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Dinutuximab

Class: Antineoplastic Agents
Chemical Name: Immunoglobulin G1, anti-(ganglioside GD2) (human-Mus musculus monoclonal ch14.18 heavy chain), disulfide with human-Mus musculus monoclonal ch14.18 light chain, dimer
Molecular Formula: C6514H10154N1752O2029S50
CAS Number: 1363687-32-4
Brands: Unituxin

Warning(s)

  • Infusion-related Effects
  • Serious and potentially life-threatening infusion-related reactions reported.1 2

  • Administer IV fluids and premedicate with an antihistamine, analgesic, and antipyretic prior to each infusion of the drug.1 Reduction of infusion rate, temporary interruption of therapy, or drug discontinuance may be necessary.1 (See Infusion-related Effects under Dosage and Administration and also under Cautions.)

  • Peripheral Neuropathy
  • Causes severe motor neuropathy and peripheral sensory neuropathy; severe neuropathic pain occurs in most patients.1 2 (See Pain and also Peripheral Neuropathy under Cautions.)

  • Discontinuance of therapy may be necessary.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Introduction

Antineoplastic agent; a chimeric human-murine anti-glycolipid disialoganglioside (anti-GD2) monoclonal antibody.1 2 6 7 11

Uses for Dinutuximab

Neuroblastoma

Used in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), and isotretinoin for the treatment of high-risk neuroblastoma in pediatric patients who previously achieved at least a partial response to first-line antineoplastic therapy and multimodality therapy (designated an orphan drug by FDA for this use).1 2 3

Efficacy in combination with sargramostim, aldesleukin, and isotretinoin determined based on investigator-assessed event-free survival.1 2

Dinutuximab Dosage and Administration

General

Restricted Distribution Program

  • Available only through a specialty pharmacy.9 Consult the Unituxin website for specific information (https://www.unituxin.com/pharmacist-information/ordering-distribution).9

Adequacy of Organ Function

  • Confirm adequacy of pulmonary, hematologic, hepatic, and renal function as defined below before the first dinutuximab infusion in each cycle.1

  • Pulmonary: No dyspnea at rest and peripheral arterial oxygen saturation ≥94% on room air.1

  • Hematologic: Platelet count ≥20,000/mm3 and total absolute phagocyte count [APC] ≥1000/mm3.13

  • Hepatic: Total bilirubin concentration <1.5 times the ULN and ALT concentration <5 times the ULN.1

  • Renal: GFR ≥70 mL/minute per 1.73 m2.1

Premedication for Infusion-related Reactions

  • Administer an antihistamine (e.g., diphenhydramine hydrochloride 0.5–1 mg/kg [maximum 50 mg] IV over 10–15 minutes) beginning 20 minutes before each dinutuximab infusion and every 4–6 hours as tolerated during infusion.1 5

  • Administer acetaminophen 10–15 mg/kg (maximum 650 mg) orally 20 minutes before each dinutuximab infusion and then every 4–6 hours as needed for fever or pain.1 10

  • If persistent fever or pain occurs, administer ibuprofen 5–10 mg/kg every 6 hours as needed.1

Pain Management

  • Premedicate with morphine sulfate 50 mcg/kg IV immediately before each dinutuximab infusion,1 5 followed by continuous infusion of 20–50 mcg/kg per hour during and for 2 hours following completion of the dinutuximab infusion.1 Clinically stable patients may receive additional morphine sulfate doses of 25–50 mcg/kg IV every 2 hours as needed for pain followed by an increase in the morphine sulfate infusion rate.1

  • Consider fentanyl or hydromorphone if morphine is not tolerated.1

  • If pain persists despite use of opiate analgesics, consider gabapentin or lidocaine in conjunction with IV morphine.1

Hydration

  • Administer 0.9% sodium chloride injection 10 mL/kg IV over 1 hour immediately before each dinutuximab infusion.1

Administration

IV Administration

For solution compatibility information, see Compatibility under Stability.

Administer by IV infusion over 10–20 hours.1 Do not administer by rapid IV injection (e.g., IV push or bolus).1

Dinutuximab injection concentrate must be diluted prior to administration.1 Initiate IV infusion within 4 hours of dilution.1 (See Storage under Stability.)

