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    Monoclonal Antibodies that Target the Programmed Death-1 (PD-1) and Programmed Death-Ligand 1 (PD-L1) Pathways

    DEA CLASS

    Rx

    DESCRIPTION

    Human programmed death-ligand 1 (PD-L1) blocking monoclonal antibody
    Used for certain types of urothelial carcinoma, NSCLC, and SCLC
    Immune-mediated reactions have been reported; treatment may need to be withheld or permanently discontinued

    COMMON BRAND NAMES

    IMFINZI

    HOW SUPPLIED

    IMFINZI Intravenous Inj Sol: 1mL, 50mg

    DOSAGE & INDICATIONS

    For the treatment of urothelial carcinoma.
    For the treatment of locally advanced or metastatic urothelial carcinoma, in patients with disease progression on or following platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy.
    Intravenous dosage
    Adults

    10 mg/kg IV over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. In a multicenter, open-label clinical trial, patients with locally advanced or metastatic urothelial carcinoma who had progressed on or after platinum-based chemotherapy received treatment with durvalumab; patients with a history of immunodeficiency or autoimmune disease were excluded, along with patients who had medical conditions requiring immunosuppression. After a median follow-up of 5.6 months, the objective response rate (ORR) was 17% (complete response (CR), 2.7%; partial response (PR), 14.3%); the median duration of response was not reached (range, 0.9+ to 19.9+ months). Response rates were higher in patients with high levels of PD-L1 expression (ORR 26.3%; CR 3.2%; PR 23.2%) or PD-L1 expression not evaluable (ORR 21.4%; CR 7.1%; PR 14.3%) compared to low or negative PD-L1 expression (ORR 4.1%; CR 1.4%; PR 2.7%). In these patients, the median duration of response was not reached in patients with high PD-L1 or PD-L1 not evaluable and was 12.3 months for patients with low or negative PD-L1 expression. Among the total 31 responding patients, 14 patients (45%) had ongoing responses of 6 months or longer and five patients (16%) had ongoing responses of 12 months or longer.

    For the treatment of unresectable stage III non-small cell lung cancer (NSCLC) whose disease has not progressed following concurrent platinum-based chemoradiotherapy.
    Intravenous dosage
    Adults

    10 mg/kg IV over 60 minutes, every 2 weeks until disease progression or unacceptable toxicity for up to 12 months. In a planned interim analysis of a multicenter, randomized, double-blind, phase 3 clinical trial (the PACIFIC trial), consolidation treatment for up to 12 months with durvalumab after standard platinum-based chemoradiotherapy significantly prolonged median PFS by blinded independent central review (BICR) in patients with locally advanced or unresectable non-small cell lung cancer (NSCLC) compared with placebo (16.8 months vs. 5.6 months). The benefit in PFS was consistent across 35 prespecified subgroups, including PD-L1 25% or higher, PD-L1 less than 25%, and never smokers; hazard ratios for patients who were EGFR mutation-positive or -unknown were not clinically significant. Median overall survival was also significantly improved in the durvalumab arm (not reached vs. 28.7 months).[62499] [61913]

    For the treatment of small cell lung cancer (SCLC).
    NOTE: Durvalumab has been designated by the FDA as an orphan drug for the treatment of SCLC.
    For the first-line treatment of extensive-stage small cell lung cancer (SCLC), in combination with carboplatin and etoposide.
    Intravenous dosage
    Adults weighing more than 30 kg

    1,500 mg IV over 60 minutes on day 1, followed by carboplatin (AUC 5 to 6 IV on day 1) and etoposide (80 to 100 mg/m2 IV on days 1 to 3), every 3 weeks for 4 cycles; administer durvalumab prior to chemotherapy when given on the same day. After completion of 4 cycles of durvalumab plus chemotherapy, continue durvalumab 1,500 mg IV every 4 weeks as a single agent until disease progression or unacceptable toxicity. Durvalumab significantly improved overall survival by approximately 3 months when added to platinum-etoposide chemotherapy compared with platinum-etoposide alone in patients with extensive-stage SCLC in a randomized clinical trial.

