pneumonitis was 1.1% in the durvalumab 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 durvalumab 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.
- Durvalumab 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 durvalumab, 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 durvalumab, 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 durvalumab 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.
- Durvalumab 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 durvalumab based on the severity.
- In clinical studies enrolling 1889 patients with various cancers who received durvalumab, 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 durvalumab 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).
- Durvalumab 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 durvalumab. Initiate hormone replacement therapy or medical management of hyperthyroidism as clinically indicated. Continue durvalumab for hypothyroidism and interrupt for hyperthyroidism based on the severity .
- In clinical studies enrolling 1889 patients who received durvalumab, 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 durvalumab based on the severity.
- In clinical studies enrolling 1889 patients who received durvalumab, 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 durvalumab based on the severity.
- In clinical studies enrolling 1889 patients who received durvalumab, type 1 diabetes mellitus occurred in < 0.1 % of patients. The median time to onset was 1.4 months.
- Hypophysitis: 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 durvalumab based on the severity.
- Hypopituitarism leading to adrenal insufficiency and diabetes insipidus occurred in < 0.1% of 1889 patients who received durvalumab in clinical studies.
- Durvalumab 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 durvalumab. 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 durvalumab based on the severity.
- In clinical studies enrolling 1889 patients with various cancers who received durvalumab, 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). Durvalumab 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.
- Durvalumab 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 durvalumab based on the severity.
- In clinical studies enrolling 1889 patients with various cancers who received durvalumab, 26% of patients developed rash or dermatitis and 0.4% of the patients developed vitiligo. Rash or dermatitis led to discontinuation of durvalumab 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.
- Durvalumab 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 durvalumab, immune-mediated adverse reactions can also manifest after discontinuation of durvalumab.
- 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 durvalumab, 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 less than 1% each in 1889 patients who received durvalumab: 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-Barre syndrome and Vogt-Koyanagi-Harada syndrome.
- Durvalumab can cause serious infections, including fatal cases.
- Monitor patients for signs and symptoms of infection. For Grade 3 or higher infections, withhold durvalumab and resume once clinically stable.
- In clinical studies enrolling 1889 patients with various cancers who received durvalumab, 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 durvalumab-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 durvalumab.
- Durvalumab 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 durvalumab 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%).
- Based on its mechanism of action and data from animal studies, durvalumab 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 durvalumab and for at least 3 months after the last dose of durvalumab.

