Olaratumab (Monograph)

Brand name: Lartruvo
Drug class: Antineoplastic Agents
- Platelet-derived Growth Factor Receptor (PDGFR) Alpha Inhibitors
- PDGF Receptor-α Inhibitors
- PDGFR-α Inhibitors
Chemical name: Disulfide with human monoclonal 3G3 κ-chain, anti-(human platelet-derived growth factor receptor α) (human monoclonal 3G3 γ-chain), immunoglobulin G1, dimer
Molecular formula: C₆₅₅₄H₁₀₀₇₆N₁₇₃₆O₂₀₄₈S₄₀
CAS number: 1024603-93-7

Introduction

Antineoplastic agent; recombinant human IgG₁ monoclonal antibody that specifically binds to platelet-derived growth factor receptor alpha (PDGFR-α).

Uses for Olaratumab

Soft Tissue Sarcoma

Used in combination with doxorubicin for the treatment of soft tissue sarcoma that is not amenable to curative treatment with surgery or radiation therapy; patients must have a histologic subtype for which an anthracycline-containing regimen is appropriate (designated an orphan drug by FDA for treatment of this cancer ).

Accelerated approval was based on progression-free and overall survival. Continued approval was contingent on verification and description of clinical benefit in confirmatory studies.

Olaratumab Dosage and Administration

General

• Consult respective manufacturers' labelings for information on dosage and method of administration of other antineoplastic agents used in combination regimens.

• Administer in setting where resuscitation equipment is readily available.

Premedication for Infusion-related Reactions

• Administer diphenhydramine hydrochloride 25–50 mg IV and dexamethasone phosphate 10–20 mg IV before olaratumab infusion on day 1 of cycle 1.

Restricted Distribution

• Available only through an expanded access program. Consult manufacturer (Lilly) at 877-285-4559 for specific information. (See Special Alerts.)

Administration

IV Administration

For solution compatibility information, see Compatibility under Stability.

Administer by IV infusion. Do not administer by rapid IV injection (e.g., IV push or bolus).

Do not administer with any other drug or electrolytes simultaneously in the same IV line.

Flush IV line with 0.9% sodium chloride injection after olaratumab administration.

Dilution

Must be diluted prior to IV infusion.

Do not shake vial.

Withdraw appropriate volume of olaratumab injection concentrate from vial labeled as containing 10 mg/mL and dilute in 0.9% sodium chloride to yield a final volume of 250 mL.

Mix by gentle inversion; do not shake.

Do not dilute in dextrose-containing solutions or any other solutions.

Discard any partially used vials.

Rate of Administration

Administer by IV infusion over 60 minutes.

Dosage

Adults

Soft Tissue Sarcoma

IV

15 mg/kg on days 1 and 8 of each 21-day cycle; doxorubicin also is administered during cycles 1–8.

Continue olaratumab therapy until disease progression or unacceptable toxicity occurs.

Dosage Modification for Toxicity

Infusion-related Effects

IV

If grade 1 or 2 infusion-related reactions occur, interrupt the infusion; upon resolution, may resume the infusion but reduce infusion rate by 50%. (See Infusion-related Effects under Cautions.)

If grade 3 or 4 infusion-related reactions occur, permanently discontinue olaratumab therapy.

Neutropenia

IV

If febrile neutropenia, neutropenic infection, or prolonged grade 4 neutropenia (lasting >1 week) occurs, withhold olaratumab therapy until ANC ≥1000/mm³; upon resumption, permanently reduce dosage to 12 mg/kg.

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time. (See Hepatic Impairment under Cautions.)

Renal Impairment

No specific dosage recommendations at this time. (See Renal Impairment under Cautions.)

Geriatric Patients

No specific dosage recommendations. (See Geriatric Use under Cautions.)

Cautions for Olaratumab

Contraindications

• No known contraindications.

Warnings/Precautions

Infusion-related Effects

Infusion-related reactions (e.g., flushing, dyspnea, bronchospasm, fever/chills, severe hypotension, anaphylactic shock, cardiac arrest), sometimes fatal, reported; generally occur during first 2 cycles. Frequency of infusion-related reactions similar regardless of administration of premedication. Grade 1 or 2 infusion-related reactions recurred in 12 of 59 patients (20%) following resumption of infusion.

