Name of the medicinal product

Imfinzi

Qualitative and quantitative composition

Dosage Forms And Strengths

Injection: 120 mg/2.4mL (50 mg/mL) and 500 mg/10mL (50 mg/mL) clear to opalescent, colorless to slightly yellow solution in a single-dose vial.

Storage And Handling

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)

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

Manufactured for: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850 By: AstraZeneca UK Limited 1 Francis Crick Ave. Cambridge, England CB2 0AA US License No. 2043 IMFINZI is a trademark of AstraZeneca group of companies. For more information, call 1-800-236-9933 or go to www.IMFINZI.com. Revised: Apr 2017

Therapeutic indications

IMFINZI 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.

Dosage (Posology) and method of administration

Recommended Dosing

The recommended dose of IMFINZI is 10 mg/kg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.

Dose Modifications

No dose reductions are recommended. Withhold and/or discontinue IMFINZI to manage adverse reactions as described in Table 1.

Table 1: Recommended Treatment Modifications for IMFINZI

Adverse Reactions	Severity^a	IMFINZI Treatment Modification	Corticosteroid Treatment Unless Otherwise Specified
Pneumonitis	Grade 2	Withhold dose^b	Initial dose of 1 mg/kg/day to 2 mg/kg/day prednisone or equivalent followed by a taper
Pneumonitis	Grade 3 or 4	Permanently discontinue	Initial dose of 1 mg/kg/day to 4 mg/kg/day prednisone or equivalent followed by a taper
Hepatitis	Grade 2 ALT or AST > 3-5xULN or total bilirubin > 1.5-3xULN	Withhold dose^b	Initial dose of 1 mg/kg/day to 2 mg/kg/day prednisone or equivalent followed by a taper
	Grade 3 ALT or AST ≤ 8xULN or total bilirubin ≤ 5xULN	Withhold dose^b
	Grade 3 ALT or AST > 8xULN or total bilirubin > 5xULN	Permanently discontinue
	Concurrent ALT or AST > 3xULN and total bilirubin > 2xULN with no other cause	Permanently discontinue
Colitis or diarrhea	Grade 2	Withhold dose^b	Initial dose of 1 mg/kg/day to 2 mg/kg/day prednisone or equivalent followed by a taper
Colitis or diarrhea	Grade 3 or 4	Permanently discontinue
Hypothyroidism	Grade 2-4		Initiate thyroid hormone replacement as clinically indicated
Hyperthyroidism	Grade 2-4	Withhold dose until clinically stable	Symptomatic management
Adrenal insufficiency, Hypophysitis/Hypopituitarism	Grade 2-4	Withhold dose until clinically stable	Initiate 1 to 2 mg/kg/day prednisone or equivalent followed by a taper and hormone replacement as clinically indicated
Type 1 Diabetes Mellitus	Grade 2-4	Withhold dose until clinically stable	Initiate treatment with insulin as clinically indicated
Nephritis	Grade 2 Creatinine > 1.5-3x ULN	Withhold dose^b	Initial dose of 1 mg/kg/day to 2 mg/kg/day prednisone or equivalent followed by a taper
	Grade 3 Creatinine > 3-6x	Permanently discontinue

	ULN
	Grade 4 Creatinine > 6x ULN
Rash or dermatitis	Grade 2 for > 1 week	Withhold dose^b	Consider initial dose of 1 mg/kg/day to 2 mg/kg/day prednisone or equivalent followed by a taper
	Grade 3	Withhold dose^b
	Grade 4	Permanently discontinue
Infection	Grade 3 or 4	Withhold dose	Symptomatic management; treat with anti-infectives for suspected or confirmed infections
Infusion-related reactions	Grade 1 or 2	Interrupt or slow the rate of infusion	Consider pre-medications with subsequent doses
Infusion-related reactions	Grade 3 or 4	Permanently discontinue
Other	Grade 3	Withhold dose^b	Symptomatic management
Other	Grade 4	Permanently discontinue	Consider initial dose of 1 mg/kg/day to 4 mg/kg/day prednisone or equivalent followed by taper
^a Common Terminology Criteria for Adverse Events, version 4.03. ALT: alanine aminotransferase; AST: aspartate aminotransferase; ULN: upper limit of normal. ^b Based on severity of the adverse reactions, IMFINZI should be withheld and corticosteroids administered. Consider increasing dose of corticosteroids and/or other systemic immunosuppressants if there is worsening or no improvement. Corticosteroid taper should be initiated when adverse reaction improves to < Grade 1 and should be continued over at least 1 month. For adverse reactions that do not result in permanent discontinuation, resume treatment when adverse reaction returns to ≤ Grade 1 and the corticosteroid dose has been reduced to < 10 mg prednisone or equivalent per day.