# Adverse Reactions

## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- The data described in the Warnings and Precautions section reflect exposure to durvalumab in 1889 patients from the PACIFIC study (a randomized, placebo-controlled study that enrolled 475 patients with Stage III NSCLC), Study 1108 (an open-label, single-arm, multicohort study that enrolled 191 patients with urothelial carcinoma and 779 patients with various other solid tumors), and an additional open-label, single-arm trial that enrolled 444 patients with metastatic lung cancer, an indication for which durvalumab is not approved. Across all studies, durvalumab was administered at a dose of 10 mg/kg intravenously every 2 weeks. Among the 1889 patients, 38% were exposed for 6 months or more and 18% were exposed for 12 months or more.
- The data described in this section reflect exposure to durvalumab in patients with locally advanced or metastatic urothelial carcinoma enrolled in Study 1108 and in patients with Stage III NSCLC enrolled in the PACIFIC study.
- The safety data described in Table 2 reflect exposure to durvalumab in 182 patients with locally advanced or metastatic urothelial carcinoma in the urothelial carcinoma cohort of Study 1108 whose disease has progressed during or after one standard platinum-based regimen. Patients received durvalumab 10 mg/kg intravenously every 2 weeks. The median duration of exposure was 2.3 months (range: 1 day to 12.1 months).
- Thirty-one percent (31%) of patients had a drug delay or interruption for an adverse reaction. The most common (> 2%) were liver injury (4.9%), urinary tract infection (3.3%), acute kidney injury (3.3%), and musculoskeletal pain (2.7%).
- The most common adverse reactions ( 15%) were fatigue (39%), musculoskeletal pain (24%), constipation (21%), decreased appetite (19%), nausea (16%), peripheral edema (15%) and urinary tract infection (15%). The most common Grade 3 or 4 adverse reactions ( 3%) were fatigue, urinary tract infection, musculoskeletal pain, abdominal pain, dehydration, and general physical health deterioration.
- Eight patients (4.4%) who were treated with durvalumab experienced Grade 5 adverse reactions of cardiorespiratory arrest, general physical health deterioration, sepsis, ileus, pneumonitis, or immune-mediated hepatitis. Three additional patients were experiencing infection and disease progression at the time of death. durvalumab was discontinued for adverse reactions in 3.3% of patients. Serious adverse reactions occurred in 46% of patients. The most frequent serious adverse reactions (> 2%) were acute kidney injury (4.9%), urinary tract infection (4.4%), musculoskeletal pain (4.4%), liver injury (3.3%), general physical health deterioration (3.3%), sepsis, abdominal pain and pyrexia/tumor associated fever (2.7% each).
- Table 2 summarizes the adverse reactions that occurred in  10% of patients, while Table 3 summarizes the Grade 3 - 4 laboratory abnormalities that occurred in  1% of patients treated with durvalumab in the urothelial carcinoma cohort of Study 1108.
- The safety of durvalumab in patients with Stage III NSCLC who completed concurrent platinum-based chemoradiotherapy within 42 days prior to initiation of study drug was evaluated in the PACIFIC study, a multicenter, randomized, double-blind, placebo-controlled study. A total of 475 patients received durvalumab 10 mg/kg intravenously every 2 weeks. The study excluded patients who had disease progression following chemoradiation, with active or prior autoimmune disease within 2 years of initiation of the study or with medical conditions that required systemic immunosuppression.
- The study population characteristics were: median age of 64 years (range: 23 to 90), 45% age 65 years or older, 70% male, 69% White, 27% Asian, 75% former smoker, 16% current smoker, and 51% had WHO performance status of 1. All patients received definitive radiotherapy as per protocol, of which 92% received a total radiation dose of 54 Gy to 66 Gy. The median duration of exposure to durvalumab was 10 months (range: 0.2 to 12.6).
- Durvalumab was discontinued due to adverse reactions in 15% of patients. The most common adverse reactions leading to durvalumab discontinuation were pneumonitis or radiation pneumonitis in 6% of patients. Serious adverse reactions occurred in 29% of patients receiving durvalumab. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonitis or radiation pneumonitis (7%) and pneumonia (6%). Fatal pneumonitis or radiation pneumonitis and fatal pneumonia occurred in < 2% of patients and were similar across arms. The most common adverse reactions (occurring in  20% of patients) were cough, fatigue, pneumonitis or radiation pneumonitis, upper respiratory tract infections, dyspnea and rash.
- Table 4 summarizes the adverse reactions that occurred in at least 10% of patients treated with durvalumab.
- Other adverse reactions occurring in less than 10% of patients treated with durvalumab were dysphonia, dysuria, night sweats, peripheral edema, and increased susceptibility to infections.
- Table 5 summarizes the laboratory abnormalities that occurred in at least 20% of patients treated with durvalumab.
- 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 to durvalumab to the incidence of antibodies to other products may be misleading.
- Due to the limitations in assay performance, the incidence of antibody development in patients receiving durvalumab may be underestimated. Of 1570 patients who were treated with durvalumab 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.

## Postmarketing Experience
There is limited information regarding Durvalumab Postmarketing Experience in the drug label.

# Drug Interactions
There is limited information regarding Durvalumab Drug Interactions in the drug label.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA):
- Based on its mechanism of action and data from animal studies, durvalumab can cause fetal harm when administered to a pregnant woman. There are no data on the use of durvalumab in pregnant women.
- In animal reproduction studies, administration of durvalumab to pregnant cynomolgus monkeys from the confirmation of pregnancy through delivery resulted in an increase in premature delivery, fetal loss and premature neonatal death. 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 2-4% and 15-20%, respectively.
- 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 the recommended 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.
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Durvalumab in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Durvalumab during labor and delivery.

### Nursing Mothers
- There is no information regarding the presence of durvalumab in human milk, the effects on the breastfed infant, or the effects on milk production. Human IgG1 is excreted in human milk. Durvalumab was present in the milk of lactating cynomolgus monkeys and was associated with premature neonatal death.
- Because of the potential for adverse reactions in breastfed infants, advise women not to breastfeed during treatment with durvalumab and for at least 3 months after the last dose.
- 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.