    Adults weighing 30 kg or less

    20 mg/kg IV over 60 minutes on day 1, followed by carboplatin (AUC 5 to 6 IV on day 1) and etoposide (80 to 100 mg/m2 IV on days 1 to 3), every 3 weeks for 4 cycles; administer durvalumab prior to chemotherapy when given on the same day. After completion of 4 cycles of durvalumab plus chemotherapy, continue durvalumab 20 mg/kg IV every 4 weeks as a single agent until disease progression or unacceptable toxicity. Durvalumab significantly improved overall survival by approximately 3 months when added to platinum-etoposide chemotherapy compared with platinum-etoposide alone in patients with extensive-stage SCLC in a randomized clinical trial.

    For the first-line treatment of extensive-stage small cell lung cancer (SCLC), in combination with cisplatin and etoposide.
    Intravenous dosage
    Adults weighing more than 30 kg

    1,500 mg IV over 60 minutes on day 1, followed by cisplatin (75 to 80 mg/m2 IV on day 1) and etoposide (80 to 100 mg/m2 IV on days 1 to 3), every 3 weeks for 4 cycles; administer durvalumab prior to chemotherapy when given on the same day.  Administer appropriate hydration prior to cisplatin administration and maintain hydration and adequate urinary output for 24 hours after cisplatin administration. After completion of 4 cycles of durvalumab plus chemotherapy, continue durvalumab 1,500 mg IV every 4 weeks as a single agent until disease progression or unacceptable toxicity. Durvalumab significantly improved overall survival by approximately 3 months when added to platinum-etoposide chemotherapy compared with platinum-etoposide alone in patients with extensive-stage SCLC in a randomized clinical trial.

    Adults weighing 30 kg or less

    20 mg/kg IV over 60 minutes on day 1, followed by cisplatin (75 to 80 mg/m2 IV on day 1) and etoposide (80 to 100 mg/m2 IV on days 1 to 3), every 3 weeks for 4 cycles; administer durvalumab prior to chemotherapy when given on the same day.  Administer appropriate hydration prior to cisplatin administration and maintain hydration and adequate urinary output for 24 hours after cisplatin administration. After completion of 4 cycles of durvalumab plus chemotherapy, continue durvalumab 20 mg/kg IV every 4 weeks as a single agent until disease progression or unacceptable toxicity. Durvalumab significantly improved overall survival by approximately 3 months when added to platinum-etoposide chemotherapy compared with platinum-etoposide alone in patients with extensive-stage SCLC in a randomized clinical trial.

    MAXIMUM DOSAGE

    Adults

    Urothelial cancer and NSCLC: 10 mg/kg IV every 2 weeks.
    SCLC: 1,500 mg IV every 3 or 4 weeks.

    Geriatric

    Urothelial cancer and NSCLC: 10 mg/kg IV every 2 weeks.
    SCLC: 1,500 mg IV every 3 or 4 weeks.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Treatment-Related Immune-Mediated HepatitisNo Tumor Involvement of the LiverAST or ALT level of more than 3 to 8 times the ULN or a total bilirubin level of more than 1.5 to 3 times the ULN: Hold durvalumab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper). Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper. Permanently discontinue durvalumab in patients who do not have a complete or partial resolution of toxicity or who cannot reduce their daily prednisone dose to less than 10 mg (or equivalent) within 12 weeks of initiating steroids. AST or ALT level more than 8 times the ULN or a total bilirubin level more than 3-times the ULN: Permanently discontinue durvalumab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper starting when the toxicity resolves to grade 1 or less).Tumor Involvement of the LiverBaseline AST or ALT level at the ULN or less: Hold or permanently discontinue durvalumab based on recommendations for hepatitis with no tumor involvement of the liver.Baseline AST or ALT level of more than 1 to 3 times the ULNAST or ALT level of more than 5 to 10 times the ULN: Hold durvalumab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper). Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper. Permanently discontinue durvalumab in patients who do not have a complete or partial resolution of toxicity or who cannot reduce their daily prednisone dose to less than 10 mg (or equivalent) within 12 weeks of initiating steroids. Baseline AST or ALT level of more than 3 to 5 times the ULNAST or ALT level of more than 8 to 10 times the ULN: Hold durvalumab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper). Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper. Permanently discontinue durvalumab in patients who do not have a complete or partial resolution of toxicity or who cannot reduce their daily prednisone dose to less than 10 mg (or equivalent) within 12 weeks of initiating steroids. Any Baseline AST or ALT levelAST or ALT level more than 10 times the ULN or a total bilirubin level to more than 3 times the ULN: Permanently discontinue durvalumab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper starting when the toxicity resolves to grade 1 or less).