Preparation And Administration

Preparation

Visually inspect drug product for particulate matter and discoloration. IMFINZI is clear to opalescent, colorless to slightly yellow solution, free from visible particles. 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 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.
Discard partially used or empty vials of IMFINZI.

Storage Of Infusion Solution

IMFINZI 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 2°C to 8°C (36°F to 46°F)
4 hours at room temperature up to 25°C (77°F)

Do not freeze.

Do not shake.

Administration

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.

Contraindications

None.

Special warnings and precautions for use

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Immune-Mediated Pneumonitis

Immune-mediated pneumonitis or interstitial lung disease occurred in patients receiving IMFINZI. Monitor patients for signs and symptoms of pneumonitis. Evaluate patients with suspected pneumonitis with radiographic imaging and manage with treatment modifications and corticosteroids.

In Study 1 (n=182), one patient (0.5%) died from immune-mediated pneumonitis. In the combined safety database (n=1414), of patients treated with IMFINZI 10 mg/kg every 2 weeks, immune-mediated pneumonitis occurred in 32 (2.3%) patients including fatal pneumonitis in one (0.1%) patient and Grade 3-4 in six (0.4%) patients. The median time to onset was 55.5 days (range: 24-423 days). Seventeen Ã‚Â (1.2%) patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). IMFINZI was interrupted in 12 patients and discontinued in five (0.4%) patients. Resolution occurred in 18 (1.3%) patients.

Immune-Mediated Hepatitis

Immune-mediated hepatitis occurred in patients receiving IMFINZI. Monitor patients for abnormal liver tests each cycle during treatment with IMFINZI. Manage immune-mediated hepatitis with treatment modifications and corticosteroids.

In Study 1, one (0.5%) patient died from immune-mediated hepatitis. An additional two (1.1%) patients experienced immune-mediated hepatitis, including Grade 3 in one (0.5%) patient. In the combined safety database, immune-mediated hepatitis occurred in 16 (1.1%) patients including fatal hepatitis in one ( < 0.1%) patient and Grade 3 in nine (0.6%) patients. The median time to onset was 51.5 days (range: 15-312 days). Twelve (0.8%) of the 16 patients received high-dose corticosteroid treatment. One patient also received mycophenolate treatment. IMFINZI was interrupted in five (0.3%) patients and discontinued in three (0.2%) patients. Resolution occurred in nine (0.6%) patients. In the combined safety database, Grade 3 or 4 elevations in ALT occurred in 40/1342 (3.0%) of patients, AST in 58/1336 (4.3%), and total bilirubin in 37/1341 (2.8%) of patients.

Immune-Mediated Colitis

Immune-mediated colitis or diarrhea occurred in patients receiving IMFINZI. Monitor patients for signs and symptoms of colitis or diarrhea and manage with treatment modifications, anti-diarrheal agents, and corticosteroids.