### Pediatric Use
- The safety and effectiveness of durvalumab have not been established in pediatric patients.

### Geriatic Use
- Of the 182 patients treated with durvalumab 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 durvalumab 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.

### Gender
There is no FDA guidance on the use of Durvalumab with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Durvalumab with respect to specific racial populations.

### Renal Impairment
There is no FDA guidance on the use of Durvalumab in patients with renal impairment.

### Hepatic Impairment
There is no FDA guidance on the use of Durvalumab in patients with hepatic impairment.

### Females of Reproductive Potential and Males
Females
- Based on its mechanism of action and data from animal studies, durvalumab can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with durvalumab and for at least 3 months following the last dose of durvaluab.

### Immunocompromised Patients
There is no FDA guidance one the use of Durvalumab in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- 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.
- Do not shake the vial.
- Withdraw the required volume from the vial(s) of durvalumab 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.
- Discard partially used or empty vials of durvalumab.
- Durvalumab does not contain a preservative.
- Administer infusion solution immediately once prepared. If infusion solution is not administered immediately and needs to be stored, the total time from vial puncture to the start of the administration should not exceed:
- 24 hours in a refrigerator at 2C to 8C (36F to 46F)
- 4 hours at room temperature up to 25C (77F)
- Do not freeze.
- Do not shake.
- 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.
- Do not co-administer other drugs through the same infusion line.

### Monitoring
- Tumor response indicates efficacy
- Chemistry: During and after therapy
- Liver function: During each treatment cycle
- Thyroid function: Prior to initiation and periodically throughout treatment
- Blood glucose: During treatment
- Renal function: Prior to and during each treatment cycle
- Signs or symptoms of endocrinopathies
- Signs or symptoms of adrenal insufficiency
- Signs or symptoms of diabetes
- Signs or symptoms of hypophysitis or hypopituitarism
- Signs or symptoms of immune thrombotic thrombocytopenia
- Signs and symptoms of infusion-related reactions
- Signs and symptoms of diarrhea or colitis
- Signs and symptoms of hepatitis: During and after therapy
- Signs and symptoms of infection
- Signs and symptoms of pneumonitis
- Signs and symptoms of rash

# IV Compatibility
There is limited information regarding the compatibility of Durvalumab and IV administrations.

# Overdosage
- There is no information on overdose with durvalumab.

# Pharmacology

## Mechanism of Action
- Expression of programmed cell death ligand-1 (PD-L1) can be induced by inflammatory signals (e.g., IFN-gamma) and can be expressed on both tumor cells and tumor-associated immune cells in the tumor microenvironment. PD-L1 blocks T-cell function and activation through interaction with PD-1 and CD80 (B7.1). By binding to its receptors, PD-L1 reduces cytotoxic T-cell activity, proliferation, and cytokine production.
- Durvalumab is a human immunoglobulin G1 kappa (IgG1) monoclonal antibody that binds to PD-L1 and blocks the interaction of PD-L1 with PD-1 and CD80 (B7.1). Blockade of PD-L1/PD-1 and PD-L1/CD80 interactions releases the inhibition of immune responses, without inducing antibody dependent cell-mediated cytotoxicity (ADCC).
- PD-L1 blockade with durvalumab led to increased T-cell activation in vitro and decreased tumor size in co-engrafted human tumor and immune cell xenograft mouse models.

## Structure
There is limited information regarding Durvalumab Structure in the drug label.

## Pharmacodynamics
- The exposure-response relationships of efficacy and safety are unknown.
- Durvalumab is unlikely to prolong the QT/QTc interval.