Dilution

Dilute appropriate dose in an infusion bag containing 100 mL of 0.9% sodium chloride injection.1 Mix by gentle inversion; do not shake.1 Discard any partially used vials.1

Rate of Administration

Infuse at initial rate of 0.875 mg/m2 per hour for 30 minutes.1

May gradually increase infusion rate, as tolerated, to maximum of 1.75 mg/m2 per hour.1

Dosage

Pediatric Patients

Neuroblastoma
IV

Cycles 1, 3 and 5: 17.5 mg/m2 daily on days 4–7 of a 24-day cycle; GM-CSF and isotretinoin also are administered during these cycles.1

Cycles 2 and 4: 17.5 mg/m2 daily on days 8–11 of a 32-day cycle; IL-2 and isotretinoin also are administered during these cycles.1

Cycle 6: Isotretinoin only.1

Dinutuximab was continued for a maximum of 5 cycles in the principal efficacy study.1

Consult respective manufacturers' labelings or published protocols for information on dosage and method and sequence of administration of other antineoplastic agents used in combination with dinutuximab.

Dosage Modification for Toxicity

Some adverse effects require temporary interruption of therapy or permanent discontinuance.1 (See Cautions.)

Toxicities Requiring Discontinuance of Therapy1

Grade 3 or 4 anaphylaxis

Grade 3 or 4 serum sickness

Grade 3 pain unresponsive to optimal pain management

Grade 4 peripheral sensory neuropathy

Grade 3 peripheral sensory neuropathy that interferes with daily activities for >2 weeks

Grade 2 peripheral motor neuropathy

Subtotal or total loss of vision

Grade 4 hyponatremia despite appropriate fluid management

Hemolytic uremic syndrome

Infusion-related Effects
IV

If mild or moderate infusion-related reactions (e.g., transient rash, fever, rigors, localized urticaria) occur, initiate appropriate symptomatic therapy and reduce the infusion rate by 50%; if the reaction responds promptly to symptomatic therapy, infusion rate may be gradually increased up to a maximum rate of 1.75 mg/m2 per hour upon resolution of the reaction.1

If prolonged or severe infusion-related reactions (e.g., mild bronchospasm without other symptoms, angioedema that does not affect the airway) occur, immediately interrupt the infusion; if the reaction resolves rapidly, resume the infusion but reduce infusion rate by 50%.1

If a second episode of prolonged or severe infusion-related reactions occur, interrupt therapy until the next day.1 If the reaction has resolved and continued therapy is warranted, premedicate with hydrocortisone 1 mg/kg (maximum 50 mg) IV and administer dinutuximab at an infusion rate of 0.875 mg/m2 per hour in an intensive care unit (ICU).1

If a third episode of prolonged or severe infusion-related reaction or if a life-threatening infusion-related reaction occurs, permanently discontinue dinutuximab therapy.1

Capillary Leak Syndrome
IV

If moderate or severe capillary leak syndrome occurs, immediately interrupt therapy until resolution; resume therapy but reduce infusion rate by 50%.1

If life-threatening capillary leak syndrome occurs, discontinue the current cycle of dinutuximab.1 Once resolution occurs, reduce infusion rate by 50% for subsequent cycles.1 If life-threatening capillary leak syndrome recurs, permanently discontinue dinutuximab therapy.1

Hypotension
IV

If symptomatic hypotension, SBP less than the lower limit of normal for age, or reduction in SBP by >15% compared with baseline occurs, interrupt therapy until resolution; resume therapy but reduce infusion rate by 50%.1 If BP remains stable for ≥2 hours, may increase infusion rate, as tolerated, up to a maximum rate of 1.75 mg/m2 per hour.1

Infectious Complications
IV

If severe systemic infection or sepsis occurs, interrupt therapy until resolution.1

Ocular Effects
IV

In patients with dilated pupils with sluggish light reflex or other visual disturbances that do not cause vision loss, interrupt therapy until resolution.1 If continued therapy is warranted, reduce dinutuximab dosage by 50%.1

If a second episode of ocular toxicity occurs or if ocular toxicity is accompanied by visual impairment, permanently discontinue dinutuximab therapy.1

Pain
IV

If severe pain occurs, reduce infusion rate to 0.875 mg/m2 per hour.1 If pain persists despite optimal medical management and reduction of the infusion rate, discontinue dinutuximab therapy.1

Special Populations

Hepatic Impairment

Not studied; no specific dosage recommendations at this time.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

Not studied; no specific dosage recommendations at this time.1 (See Renal Impairment under Cautions.)