    Renal Impairment

    Treatment-Related Immune-Mediated Nephritis with Renal Dysfunction Grade 2 or 3 increased serum creatinine (SCr) level: Hold durvalumab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper). Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper. Permanently discontinue durvalumab in patients who do not have a complete or partial resolution of toxicity or who cannot reduce their daily prednisone dose to less than 10 mg (or equivalent) within 12 weeks of initiating steroids. Grade 4 increased SCr level: Permanently discontinue durvalumab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper starting when the toxicity resolves to grade 1 or less).

    ADMINISTRATION

    Injectable Administration

    Visually inspect drug product for particulate matter and discoloration. Durvalumab 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 durvalumab.
    Administer durvalumab prior to chemotherapy when given on the same day.

    Intravenous Administration

    Preparation:
    Withdraw the required volume of drug and transfer into an intravenous container containing 0.9% Sodium Chloride Injection or 5% Dextrose Injection, to prepare an infusion with a final concentration ranging from 1 mg/mL to 15 mg/mL.
    Mix diluted solution by gentle inversion. Do not shake.
    Discard partially used or empty vials of durvalumab.
     
    Storage of Diluted Solution:
    Durvalumab does not contain a preservative; administer immediately after preparation.
    If storage of the diluted solution is necessary, the total time from vial puncture to the start of administration should be less than 24 hours if refrigerated (2 to 8 degrees C; 36 to 46 degrees F), or less than 4 hours at room temperature (up to 25 degrees C; up to 77 degrees F). Do not freeze.
     
    Intravenous Infusion:
    Administer the diluted infusion over 60 minutes through an intravenous line containing sterile, low protein binding 0.2 or 0.22 micron in-line filter.
    Do not coadminister with other drugs through the same intravenous line.

    STORAGE

    IMFINZI:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Do not freeze
    - Protect from light
    - See package insert for detailed storage information
    - Store between 36 to 46 degrees F
    - Store in original container

    CONTRAINDICATIONS / PRECAUTIONS

    Pneumonitis, pulmonary disease

    Use durvalumab with caution in patients with pre-existing pulmonary disease. Immune-mediated pneumonitis or interstitial lung disease (ILD) has been reported with durvalumab therapy; one case was fatal. Monitor patients for signs or symptoms (e.g., new or worsening chest pain or shortness of breath) of pneumonitis. If patients have suspected pneumonitis, evaluate with radiographic imaging; an interruption or discontinuation of therapy and treatment with high-dose corticosteroids (followed by a steroid taper) may be necessary.

    Hepatic disease, hepatitis

    Use durvalumab with caution in patients with pre-existing hepatic disease; the clinical trial resulting in FDA approval excluded patients with a history of hepatitis B or C infection, and the effect of moderate or severe hepatic impairment on the pharmacokinetics of durvalumab is unknown. Immune-mediated hepatitis has been reported with durvalumab therapy; one case was fatal. Monitor patients for abnormal liver tests prior to each cycle of treatment with durvalumab. Immune-mediated hepatitis should be managed with an interruption or discontinuation of therapy and treatment with high-dose corticosteroids (followed by a steroid taper).

    Colitis, Crohn's disease, diarrhea, inflammatory bowel disease, ulcerative colitis

    Use durvalumab with caution in patients with pre-existing inflammatory bowel disease such as ulcerative colitis or Crohn's disease. Diarrhea and immune-mediated colitis have occurred with durvalumab therapy. Monitor patients for signs and symptoms of colitis (e.g., diarrhea or severe abdominal pain). Treatment with high-dose corticosteroids (followed by a steroid taper), along with an interruption or discontinuation of therapy, may be necessary.

    Hyperthyroidism, hypothyroidism, thyroid disease

    Thyroid disease/disorders such as hypothyroidism and hyperthyroidism have occurred in patients who received durvalumab therapy. Monitor thyroid function tests (TFTs) at baseline and periodically during treatment. Hypothyroidism may be managed with hormone replacement therapy and does not require an interruption of durvalumab treatment. Interrupt durvalumab therapy until the patient is clinically stable for grade 2 or higher hyperthyroidism and manage medically.

    Adrenal insufficiency, hypophysitis, hypopituitarism

    Immune-mediated adrenal insufficiency and hypophysitis/hypopituitarism have occurred in patients treated with durvalumab. Monitor patients for signs and symptoms of adrenal insufficiency (e.g., hypotension, decreased cortisol level, fatigue, weakness, and weight loss) and hypophysitis (e.g., decreased pituitary hormone levels, pituitary gland inflammation, severe intractable headache, and vision impairment) during and after durvalumab treatment. An interruption of therapy, treatment with high-dose corticosteroids, and hormone replacement may be necessary.