## Pharmacokinetics
- The pharmacokinetics of durvalumab was studied in 1902 patients with doses ranging from 0.1 mg/kg (0.01 times the approved recommended dosage) to 20 mg/kg (2 times the approved recommended dosage) administered once every two, three or four weeks.
- PK exposure increased more than dose-proportionally at doses < 3 mg/kg (0.3 times the approved recommended dosage) and dose proportionally at doses  to 3 mg/kg every 2 weeks. Steady state was achieved at approximately 16 weeks.
- The geometric mean (% coefficient of variation ) steady state volume of distribution was 5.6 (18%) L.
- Durvalumab clearance decreases over time, with a mean maximal reduction (CV%) from baseline values of approximately 23% (57%) resulting in a geometric mean (CV%) steady state clearance (CLss) of 8.2 mL/h (39%) at day 365; the decrease in CLss is not considered clinically relevant. The geometric mean (CV%) terminal half-life, based on baseline CL was approximately 18 (24%) days.
- Age (1996 years), body weight (34-149 kg), sex, albumin levels, lactate dehydrogenase (LDH) levels, creatinine levels, soluble PD-L1, tumor type, race, mild renal impairment (creatinine clearance (CLcr) 60 to 89 mL/min), moderate renal impairment (CLcr 30 to 59 mL/min), mild hepatic impairment (bilirubin  ULN and AST > ULN or bilirubin > 1 to 1.5x ULN and any AST), or ECOG/WHO performance status had no clinically significant effect on the pharmacokinetics of durvalumab.
- The effect of severe renal impairment (CLcr 15 to 29 mL/min) or moderate hepatic impairment (bilirubin > 1.5 to 3x ULN and any AST) or severe hepatic impairment (bilirubin > 3x ULN and any AST) on the pharmacokinetics of durvalumab is unknown.

## Nonclinical Toxicology
- The carcinogenic and genotoxic potential of durvalumab have not been evaluated.
- Animal fertility studies have not been conducted with durvalumab. In repeat-dose toxicology studies with durvalumab in sexually mature cynomolgus monkeys of up to 3 months duration, there were no notable effects on the male and female reproductive organs.
- In animal models, inhibition of PD-L1/PD-1 signaling increased the severity of some infections and enhanced inflammatory responses. M. tuberculosis-infected PD-1 knockout mice exhibit markedly decreased survival compared with wild-type controls, which correlated with increased bacterial proliferation and inflammatory responses in these animals. PD-L1 and PD-1 knockout mice have also shown decreased survival following infection with lymphocytic choriomeningitis virus.

# Clinical Studies
- The efficacy of durvalumab was evaluated in the urothelial carcinoma cohort of Study 1108 (NCT01693562), a multicenter, multi-cohort, open-label clinical trial. In Study 1108, 182 patients with locally advanced or metastatic urothelial carcinoma were enrolled. Patients had progressed while on or after a platinum-based therapy, including those who progressed within 12 months of receiving therapy in a neo-adjuvant or adjuvant setting. These patients had initiated durvalumab at least 13 weeks prior to the data cut-off date. The trial excluded patients with a history of immunodeficiency; medical conditions that required systemic immunosuppression (not to exceed 10 mg per day of prednisone or equivalent); history of severe autoimmune disease; untreated CNS metastases; HIV; active tuberculosis, or hepatitis B or C infection. All patients received durvalumab 10 mg/kg intravenously every 2 weeks for up to 12 months or until unacceptable toxicity or disease progression. Tumor assessments were performed at Weeks 6, 12 and 16, then every 8 weeks for the first year and every 12 weeks thereafter. The major efficacy outcome measures were confirmed Overall Response Rate (ORR) according to RECIST v1.1 as assessed by Blinded Independent Central Review (BICR), and duration of response (DoR).
- The median age was 67 years (range: 34 to 88), 72% were male, 64% were White. Sixty-six percent (66%) of patients had visceral metastasis (bone, liver, or lung), including 34% with liver metastasis. Lymph node only metastasis were present in 13% of patients. Sixty-six percent (66%) of patients had ECOG score of 1 and 41% of patients had a baseline creatinine clearance < 60 mL/min. The Bellmunt risk score (which includes ECOG score, baseline hemoglobin, and liver metastases) was 0 in 23%, 1 in 38%, 2 in 29%, and 3 in 9% of patients. Twenty percent (20%) of patients had disease progression following platinum-containing neoadjuvant or adjuvant chemotherapy as their only prior line of therapy. Seventy percent (70%) of patients received prior cisplatin, 30% prior carboplatin and 35% received  2 prior lines of systemic therapy.
- Tumor specimens were evaluated prospectively for PD-L1 expression on tumor cells (TC) and immune cells (IC) at a central laboratory using the VENTANA PD-L1 (SP263) Assay. Of the 182 patients, 52% were classified as PD-L1 high (if ICs involve > 1% of the tumor area, TC  25% or IC  25%; if ICs involve  1% of the tumor area, TC  25% or IC = 100%), 40% as PD-L1 low/negative (did not meet criterion for PD-L1 high), and samples for 8% were not evaluable.
- Table 6 summarizes the results in the urothelial carcinoma cohort of Study 1108. The median follow-up time was 5.6 months. In 37 patients who had received only neoadjuvant or adjuvant therapy prior to study entry, 24% responded.
- Among the total 31 responding patients, 45% had ongoing responses of 6 months or longer and 16% had ongoing responses of 12 months or longer.
- The efficacy of durvalumab was evaluated in the PACIFIC study (NCT02125461), a multicenter, randomized, double-blind, placebo-controlled study in patients with unresectable Stage III NSCLC who completed at least 2 cycles of concurrent platinum-based chemotherapy and definitive radiation within 42 days prior to initiation of the study drug and had a WHO performance status of 0 or 1. The study excluded patients who had progressed following concurrent chemoradiation, patients with active or prior documented autoimmune disease within 2 years of initiation of the study or patients with medical conditions that required systemic immunosuppression. Randomization was stratified by sex, age (< 65 years vs.  65 years) and smoking history (smoker vs. non-smoker). Patients were randomized 2:1 to receive durvalumab 10 mg/kg or placebo intravenously every 2 weeks for up to 12 months or until unacceptable toxicity or confirmed RECIST 1.1-defined progression. Assessment of tumor status was performed every 8 weeks. The major efficacy outcome measures were progression-free survival (PFS) as assessed by a BICR RECIST 1.1 and overall survival (OS). Additional efficacy outcome measures included ORR assessed by BICR.
- A total of 713 patients were randomized: 476 patients to the durvalumab arm and 237 to the placebo arm. The study population characteristics were: median age of 64 years (range: 23 to 90); 70% male; 69% White and 27% Asian; 16% current smokers, 75% former smokers and 9% never smokers; 51% WHO performance status of 1; 53% with Stage IIIA and 45% were Stage IIIB; 46% with squamous and 54% with non-squamous histology. All patients received definitive radiotherapy as per protocol, of which 92% received a total radiation dose of 54 Gy to 66 Gy; 99% of patients received concomitant platinum-based chemotherapy (55% cisplatin-based, 42% carboplatin-based chemotherapy and 2% switched between cisplatin and carboplatin).
- The pre-specified interim PFS analysis based on 371 events (81% of total planned events) demonstrated a statistically significant improvement in PFS in patients randomized to durvalumab compared to placebo. Results are presented in Table 7 and Figure 1. OS data were not mature at the time of the interim PFS analysis.

