olaratumab (Discontinued)

Brand and Other Names:Lartruvo
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

IV solution

  • 500mg/50mL vial (10mg/mL)
  • Withdrawn from global market

Olaratumab withdrawn from global market

Withdrawn from the global market: Results of ANNOUNCE, the phase III trial of olaratumab in combination with doxorubicin in patients with advanced or metastatic soft tissue sarcomas did not confirm clinical benefit of olaratumab in combination with doxorubicin compared to doxorubicin alone

April 25, 2019 press release

  • In January 2019, Eli Lilly and Company reported the results of ANNOUNCE, the Phase III trial of olaratumab in combination with doxorubicin in patients with advanced or metastatic STS
  • Trial results did not confirm clinical benefit of olaratumab in combination with doxorubicin compared to doxorubicin
  • Patients who are currently receiving olaratumab may, in consultation with their physician, continue therapy if they are receiving clinical benefit; Lilly is establishing an access program for these patients
  • No new patients should receive olaratumab, outside of participation in ongoing clinical trials

Soft Tissue Sarcoma

Indicated, in combination with doxorubicin

  • In presence of histologic subtype for which an anthracycline-containing regimen is appropriate and
  • Not amenable to curative treatment with radiotherapy or surgery

15 mg/kg IV infused over 1 hr on Days 1 and 8 of each 21-day cycle

Administer with doxorubicin (75 mg/m² on Day 1) for the first 8 cycles

Continue until disease progression or unacceptable toxicity

Dosage Modifications

Infusion-related reactions

  • Grade 3 or 4: Permanently discontinue
  • Grade 1 or 2: Interrupt infusion; after resolution, resume IV infusion at 50% of the initial rate

Neutropenia

  • Grade 4 neutropenia >1 wk or neutropenic fever/infection: Discontinue until the ANC is ≥1000 /mm3 and then permanently reduce dose to 12 mg/kg

Hepatic impairment

  • Mild-to-moderate: No dosage adjustments provided in the manufacturer’s labeling
  • Severe: No dosage adjustments provided in the manufacturer’s labeling

Renal impairment

  • Mild-to-moderate (CrCl 30-89 mL/min): No dosage adjustment required
  • Severe (CrCl 15-29 mL/min): Unknown

Safety and efficacy not established

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Adverse Effects

>10%

Lymphopenia, all grades (77%)

Nausea, all grades (73%)

Fatigue, all grades (69%)

Neutropenia, all grades (65%)

Musculoskeletal pain, all grades (64%)

Thrombocytopenia, all grades (63%)

Mucositis, all grades (53%)

Alopecia, all grades (52%)

Hyperglycemia, all grades (52%)

Neutropenia, grade 3-4 (48%)

Vomiting, all grades (45%)

Lymphopenia, grade 3-4 (44%)

Diarrhea, all grades (34%)

Increased aPTT, all grades (33%)

Decreased appetite, all grades (31%)

Abdominal pain, all grades (23%)

Neuropathy, all grades (22%)

Hypokalemia, all grades (21%)

Hypophosphatemia, all grades (21%)

Headache, all grades (20%)

Increased alkaline phosphatase, all grades (16%)

Hypomagnesemia, all grades (16%)

Infusion-related reactions, all grades (13%)

Anxiety, all grades (11%)

Dry eyes, all grades (11%)

1-10%

Fatigue, grade 3-4 (9%)

Musculoskeletal pain, grade 3-4 (8%)

Hypokalemia, grade 3-4 (8%)

Thrombocytopenia, grade 3-4 (6%)

Increases aPTT, grade 3-4 (5%)

Hypophosphatemia, grade 3-4 (5%)

Abdominal pain, grade 3-4 (3%)

Diarrhea, grade 3-4 (3%)

Mucositis, grade 3-4 (3%)

Infusion-related reactions, grade 3-4 (3%)

Nausea, grade 3-4 (2%)

Decreased appetite, grade 3-4 (2%)

Hyperglycemia, grade 3-4 (2%)

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Warnings

Contraindications

None

Cautions

Combination with doxorubicin may increase incidence of GI toxicity, including diarrhea, nausea, vomiting, and abdominal pain