    Autoimmune disease, immunosuppression, organ transplant, systemic lupus erythematosus (SLE)

    Use durvalumab with caution in patients with autoimmune disease (e.g., systemic lupus erythematosus (SLE)) or conditions that require immunosuppression (e.g., chronic corticosteroid use) and in patients who have previously had an organ transplant. These patient populations were excluded from clinical trials; the mechanism of action of durvalumab involves modulation of the immune system.

    Diabetes mellitus, type 1 diabetes mellitus

    Immune-related type 1 diabetes mellitus has occurred in patients receiving treatment with durvalumab. Monitor patients for hyperglycemia and other signs and symptoms of diabetes. Initiate insulin for type 1 diabetes; an interruption of durvalumab therapy may be necessary.

    Serious rash

    An immune-mediated serious rash has occurred in patients receiving treatment with durvalumab. Monitor patients for signs and symptoms of rash. An interruption or discontinuation of durvalumab therapy may be necessary, along with treatment with high-dose corticosteroids.

    Renal disease, renal impairment

    Immune-mediated nephritis has occurred in patients treated with durvalumab. Monitor renal function at baseline and before each cycle of treatment. No initial dose adjustment is recommended in patients with renal dysfunction; however, use durvalumab with caution in patients with renal disease or renal impairment. If immune-mediated nephritis occurs, an interruption or discontinuation of durvalumab therapy may be necessary, along with treatment with high-dose corticosteroids.

    Aseptic meningitis, hemolytic anemia, keratitis, myocarditis, uveitis

    Immune-mediated reactions such as aseptic meningitis, hemolytic anemia, immune thrombocytopenic purpura, myocarditis, myositis, and ocular inflammatory toxicity including uveitis and keratitis have occurred with durvalumab therapy. Monitor patients for signs and symptoms of immune-mediated reactions; confirm etiology or exclude other causes. Therapy may need to be temporarily withheld or permanently discontinued; administer corticosteroids as clinically indicated. If uveitis occurs in combination with other immune-mediated reactions, evaluate for Vogt-Koyanagi-Harada syndrome, which has been observed with other products in this class and may require treatment with systemic corticosteroids to reduce the risk of permanent vision loss.

    Infusion-related reactions

    Severe or life-threatening infusion-related reactions may occur in patients treated with durvalumab. Monitor patients for signs and symptoms of an infusion-related reaction. Interrupt or slow the rate of infusion in patients with mild or moderate infusion reactions; consider premedications for subsequent doses in these patients. Permanently discontinue durvalumab in patients with grade 3 or 4 infusion reactions.

    Immune-mediated reactions

    Severe and fatal immune-mediated reactions can occur with durvalumab therapy; these reactions may involve any organ system. While they usually manifest during treatment with durvalumab, they may also occur after discontinuation of therapy. Monitor patients for immune-mediated reactions; an interruption or discontinuation of therapy may be necessary, along with treatment with high-dose corticosteroids.

    Allogeneic stem cell transplant

    Fatal and other serious complications including hyperacute, acute, and chronic graft-versus-host-disease, sinusoidal obstruction syndrome (SOS) previously termed veno-occlusive disease (VOD) after reduced intensity conditioning, and a steroid-requiring febrile syndrome (without an identified infectious cause) have been reported in patients who receive an allogeneic stem cell transplant (SCT) before or after being treated with a PD-1/PD-L1 blocking antibody. Therefore, perform a risk/benefit analysis prior to starting treatment with a PD-1/PD-L1 blocking antibody, such as durvalumab, in patients who may receive or who have a history of undergoing an allogeneic SCT. Monitor patients closely for evidence of transplant-related complications and intervene promptly. Complications may occur despite intervening therapy between PD-1/PD-L1 blockade and allogeneic SCT.

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during durvalumab treatment and for at least 3 months after the last dose. Although there are no adequately controlled studies in pregnant women, durvalumab can cause fetal harm when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving durvalumab should be apprised of the potential hazard to the fetus. The PD-1/PD-L1 pathway plays a central role in preserving pregnancy by maintaining maternal immune tolerance to the fetus. In animal reproduction studies, administration of durvalumab to pregnant cynomolgus monkeys at exposures approximately 6 to 20 times higher than those observed at the recommended dose of 10 mg/kg in humans resulted in increased premature delivery, fetal loss (abortion and stillbirth), and premature neonatal death. Based on its mechanism of action, fetal exposure to durvalumab mal also increase the risk of developing immune-mediated disorders or altering the normal immune response.

