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  • CLASSES

    Antineoplastic Monoclonal Antibodies

    DEA CLASS

    Rx

    DESCRIPTION

    A human monoclonal antibody that binds platelet-derived growth factor receptor-alpha (PDGFR-alpha)
    Approved for use in soft tissue sarcoma not amenable to curative treatment with radiotherapy or surgery, in combination with doxorubicin
    Infusion-related reactions (IRR) may occur; monitor for signs and symptoms of IRR during and following the infusion and permanently discontinue therapy for grade 3 or 4 infusion-related reactions

    COMMON BRAND NAMES

    LARTRUVO

    HOW SUPPLIED

    LARTRUVO Intravenous Inj Sol: 1mL, 10mg

    DOSAGE & INDICATIONS

    For the treatment of soft-tissue sarcoma.
    NOTE: Olaratumab has been designated as an orphan drug for the treatment of soft-tissue sarcoma.
    For the treatment of soft-tissue sarcoma not amenable to curative treatment with radiotherapy or surgery, in combination with doxorubicin.
    Intravenous dosage
    Adults

    15 mg/kg IV over 60 minutes on days 1 and 8 repeated every 21 days until disease progression or unacceptable toxicity in combination with doxorubicin 75 mg/m2 IV on day 1 repeated every 21 days for up to 8 cycles. Dexrazoxane use was permitted prior to doxorubicin in cycles 5 to 8 in a clinical trial. Premedicate patients with diphenhydramine 25 to 50 mg IV and dexamethasone 10 to 20 mg IV prior to olaratumab on day 1 of cycle 1. Discontinue olaratumab in patients who develop a grade 3 or 4 infusion-related reaction. The median progression-free survival (PFS) time was improved in patients with locally advanced or metastatic soft-tissue sarcoma not previously treated with an anthracycline who received olaratumab plus doxorubicin compared with doxorubicin (6.6 months vs. 4.1 months; hazard ratio = 0.672; 95% CI, 0.442 to 1.021; p = 0.0615) in a multicenter, randomized, phase II trial (n = 133). In a planned interim analysis, this PFS survival benefit with combination therapy met a prespecified protocol-defined significance level (p-value) of 0.1999. At the final analysis, the median overall survival time was significantly improved with olaratumab plus doxorubicin compared with doxorubicin (26.5 months vs. 14.7 months; HR = 0.46; 95% CI, 0.3 to 0.71; p = 0.003). In this study, 38% of patients had leiomyosarcoma; other soft-tissue sarcoma histologies included synovial sarcoma, liposarcoma, angiosarcoma, chondrosarcoma, neurofibrosarcoma, fibrosarcoma, and undifferentiated pleomorphic sarcoma.

    MAXIMUM DOSAGE

    Adults

    15 mg/kg IV.

    Geriatric

    15 mg/kg IV.

    Adolescents

    Safety and efficacy not established.

    Children

    Safety and efficacy not established.

    Infants

    Safety and efficacy not established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Olaratumab has not been evaluated in patients with severe hepatic impairment, defined as a total bilirubin level greater than 3 times the upper limit of normal with any AST level. Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Olaratumab has not been evaluated in patients with severe renal impairment, defined as a creatinine clearance of 15 to 29 mL/min. Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Olaratumab is administered as an intravenous (IV) infusion only; do NOT give as an IV push or bolus.
    Premedicate with diphenhydramine and dexamethasone as recommended to help prevent infusion-related reactions.
    Dilution is required prior to administration.
     
    Dilution
    Withdraw the calculated dose from the 500 mg/50 mL (10 mg/mL) vial and further dilute with 0.9% sodium chloride injection, USP to a final volume of 250 mL; discard any unused portion of the vial.
    Gently invert the diluted admixture; do not shake.
    Do not mix with dextrose-containing or other solutions.
    Storage after dilution: store the diluted admixture for up to 24 hours refrigerated (2 to 8 degrees C or 36 to 46 degrees F) and for up to an additional 4 hours at room temperature (less than 25 degrees C or 77 degrees F); storage time includes the infusion time. Do not freeze. Allow the diluted admixture to warm to room temperature prior to administration.
     
    Intravenous Infusion
    Administer the diluted admixture as an IV infusion over 60 minutes.
    Flush the line with 0.9% sodium chloride injection, USP after the infusion.

    STORAGE

    LARTRUVO :
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Do not freeze
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)
    - Store in carton

    CONTRAINDICATIONS / PRECAUTIONS

    Infusion-related reactions

    Severe infusion-related reactions have been reported with olaratumab therapy; most reactions occur with the first or second infusion. Symptoms may include flushing, shortness of breath, bronchospasm, fever/chills, severe hypotension, anaphylactic shock, or cardiac arrest. Premedicate patients with diphenhydramine 25 to 50 mg IV and dexamethasone 10 to 20 mg IV prior to the olaratumab infusion on day 1 of cycle 1; however, be aware that infusion reactions may still occur in patients who receive appropriate premedication. Monitor patients for signs and symptoms of infusion reactions during and after olaratumab administration; give olaratumab in a facility that has resuscitation equipment available. Hold olaratumab and resume the infusion at a reduced rate upon symptom resolution in patients who develop grade 1 or 2 infusion reactions; permanently discontinue olaratumab in patients who develop a grade 3 or 4 infusion-related reaction.

    Infection, neutropenia

    Severe neutropenia has been reported with olaratumab use. Monitor blood counts prior to and during olaratumab therapy. Therapy interruption and dose reduction are necessary in patients who develop neutropenic fever/infection or grade 4 neutropenia lasting longer than 1 week.