Geriatric Patients

No specific dosage recommendations.1 (See Geriatric Use under Cautions.)

Cautions for Dinutuximab

Contraindications

  • History of anaphylaxis to dinutuximab.1

Warnings/Precautions

Warnings

Infusion-related Effects

Serious and potentially life-threatening infusion-related reactions (e.g., facial and upper airway edema, dyspnea, bronchospasm, stridor, urticaria, hypotension requiring urgent intervention, anaphylaxis) reported in 26% of patients;1 2 generally occur during or within 24 hours following completion of the dinutuximab infusion.1 Fatal cardiac arrest occurred in 1 of 783 patients within 24 hours of dinutuximab administration.1

Closely monitor patients for signs of infusion reactions during and for at least 4 hours following dinutuximab infusion in a setting where resuscitation equipment and agents necessary to treat infusion reactions are readily available.1

Administer IV fluids and premedicate with an antihistamine, analgesic, and antipyretic prior to each dinutuximab infusion.1 (See General under Dosage and Administration.)

Initiate appropriate treatment and supportive care for severe, prolonged, or life-threatening infusion-related reactions.1 Reduction of infusion rate, temporary interruption of therapy, or drug discontinuance may be necessary.1 (See Infusion-related Effects under Dosage and Administration.)

Peripheral Neuropathy

Peripheral neuropathy reported;1 2 median duration of peripheral sensory neuropathy is 9 days (range: 3–163 days).1 (See Actions.)

Lower extremity weakness resulting in an inability to ambulate persisted for approximately 6 weeks in one patient receiving a similar anti-GD2 monoclonal antibody for the treatment of metastatic melanoma.1 In another patient, neurogenic bladder lasted approximately 3 weeks and lower extremity weakness resulting in an inability to ambulate without assistance lasted for approximately 16 weeks; complete resolution of peripheral motor neuropathy not documented in this patient.1

Discontinuance of therapy may be necessary.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Pain

Pain despite premedication with analgesics, including IV morphine, reported commonly.1 2 Grade 3 or 4 pain usually develops during dinutuximab administration in cycle 1 and often subsides during subsequent cycles.2 5 Most commonly described as abdominal pain, generalized pain, extremity pain, back pain, neuralgia, musculoskeletal chest pain, and arthralgia.1 2

Premedicate with analgesics, including an IV opiate analgesic; initiate prior to each dinutuximab infusion and continue for 2 hours following completion of infusion.1 (See Pain Management under Dosage and Administration.)

Reduction of infusion rate or discontinuance of therapy may be necessary.1 (See Pain under Dosage and Administration.)

Other Warnings and Precautions

Capillary Leak Syndrome

Capillary leak syndrome reported.1 2 5 10 Generally occurs more frequently during cycles containing IL-2.1 2 5 10

Initiate supportive treatment (i.e., respiratory support, albumin replacement therapy)5 if capillary leak syndrome occurs.1 Temporary interruption followed by reduction of infusion rate or discontinuance of therapy may be necessary.1 (See Capillary Leak Syndrome under Dosage and Administration.)

Hypotension

Hypotension reported.1 2

Closely monitor BP during therapy.1 Administer adequate IV fluids immediately before each dinutuximab infusion.1 (See Hydration under Dosage and Administration.)

Initiate supportive treatment if symptomatic hypotension, SBP less than the LLN for age, or reduction in SBP by >15% compared with baseline occurs.1 Temporary interruption of therapy followed by reduction of infusion rate or discontinuance of therapy may be necessary.1 (See Hypotension under Dosage and Administration.)