    Contraception requirements, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during durvalumab treatment. Durvalumab can be teratogenic if taken by the mother during pregnancy. Females of reproductive potential should avoid pregnancy and use effective contraception during and for at least 3 months after treatment with durvalumab. Females of reproductive potential should undergo pregnancy testing prior to initiation of durvalumab. Women who become pregnant while receiving durvalumab should be apprised of the potential hazard to the fetus.

    Breast-feeding

    Due to the potential for serious adverse reactions in nursing infants from durvalumab, advise women to discontinue breast-feeding during treatment and for 3 months after the final dose. It is not known whether durvalumab is present in human milk, although many drugs are excreted in human milk.

    Guillain-Barre syndrome, myasthenia gravis, neurotoxicity

    Immune-mediated neurological toxicities including myasthenia gravis and Guillain-Barre syndrome have rarely been reported with durvalumab or other PD-1/PD-L1 inhibitors. Durvalumab therapy may need to be interrupted or discontinued depending on the severity of the neurotoxicity; treatment with systemic corticosteroids may also be necessary.

    ADVERSE REACTIONS

    Severe

    hyperkalemia / Delayed / 30.9-30.9
    lymphopenia / Delayed / 11.0-17.0
    hyponatremia / Delayed / 3.6-12.0
    infection / Delayed / 0.4-10.9
    hyperglycemia / Delayed / 3.0-8.0
    fatigue / Early / 0.8-6.0
    hepatitis / Delayed / 5.0-5.0
    elevated hepatic enzymes / Delayed / 0.6-4.7
    pneumonitis / Delayed / 1.2-4.5
    musculoskeletal pain / Early / 4.4-4.4
    hypermagnesemia / Delayed / 0-4.0
    hepatotoxicity / Delayed / 0-3.3
    abdominal pain / Early / 0.4-2.7
    dyspnea / Early / 1.5-2.2
    peripheral edema / Delayed / 0-2.0
    nausea / Early / 0-1.6
    renal failure (unspecified) / Delayed / 0-1.4
    hyperbilirubinemia / Delayed / 0-1.2
    colitis / Delayed / 0-1.1
    diarrhea / Early / 0.6-1.1
    constipation / Delayed / 0-1.1
    rash / Early / 0.6-1.0
    Stevens-Johnson syndrome / Delayed / 0-1.0
    toxic epidermal necrolysis / Delayed / 0-1.0
    uveitis / Delayed / 0-1.0
    Vogt-Koyanagi-Harada syndrome / Delayed / 0-1.0
    keratitis / Delayed / 0-1.0
    hemolytic anemia / Delayed / 0-1.0
    neutropenia / Delayed / 0-1.0
    myocarditis / Delayed / 0-1.0
    aseptic meningitis / Delayed / 0-1.0
    anorexia / Delayed / 0-1.0
    fever / Early / 0.2-1.0
    cough / Delayed / 0-0.8
    hypocalcemia / Delayed / 0.2-0.2
    diabetes insipidus / Delayed / 0-0.1
    adrenocortical insufficiency / Delayed / 0-0.1
    myasthenia gravis / Delayed / 0-0.1
    pulmonary fibrosis / Delayed / Incidence not known
    ileus / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    glomerulonephritis / Delayed / Incidence not known
    interstitial nephritis / Delayed / Incidence not known
    vasculitis / Delayed / Incidence not known
    rhabdomyolysis / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    Guillain-Barre syndrome / Delayed / Incidence not known
    sinusoidal obstruction syndrome (SOS) / Delayed / Incidence not known
    veno-occlusive disease (VOD) / Delayed / Incidence not known
    graft-versus-host disease (GVHD) / Delayed / Incidence not known

