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Durvalumab

Class: Antineoplastic Agents
Brands: Imfinzi

Introduction

Durvalumab is an antineoplastic agent.

Uses for Durvalumab

Durvalumab has the following uses:

Durvalumab is a programmed death-ligand 1 (PD-L1) blocking antibody indicated for the treatment of patients with 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.1

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.1

Durvalumab Dosage and Administration

General

Durvalumab is available in the following dosage form(s) and strength(s):

  • Injection: 500 mg/10 mL (50 mg/mL) solution in a single-dose vial.1

  • Injection: 120 mg/2.4 mL (50 mg/mL) solution in a single-dose vial.1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

  • Administer 10 mg/kg as an intravenous infusion over 60 minutes every 2 weeks.1

  • Dilute prior to intravenous infusion.1

Cautions for Durvalumab

Contraindications

None.1

Warnings/Precautions

Immune-mediated Pneumonitis

Immune-mediated pneumonitis or interstitial lung disease occurred in patients receiving durvalumab. Monitor patients for signs and symptoms of pneumonitis. Evaluate patients with suspected pneumonitis with radiographic imaging and manage with treatment modifications and corticosteroids.1

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 durvalumab 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 (1.2%) patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Durvalumab was interrupted in 12 patients and discontinued in five (0.4%) patients. Resolution occurred in 18 (1.3%) patients.1

Immune-mediated Hepatitis

Immune-mediated hepatitis occurred in patients receiving durvalumab. Monitor patients for abnormal liver tests each cycle during treatment with durvalumab. Manage immune-mediated hepatitis with treatment modifications and corticosteroids.1

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. Durvalumab 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%) of patients, AST in 58/1336 (4.3%), and total bilirubin in 37/1341 (2.8%) of patients.1

Immune-mediated Colitis

Immune-mediated colitis or diarrhea occurred in patients receiving durvalumab. Monitor patients for signs and symptoms of colitis or diarrhea and manage with treatment modifications, antidiarrheal agents, and corticosteroids.1

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 nonsteroidal immunosuppressants. Durvalumab was interrupted in five (0.4%) patients and discontinued in six (0.4%) patients. Resolution occurred in 11 (0.8%) patients.1

Immune-mediated Endocrinopathies

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

Thyroid Disorders

Monitor thyroid function prior to and periodically during treatment with durvalumab. Asymptomatic patients with abnormal thyroid function tests can receive durvalumab. Manage patients with abnormal thyroid function tests with hormone replacement (if indicated) and treatment modifications.1

In 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.1

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.1

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.1

Adrenal Insufficiency

Monitor patients for clinical signs and symptoms of adrenal insufficiency. Administer corticosteroids and hormone replacement as clinically indicated.1

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.1

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.1

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.1

Other Immune-mediated Adverse Reactions

Durvalumab 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 durvalumab.1

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.1

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.1

Nephritis

Monitor patients for abnormal renal function tests prior to and each cycle during treatment with durvalumab 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. Durvalumab was discontinued in all three patients. Resolution occurred in all three patients.1

Infection

Severe infections, including sepsis, necrotizing fasciitis, and osteomyelitis, occurred in patients receiving durvalumab. Monitor patients for signs and symptoms of infection and treat with anti-infectives for suspected or confirmed infections. Withhold durvalumab for ≥Grade 3 infection.1

In Study 1, infections occurred in 54 (29.7%) patients. Grade 3 or 4 infection occurred in eleven (6%) 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.1

Infusion-related Reactions

Severe infusion-related reactions have been reported in patients receiving durvalumab. 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 durvalumab in patients with Grade 3 or 4 infusion reactions.1

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.1

Embryofetal Toxicity

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.1

Specific Populations

Pregnancy

Risk Summary: 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.1

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. 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.1

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.1

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.1

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.1

Because of the potential for adverse reactions in breastfed infants from durvalumab, advise a lactating woman not to breastfeed during treatment with durvalumab and for at least 3 months after the last dose.1

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.1

Females And Males Of Reproductive Potential

Based on its mechanism of action, 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 durvalumab.1

Pediatric Use

The safety and effectiveness of durvalumab have not been established in pediatric patients.1

Geriatric Use

Of the 182 patients treated with durvalumab, 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.1

Common Adverse Effects

Most common adverse events (reported in ≥15% of patients) were fatigue, musculoskeletal pain, constipation, decreased appetite, nausea, peripheral edema, and urinary tract infection.1

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Please see product labeling for drug interaction information.

Actions

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.1

Durvalumab is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that 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).1

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.1

Advice to Patients

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide).1

Inform patients of the risk of immune-mediated adverse reactions that may require corticosteroid treatment and interruption or discontinuation of durvalumab, including: 1

Pneumonitis: Advise patients to contact their healthcare provider immediately for any new or worsening cough, chest pain, or shortness of breath.1

Hepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, pain on the right side of abdomen, lethargy, or easy bruising or bleeding.1

Colitis: Advise patients to contact their healthcare provider immediately for diarrhea, blood or mucus in stools, or severe abdominal pain.1

Endocrinopathies: Advise patients to contact their healthcare provider immediately for signs or symptoms of hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis or type 1 diabetes mellitus.1

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.1

Infection: Advise patients to contact their healthcare provider immediately for infection.1

Infusion-Related Reactions: Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion-related reactions.1

Embryofetal 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.1

Lactation: Advise female patients not to breastfeed while taking durvalumab and for at least 3 months after the last dose.1

Additional Information

AHFS First Release. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Durvalumab

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, Solution

120 mg/2.4 mL

Imfinzi

AstraZeneca

500 mg/10 mL

Imfinzi

AstraZeneca

AHFS Drug Information. © Copyright 2017, Selected Revisions May 15, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. AstraZeneca Pharmaceuticals LP. IMFINZI (Durvalumab) INTRAVENOUS prescribing information. 2017 May.

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