In Study 1, colitis or diarrhea occurred in 23 (12.6%) patients including Grade 3 or 4 diarrhea in two (1.1%) patients. No patients in Study 1 received systemic corticosteroids or immunosuppressants for diarrhea or colitis. In the combined safety database, immune-mediated colitis or diarrhea occurred in 18 (1.3%) patients including Grade 4 in one ( < 0.1%) and Grade 3 in four (0.3%) patients. The median time to onset was 73 days (range: 13-345 days). Of these patients, one ( < 0.1%) had Grade 4 and four (0.3%) had Grade 3 immune-mediated colitis or diarrhea. Ten (0.7%) of the 18 patients received high-dose corticosteroid treatment. Two (0.1%) patients received non-steroidal immunosuppressants. IMFINZI was interrupted in five (0.4%) patients and discontinued in six (0.4%) patients. Resolution occurred in 11 (0.8%) patients.

Immune-Mediated Endocrinopathies

Immune-related thyroid disorders, adrenal insufficiency, type 1 diabetes mellitus and hypophysitis/hypopituitarism have occurred in patients receiving IMFINZI. Monitor patients for clinical signs and symptoms of endocrinopathies.

Thyroid Disorders

Monitor thyroid function prior to and periodically during treatment with IMFINZI. Asymptomatic patients with abnormal thyroid function tests can receive IMFINZI. Manage patients with abnormal thyroid function tests with hormone replacement (if indicated) and treatment modifications.

In the Study 1, hypothyroidism or thyroiditis leading to hypothyroidism occurred in ten (5.5%) patients. All patients had Grade 1-2 hypothyroidism. The median time to first onset was 42 days (range: 15-239). Thyroid stimulating hormone (TSH) was elevated and above the patient's baseline in 25 (15.3%) of 163 patients with a follow-up measurement.

In Study 1, hyperthyroidism or thyroiditis leading to hyperthyroidism occurred in nine (4.9%) patients. All patients had Grade 1-2 hyperthyroidism. The median time to first onset was 43 days (range: 14-71). Thyroid stimulating hormone (TSH) was decreased and below the patient's baseline in 26 (16%) of 163 patients with a follow-up measurement.

In the combined safety database, hypothyroidism occurred in 136 (9.6%) patients, while hyperthyroidism occurred in 81 (5.7%) patients. Thyroiditis occurred in ten patients, including Grade 3 in one patient who had a myocardial infarction. In nine patients with thyroiditis, transient hyperthyroidism preceded hypothyroidism. Treatment with a beta-blocker and/or thioamide was administered for hyperthyroidism in five of these patients.

Adrenal Insufficiency

Monitor patients for clinical signs and symptoms of adrenal insufficiency. Administer corticosteroids and hormone replacement as clinically indicated.

In Study 1, adrenal insufficiency occurred in one (0.5%) patient (Grade 1). In the combined safety database, adrenal insufficiency occurred in 13 (0.9%) patients, including Grade 3 in two (0.1%) patients. Seven (0.5%) of these patients were treated with systemic corticosteroids.

Type 1 Diabetes Mellitus

Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate insulin for type 1 diabetes mellitus and manage patients with treatment modifications. New onset type 1 diabetes mellitus without an alternative etiology occurred in one patient ( < 0.1%) in the combined safety database.

Hypophysitis

Monitor for signs and symptoms of hypophysitis or hypopituitarism. Administer corticosteroids and hormone replacement as clinically indicated. Hypopituitarism leading to adrenal insufficiency and diabetes insipidus occurred in one patient ( < 0.1%) in the combined safety database.

Other Immune-Mediated Adverse Reactions

IMFINZI has caused immune-mediated rash. Other immune-related adverse reactions, including aseptic meningitis, hemolytic anemia, immune thrombocytopenic purpura, myocarditis, myositis, nephritis, and ocular inflammatory toxicity including uveitis and keratitis, have occurred in ≤ 1.0% of patients treated with IMFINZI.

Immune-mediated Rash

Monitor for signs and symptoms of rash. In Study 1, 20 (11.0%) of patients developed rash including Grade 3 rash in one (0.5%) patient. In the combined safety database, 220 (15.6%) patients developed rash and four (0.3%) patients developed vitiligo. Systemic corticosteroids were administered in 17 (1.2%) patients. The rash resolved in 133 (9.4%) patients.