    Moderate

    dysuria / Early / 0-10.0
    dysphonia / Delayed / 0-10.0
    hypercalcemia / Delayed / 0-3.0
    antibody formation / Delayed / 2.9-2.9
    hypoalbuminemia / Delayed / 0-1.2
    bullous rash / Early / 0-1.0
    iritis / Delayed / 0-1.0
    ocular inflammation / Early / 0-1.0
    hypokalemia / Delayed / 0-1.0
    infusion-related reactions / Rapid / 0.3-0.3
    hypopituitarism / Delayed / 0-0.1
    dehydration / Delayed / 3.0
    flank pain / Delayed / Incidence not known
    hypophysitis / Delayed / Incidence not known
    diabetes mellitus / Delayed / Incidence not known
    erythema / Early / Incidence not known
    psoriasis / Delayed / Incidence not known
    psoriaform rash / Delayed / Incidence not known
    anemia / Delayed / Incidence not known
    cystitis / Delayed / Incidence not known
    edema / Delayed / Incidence not known
    paresis / Delayed / Incidence not known

    Mild

    pruritus / Rapid / 0-12.0
    night sweats / Early / 0-10.0
    purpura / Delayed / 0-1.0
    vomiting / Early / Incidence not known
    acneiform rash / Delayed / Incidence not known
    maculopapular rash / Early / Incidence not known
    lichen planus-like eruption / Delayed / Incidence not known
    pharyngitis / Delayed / Incidence not known
    rhinitis / Early / Incidence not known
    sinusitis / Delayed / Incidence not known
    laryngitis / Delayed / Incidence not known
    back pain / Delayed / Incidence not known
    myalgia / Early / Incidence not known
    lethargy / Early / Incidence not known
    asthenia / Delayed / Incidence not known
    malaise / Early / Incidence not known
    alopecia / Delayed / Incidence not known

    DRUG INTERACTIONS

    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.

    PREGNANCY AND LACTATION

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during durvalumab treatment and for at least 3 months after the last dose. Although there are no adequately controlled studies in pregnant women, durvalumab can cause fetal harm when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving durvalumab should be apprised of the potential hazard to the fetus. The PD-1/PD-L1 pathway plays a central role in preserving pregnancy by maintaining maternal immune tolerance to the fetus. In animal reproduction studies, administration of durvalumab to pregnant cynomolgus monkeys at exposures approximately 6 to 20 times higher than those observed at the recommended dose of 10 mg/kg in humans resulted in increased premature delivery, fetal loss (abortion and stillbirth), and premature neonatal death. Based on its mechanism of action, fetal exposure to durvalumab mal also increase the risk of developing immune-mediated disorders or altering the normal immune response.

    Due to the potential for serious adverse reactions in nursing infants from durvalumab, advise women to discontinue breast-feeding during treatment and for 3 months after the final dose. It is not known whether durvalumab is present in human milk, although many drugs are excreted in human milk.

    MECHANISM OF ACTION

    Durvalumab is a human IgG1 kappa (IgG1k) monoclonal antibody, produced in Chinese Hamster Ovary (CHO) cell suspension culture, that inhibits programmed death ligand 1 (PD-L1) interactions with the PD-1 and CD80 (B7.1) molecules. PD-L1 may be expressed on tumor cells and/or tumor-infiltrating immune cells, can be induced by inflammatory signals (e.g., IFN-gamma), and can contribute to inhibition of the anti-tumor immune response in the tumor microenvironment; PD-1 and B7.1 receptors are found on T-cells and antigen-presenting cells. The PD-1 pathway regulates the balance between T-cell activation and protection of healthy tissues from immune-mediated damage. In cancer, the PD-1 pathway is thought to play an important role in the interaction of tumor cells with the host immune response. 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.

    PHARMACOKINETICS

    Durvalumab is administered intravenously. Exposure to durvalumab increases more than dose-proportionally at doses less than 3 mg/kg (0.3 times the approved dosage), but increases in a dose-proportional manner at doses greater than or equal to 3 mg/kg every 2 weeks. In a pharmacokinetic study (n = 1,902), steady-state was reached in approximately 16 weeks when administered at doses up to 2 times the recommended dosage every 2, 3, or 4 weeks. The geometric mean volume of distribution at steady state (% coefficient of variation, CV%) was 5.6 liters (CV%, 18%). The mean clearance of durvalumab at steady-state is 8.2 mL/hour (CV%, 39%). Clearance decreases over time, with a mean maximal reduction from baseline of approximately 23% (CV%, 57%); however, the decrease in clearance at steady state is not clinically relevant. The mean terminal half-life was 18 days (CV%, 24%). The pharmacokinetics of durvalumab are similar when assessed as a single-agent and when given in combination with chemotherapy.
     
    Affected cytochrome P450 isoenzymes and transporters: None.