Monitor patients for manifestations of infusion reactions during and following olaratumab infusion in a setting where resuscitation equipment is readily available.

Premedicate with diphenhydramine and dexamethasone prior to first dose of olaratumab during cycle 1. (See Premedication for Infusion-related Reactions under Dosage and Administration.) If infusion-related reactions occur, temporary interruption followed by reduction in the infusion rate or permanent drug discontinuance may be required. (See Infusion-related Effects under Dosage and Administration.)

Combination Therapy

When used in combination with doxorubicin, consider cautions, precautions, and contraindications of doxorubicin.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.

Avoid pregnancy during therapy. Women of childbearing potential should use an effective contraceptive method while receiving olaratumab and for 3 months after the drug is discontinued. If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard.

Immunogenicity

Antibodies to olaratumab, including neutralizing antibodies to the drug, reported.

Impairment of Fertility

May impair male fertility.

Specific Populations

Pregnancy

May cause fetal harm. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether distributed into human milk. Discontinue nursing during therapy and for 3 months after drug discontinuance

Effects of the drug on nursing infants or on human milk production are unknown.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger adults.

Hepatic Impairment

Pharmacokinetics not affected by mild to moderate hepatic impairment (total bilirubin concentration at or below ULN with AST concentration exceeding ULN or total bilirubin concentration above ULN, but not >3 times the ULN, with any AST concentration).

Not studied in patients with severe hepatic impairment (total bilirubin concentration >3 times the ULN with any AST concentration).

Renal Impairment

Pharmacokinetics not affected by mild to moderate renal impairment (Cl_cr 30–89 mL/minute).

Not studied in patients with severe renal impairment (Cl_cr 15–29 mL/minute).

Common Adverse Effects

Lymphopenia, nausea, fatigue, neutropenia, musculoskeletal pain, thrombocytopenia, mucositis, alopecia, hyperglycemia, vomiting, leukopenia, diarrhea, increased aPTT, decreased appetite, abdominal pain, pyrexia, neuropathy, hypokalemia, hypophosphatemia, headache, increased alkaline phosphatase concentrations, hypomagnesemia, peripheral edema, infusion-related reactions (including hypersensitivity and angioedema), anxiety, dry eyes.

Drug Interactions

Specific Drugs

Olaratumab Pharmacokinetics

Absorption

Bioavailability

Steady-state concentrations are achieved during cycle 3 following administration of olaratumab 15 mg/kg IV on days 1 and 8 along with doxorubicin hydrochloride 75 mg/m² IV on day 1 of each 21-day cycle.

Elimination

Half-life

Approximately 11 days.

Special Populations

Mild to moderate hepatic impairment: Pharmacokinetics not affected.

Severe hepatic impairment: Not studied.

Mild to moderate renal impairment: Pharmacokinetics not affected.

Severe renal impairment: Not studied.

Age (over range of 22–85 years), gender, and race do not substantially affect pharmacokinetics. Clearance increases with increasing body weight.

Stability

Storage

Parenteral

Injection

2–8°C in original carton to protect from light. Do not freeze or shake.

Diluted solution: 2–8°C for up to 24 hours followed by an additional 8 hours (including infusion time) at room temperature (<25°C). Do not freeze or shake.

Compatibility

Parenteral

Solution Compatibility1

Actions

• A recombinant human IgG₁ monoclonal antibody that binds specifically to PDGFR-α (a receptor tyrosine kinase expressed on cells of mesenchymal origin), resulting in inhibition of downstream signaling.

• Antitumor activity against selected sarcoma cell lines demonstrated in vitro and in vivo.

• Disrupts PDGFR-α signaling in tumor implant models.

Advice to Patients

• Risk of infusion-related reactions; importance of reporting signs and symptoms of such reactions (e.g., flushing, dyspnea, bronchospasm, fever/chills).

• Risk of fetal harm. Necessity of advising women of childbearing potential that they should use an effective method of contraception while receiving the drug and for 3 months after discontinuance of therapy. Importance of women informing clinicians if they are pregnant. If pregnancy occurs, advise of potential fetal risk.

• Necessity of advising women to avoid breast-feeding during therapy and for 3 months after discontinuance of therapy.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

• Importance of informing patients of other important precautionary information. (See Cautions.)

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.

Distribution of olaratumab is limited to certain patients through an expanded access program. (See Restricted Distribution under Dosage and Administration.)

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