Immune Thrombocytopenic Purpura

Monitor patients for signs and symptoms of immune thrombocytopenic purpura. In the combined safety database, immune thrombocytopenic purpura led to death in one ( < 0.1%) patient. The patient received high-dose corticosteroids, human immunoglobulin, and rituximab.

Nephritis

Monitor patients for abnormal renal function tests prior to and each cycle during treatment with IMFINZI and manage with treatment modifications and corticosteroids. In Study 1, one patient received systemic corticosteroids for immune-mediated nephritis. In the combined safety database, immune-mediated nephritis occurred in three (0.2%) patients including Grade 3 in two (0.1%) patients. All three patients received high-dose corticosteroids treatment. IMFINZI was discontinued in all three patients. Resolution occurred in all three patients.

Infection

Severe infections, including sepsis, necrotizing fasciitis, and osteomyelitis, occurred in patients receiving IMFINZI. Monitor patients for signs and symptoms of infection and treat with anti-infectives for suspected or confirmed infections. Withhold IMFINZI for ≥ Grade 3 infection.

In Study 1, infections occurred in 54 (29.7%) patients. Grade 3 or 4 infection occurred in eleven (6.0%) patients, while five (2.7%) patients were experiencing infection at the time of death. Urinary tract infections were the most common cause of Grade 3 or higher infection, occurring in eight (4.4%) patients. In the combined safety database, infections occurred in 531 (37.6%) patients.

Infusion-Related Reactions

Severe infusion-related reactions have been reported in patients receiving IMFINZI. Monitor for signs and symptoms of an infusion-related reaction. Interrupt or slow the rate of infusion in patients with mild or moderate infusion reactions. Permanently discontinue IMFINZI in patients with Grade 3 or 4 infusion reactions.

Infusion related reactions occurred in three (1.6%) patients in Study 1 and 26 (1.8%) patients in the combined safety database. There were five (0.4%) Grade 3 and no Grade 4 or 5 reactions. Four (0.3%) patients developed urticaria within 48 hours of dosing.

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 at least 3 months after the last dose of IMFINZI.

Patient Counseling Information

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:

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, hypophysitis or type 1 diabetes mellitus.
Other Immune-Mediated Adverse Reactions: Advise patients to contact their healthcare provider immediately for signs or symptoms of rash, nephritis, 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 IMFINZI 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 IMFINZI.
Lactation: Advise female patients not to breastfeed while taking IMFINZI and for at least 3 months after the last dose.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

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.

Use In Specific Populations

Pregnancy

Risk summary

Based on its mechanism of action and data from animal studies, IMFINZI can cause fetal harm when administered to a pregnant woman. There are no 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 resulted in increased 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 2-4% and 15-20%, 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 the clinical dose of 10 mg/kg of durvalumab (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 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 (see Data).

Because of the potential for adverse reactions in breastfed infants from durvalumab, advise a lactating woman not to breastfeed during treatment with IMFINZI and for at least 3 months after the last dose.

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 clinical dose of 10 mg/kg of durvalumab (based on AUC). Administration of durvalumab resulted in premature neonatal death.

Females And Males Of Reproductive Potential

Contraception

Females

Based on its mechanism of action, 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.

Pediatric Use

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

Geriatric Use

Of the 182 patients treated with IMFINZI, 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 15.2% (17/112) and was 11.8% (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. Study results in patients > 65 years of age and particularly in those > 75 years of age should be viewed with caution given the small number of patients.

Interaction with other medicinal products and other forms of interaction

SIDE EFFECTS

The following adverse reactions are discussed in greater detail in other sections of the labeling.

Immune-Mediated Pneumonitis.
Immune-Mediated Hepatitis.
Immune-Mediated Colitis.
Immune-Mediated Endocrinopathies.
Other Immune-Mediated Adverse Reactions.
Infection.
Infusion-Related 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 safety data described in Table 2 reflect exposure to IMFINZI in 182 patients with locally advanced or metastatic urothelial carcinoma in Study 1 whose disease has progressed during or after one standard platinum-based regimen. Patients received 10 mg/kg IMFINZI via intravenous infusion every 2 weeks. The median duration of exposure was 10.2 weeks (range: 0.14, 52.4).