    Pregnancy

    Olaratumab may cause fetal harm when administered during pregnancy, based on animal data and its mechanism of action. Advise females of reproductive potential to avoid becoming pregnant while taking olaratumab. Discuss the potential hazard to the fetus if olaratumab is used during pregnancy or if a patient becomes pregnant while taking this drug. Although no animal studies have been conducted with olaratumab, animal knockout models link disruption of platelet-derived growth factor receptor alpha (PDGFR-alpha) signaling to adverse effects on embryo-fetal development. Administration of an anti-murine PDGFR-alpha antibody to pregnant mice during organogenesis has been linked to malformations and skeletal variations.

    Contraception requirements, infertility, reproductive risk

    Discuss contraception requirements with patients due to the potential for reproductive risk with olaratumab. Females of reproductive potential should be advised to use effective contraception during and for at least 3 months after the last olaratumab dose. Discuss the potential hazard to the fetus if olaratumab is used during pregnancy or if a patient becomes pregnant while taking this drug. Olaratumab may cause male infertility, based on data from animal knockout models. The loss of platelet-derived growth factor receptor alpha pathway signaling resulted in a progressive reduction in testicular size, Leydig cell loss, and spermatogenic arrest.

    Breast-feeding

    It is not known if olaratumab is secreted in human milk or if it has effects on the breast-fed infant or on milk production. Due to the risk of serious adverse reactions in nursing infants, women should discontinue breast-feeding during olaratumab therapy and for 3 months after the last dose.

    ADVERSE REACTIONS

    Severe

    neutropenia / Delayed / 48.0-48.0
    lymphopenia / Delayed / 44.0-44.0
    cardiac arrest / Early / 0-14.0
    anaphylactic shock / Rapid / 0-14.0
    bronchospasm / Rapid / 0-14.0
    asthenia / Delayed / 9.0-9.0
    fatigue / Early / 9.0-9.0
    flank pain / Delayed / 0-8.0
    muscle cramps / Delayed / 0-8.0
    arthralgia / Delayed / 0-8.0
    musculoskeletal pain / Early / 8.0-8.0
    bone pain / Delayed / 0-8.0
    back pain / Delayed / 0-8.0
    myalgia / Early / 0-8.0
    hypokalemia / Delayed / 8.0-8.0
    thrombocytopenia / Delayed / 6.0-6.0
    hypophosphatemia / Delayed / 5.0-5.0
    prolonged bleeding time / Delayed / 5.0-5.0
    diarrhea / Early / 3.0-3.0
    abdominal pain / Early / 3.0-3.0
    oral ulceration / Delayed / 3.0-3.0
    chills / Rapid / 0-2.3
    fever / Early / 0-2.3
    flushing / Rapid / 0-2.3
    hypotension / Rapid / 0-2.3
    infusion-related reactions / Rapid / 2.3-2.3
    nausea / Early / 2.0-2.0
    anorexia / Delayed / 2.0-2.0
    hyperglycemia / Delayed / 2.0-2.0

    Moderate

    peripheral neuropathy / Delayed / 22.0-22.0
    hypomagnesemia / Delayed / 16.0-16.0
    elevated hepatic enzymes / Delayed / 16.0-16.0

    Mild

    alopecia / Delayed / 52.0-52.0
    vomiting / Early / 45.0-45.0
    headache / Early / 20.0-20.0
    anxiety / Delayed / 11.0-11.0
    xerophthalmia / Early / 11.0-11.0

    DRUG INTERACTIONS

    There are no drug interactions associated with Olaratumab products.

    PREGNANCY AND LACTATION

    Pregnancy

    Olaratumab may cause fetal harm when administered during pregnancy, based on animal data and its mechanism of action. Advise females of reproductive potential to avoid becoming pregnant while taking olaratumab. Discuss the potential hazard to the fetus if olaratumab is used during pregnancy or if a patient becomes pregnant while taking this drug. Although no animal studies have been conducted with olaratumab, animal knockout models link disruption of platelet-derived growth factor receptor alpha (PDGFR-alpha) signaling to adverse effects on embryo-fetal development. Administration of an anti-murine PDGFR-alpha antibody to pregnant mice during organogenesis has been linked to malformations and skeletal variations.

    It is not known if olaratumab is secreted in human milk or if it has effects on the breast-fed infant or on milk production. Due to the risk of serious adverse reactions in nursing infants, women should discontinue breast-feeding during olaratumab therapy and for 3 months after the last dose.

    MECHANISM OF ACTION

    Olaratumab is a human IgG1 monoclonal antibody that binds platelet-derived growth factor receptor-alpha (PDGFR-alpha). It blocks PDGF-AA and -BB ligand binding and prevents PDGF-AA, -BB, and -CC-induced receptor activation and downstream PDGFR-alpha pathway signaling. PDGFR-alpha is a receptor tyrosine kinase expressed on cells of mesenchymal origin; it has been detected on some tumor and stromal cells, including sarcomas. It’s signaling results in cancer cell proliferation, metastasis, and maintenance of the tumor microenvironment.

    PHARMACOKINETICS

    Olaratumab is administered intravenously. In a pharmacokinetic analysis, the mean steady state volume of distribution was 7.7 L (coefficient of variance (CV), 16%), the mean clearance was 0.56 L/day (CV, 33%), and the estimated elimination half-life was approximately 11 days (range 6 to 24 days).

    Intravenous Route

    In a pharmacokinetic analysis in 92 patients with unresectable or metastatic soft-tissue sarcoma who received olaratumab 15 mg/kg IV on days 1 and 8 repeated every 21 days, the steady state Cmax levels ranged from 419 micrograms (mcg)/mL (coefficient of variance (CV), 26.2%) and 487 mcg/mL (CV, 33%); steady state was reached during cycle 3.