A higher incidence of grade 3 and 4 lymphopenia and neutropenia and a higher incidence of thrombocytopenia reported in patients treated in combination with doxorubicin

Infusion-related reactions

  • May cause infusion-related reactions; premedicate before first dose (see Administration)
  • Infusion-related reactions may require permanent discontinuation or interruption of infusion (see Dosage Modifications)
  • Monitor during and following infusions for reactions
  • Administer in a setting with available resuscitation equipment
  • Infusion reactions grade 3 or higher reported

Embryo-fetal toxicity

  • Based on animal data and its mechanism of action, can cause fetal harm when administered to a pregnant woman
  • Advise females of reproductive potential to use effective contraception during treatment and for 3 months after the last dose
  • Advise women to inform their healthcare provider of known or suspected pregnancy
  • Also see Pregnancy
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Pregnancy

Pregnancy

Based on animal data and its mechanism of action, can cause fetal harm

There are no available data on use in pregnant women

No animal studies using olaratumab have been conducted to evaluate its effect on female reproduction and embryo-fetal development

Contraception

  • Advise females of reproductive potential to use effective contraception during treatment and for 3 months after the last dose

Infertility

  • Males: Based on animal models, may impair male fertility

Lactation

Unknown if distributed in human breast milk

Advise women not to breast feed during treatment and for 3 months following the last dose

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

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Pharmacology

Mechanism of Action

Recombinant human IgG1 monoclonal blocking antibody that binds specifically to human platelet-derived growth factor receptor-alpha (PDGFR-alpha)

PDGFR-alpha is a tyrosine kinase receptor expressed on cells of mesenchymal origin; signaling through this receptor plays a role in cell growth, chemotaxis, and mesenchymal stem cell differentiation

PDGFR-alpha has also been detected on some tumor and stromal cells, including sarcomas, where signaling can contribute to cancer cell proliferation, metastasis, and maintenance of the tumor microenvironment

The interaction between olaratumab and PDGFR-alpha prevents binding of the receptor by the PDGF-AA and -BB ligands as well as PDGF-AA, -BB, and -CC-induced receptor activation and downstream PDGFR-alpha pathway signaling

Distribution

Vd: 7.7 L (16%)

Elimination

Half-life: ~11 days (range 6-24 days)

Clearance: 0.56 L/day (33%)

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Administration

IV Compatibilities

0.9% NaCl

IV Incompatibilities

Dextrose-containing solutions

Electrolyte-containing solutions (eg, Ringers Lactate)

IV Preparation

Solution in unopened vial should appear clear to slightly opalescent, colorless to slightly yellow

Inspect vial contents for particulate matter and discoloration prior to dilution; discard if particulate matter or discolorations is identified

Withdraw calculated dose and further dilute with 0.9% NaCl to a final volume of 250 mL for IV infusion; do not use dextrose-containing or other solutions

Gently invert but do not shake

Do not freeze the diluted solution

Store the diluted solution for up to 24 hr under refrigeration at 2-8°C (36-46°F) and for up to an additional 4 hr at room temperature (<25°C [77°F])

Storage times include the duration of infusion; if refrigerated, allow the diluted solution to come to room temperature before administration

Discard vial with any unused portion

IV Administration

Premedication

  • Premedicate with diphenhydramine (25-50 mg IV) and dexamethasone (10-20 mg IV) before olaratumab dose on Day 1 of cycle 1

Intravenous infusion

  • Do not administer as IV push or bolus
  • Do not infuse with electrolytes or other medications through the same IV line
  • Visually inspect the diluted solution for particulate matter and discoloration prior to administration; if particulate matter or discolorations is identified, discard the solution
  • Administer diluted solution as an IV infusion over 1 hr
  • Flush the line with 0.9% NaCl at end of infusion

Storage

Unopened vial

  • Preservative-free solution
  • Refrigerate at 2-8°C (36-46°F) until time of use
  • Keep the vial in the outer carton to protect from light
  • Do not freeze
  • Do not shake vial

Diluted solution

  • Refrigerate for up to 24 hr at 2-8°C (36-46°F) and for up to an additional 4 hr at room temperature (<25°C [77°F])
  • Do not freeze
  • Do not shake diluted solution
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Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.