# How Supplied
- IMFINZI (durvalumab) Injection is a clear to opalescent, colorless to slightly yellow solution supplied in a carton containing one single-dose vial either as:
- 500 mg/10 mL (NDC 0310-4611-50)
- 120 mg/2.4 mL (NDC 0310-4500-12)

## Storage
- Store in a refrigerator at 2C to 8C (36F to 46F) in original carton to protect from light.
- Do not freeze. Do not shake.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
- Advise the patient to read the FDA-approved patient labeling.
- Inform patients of the risk of immune-mediated adverse reactions that may require corticosteroid treatment and interruption or discontinuation of durvalumab, 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 mucus in stools, or severe abdominal pain.
- Endocrinopathies: Advise patients to contact their healthcare provider immediately for signs or symptoms of hypothyroidism, hyperthyroidism, adrenal insufficiency, type 1 diabetes mellitus, or hypophysitis.
- 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.
- Other Immune-Mediated Adverse Reactions: Advise patients to contact their healthcare provider immediately for signs or symptoms of aseptic meningitis, thrombocytopenic purpura, myocarditis, hemolytic anemia, myositis, uveitis and keratitis.
- Infection: Advise patients to contact their healthcare provider immediately for infection.
- Infusion-Related Reactions: Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion-related reactions.
- Embryo-Fetal Toxicity: Advise females of reproductive potential that durvalumab 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 3 months after the last dose of durvalumab.
- Lactation: Advise female patients not to breastfeed while taking durvalumab and for at least 3 months after the last dose.

# Precautions with Alcohol
Alcohol-Durvalumab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.

# Brand Names
- Imfinzi

# Look-Alike Drug Names
There is limited information regarding Durvalumab Look-Alike Drug Names in the drug label.

# Drug Shortage Status
Drug Shortage

# Price