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 IMFINZI experienced Grade 5 adverse events 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. IMFINZI 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, pyrexia/tumor associated fever (2.7% each).

Immune-mediated adverse reactions requiring systemic corticosteroids or hormone replacement therapy occurred in 8.2% (15/182) patients, including 5.5% (10/182) patients who required systemic corticosteroid therapy and 2.7% (5/182) patients who required only hormone replacement therapy. Seven patients (3.8%) received an oral prednisone dose equivalent to > 40 mg daily for an immune-mediated adverse reaction.

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

Table 2: Adverse Reactions in ≥ 10% of Patients in UC Cohort Study 1

Adverse Reaction	IMFINZI N=182
All Grades (%)	Grades 3 - 4 (%)
All Adverse Reactions	96	43
Gastrointestinal Disorders
Constipation	21	1
Nausea	16	2
Abdominal pain¹	14	3
Diarrhea/Colitis	13	1
General Disorders and Administration
Fatigue²	39	6
Peripheral edema³	15	2
Pyrexia/Tumor associated fever	14	1
Infections
Urinary tract infection⁴	15	4
Metabolism and Nutrition Disorders
Decreased appetite/Hypophagia	19	1
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal pain⁵	24	4
Respiratory, Thoracic, and MediastinaDisorders
Dyspnea/Exertional Dyspnea	13	2
Cough/Productive Cough	10	0
Skin and Subcutaneous Tissue Disorders
Rash⁶	11	1
¹ Includes abdominal pain upper, abdominal pain lower and flank pain ² Includes asthenia, lethargy, and malaise ³ Includes edema, localized edema, edema peripheral, lymphedema, peripheral swelling, scrotal edema, and scrotal swelling ⁴ Includes cystitis, candiduria and urosepsis ⁵ Includes back pain, musculoskeletal chest pain, musculoskeletal pain and discomfort, myalgia, and neck pain ⁶ Includes dermatitis, dermatitis acneiform, dermatitis psoriasiform, psoriasis, rash maculo-papular, rash pruritic, Â rash papular, rash pustular, skin toxicity, eczema, erythema, erythema multiforme, rash erythematous, acne, and Â lichen planus

Table 3: Grade 3-4 Laboratory Abnormalities Worsened from Baseline Occurring in ≥ 1% Patients in UC Cohort Study 1

Laboratory Test	Grade 3 - 4 %
Hyponatremia	12
Lymphopenia	11
Anemia	8
Increased alkaline phosphatase	4
Hypermagnesemia	4
Hypercalcemia	3
Hyperglycemia	3
Increased AST	2
Increased ALT	1
Hyperbilirubinemia	1
Increased creatinine	1
Neutropenia	1
Hyperkalemia	1
Hypokalemia	1
Hypoalbuminemia	1

Immunogenicity

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 IMFINZI 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 IMFINZI has not been adequately determined. Of 1124 patients who were treated with IMFINZI 10 mg/kg every 2 weeks and evaluable for the presence of anti-drug antibodies (ADAs), 3.3% patients tested positive for treatment-emergent ADAs. The clinical significance of anti-durvalumab antibodies is unknown.

DRUG INTERACTIONS

No information provided.

Fertility, pregnancy and lactation

Risk summary

Based on its mechanism of action and data from animal studies, IMFINZI can cause fetal harm when administered to a pregnant woman. There are no 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 resulted in increased 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 2-4% and 15-20%, 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 the clinical dose of 10 mg/kg of durvalumab (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.

Undesirable effects

The following adverse reactions are discussed in greater detail in other sections of the labeling.

Immune-Mediated Pneumonitis.
Immune-Mediated Hepatitis.
Immune-Mediated Colitis.
Immune-Mediated Endocrinopathies.
Other Immune-Mediated Adverse Reactions.
Infection.
Infusion-Related Reactions.