Infectious Complications

Serious infections (e.g., bacteremia, sepsis) reported.1

Monitor for signs and symptoms of systemic infection.1 If a systemic infection develops, interrupt dinutuximab therapy until the infection resolves.1

Ocular Effects

Adverse ocular effects (e.g., blurred vision, photophobia, mydriasis, fixed or unequal pupils, optic nerve disorder, eyelid ptosis, papilledema) reported.1 Generally resolves over time;5 in patients with documented resolution, median duration of ocular disorder was 4 days (range: 0–221 days).1

Temporary interruption of therapy followed by dosage reduction or drug discontinuance may be required.1 (See Ocular Effects under Dosage and Administration.)

Hematologic Effects

Severe thrombocytopenia, anemia, neutropenia, and febrile neutropenia reported.1

Closely monitor peripheral blood cell counts during therapy.1

Electrolyte Abnormalities

Electrolyte abnormalities (i.e., hyponatremia, hypokalemia, hypocalcemia) reported.1 Severe hyponatremia caused by SIADH occurred in 2 of 12 adults receiving a similar anti-GD2 monoclonal antibody for the treatment of metastatic melanoma.1

Monitor serum electrolytes daily during therapy.1 Discontinuance of therapy may be necessary.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Atypical Hemolytic Uremic Syndrome

Hemolytic uremic syndrome occurring in the absence of documented infection and resulting in renal insufficiency, electrolyte abnormalities, anemia, and hypertension reported in 2 patients, approximately 4 days following cycle 1, in an expanded access study.1 10 Hemolytic uremic syndrome recurred following reinitiation of the drug in one patient.1

If hemolytic uremic syndrome occurs, discontinue dinutuximab therapy and initiate appropriate treatment.1

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.1 Fetal exposure to dinutuximab may be greater during the third trimester of pregnancy.1

Avoid pregnancy during therapy.1 Women of childbearing potential should use an effective contraceptive method while receiving the drug and for ≥2 months after the drug is discontinued.1 If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard.1

Immunogenicity

Antibodies to dinutuximab, including neutralizing antibodies to the drug, reported.1

Specific Populations

Pregnancy

May cause fetal harm.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether dinutuximab is distributed into milk; however, human IgG is distributed into milk.1 Discontinue nursing during therapy and for 6 months after therapy.1 5

Effects of the drug on nursing infants or on human milk production are unknown.1

Pediatric Use

Safety and efficacy not established in infants <11 months of age.1

Geriatric Use

Safety and efficacy not established.1

Hepatic Impairment

Not studied in patients with hepatic impairment.1

Renal Impairment

Not studied in patients with renal impairment.1

Common Adverse Effects

Pain,1 2 pyrexia,1 2 thrombocytopenia,1 lymphopenia,1 infusion-related reactions,1 2 hypotension,1 hyponatremia,1 elevated aminotransferase (i.e., AST, ALT),1 anemia,1 vomiting,1 diarrhea,1 hypokalemia,1 2 capillary leak syndrome,1 neutropenia,1 urticaria,1 hypoalbuminemia,1 hypocalcemia,1 infection.2

Interactions for Dinutuximab

No formal drug interaction studies to date.1

Immunosuppressive Therapy

Concomitant immunosuppressive therapy may interfere with the mechanism of action of dinutuximab.1 Principal efficacy study excluded patients requiring such concomitant therapy.1

Specific Drugs

Drug

Interaction

Comments

Corticosteroids

May interfere with mechanism of action of dinutuximab1 5

Avoid concomitant use5 (unless required for management of dinutuximab-related toxicity1 5 10 )

Immune globulin IV

May interfere with mechanism of action of dinutuximab1

Do not administer within 2 weeks before or 1 week after each course of dinutuximab5 10

Dinutuximab Pharmacokinetics

Distribution

Extent

Not known whether dinutuximab is distributed into milk.1

Elimination

Half-life

10 days.1

Stability

Storage

Parenteral

Injection Concentrate

2–8°C in original carton to protect from light.1 Do not freeze or shake.1

Diluted solution: 2–8°C.1 Discard 24 hours after dilution.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility1

Compatible

Sodium chloride 0.9%

Actions

  • Binds selectively to GD2,5 a glycolipid minimally expressed on surface of normal cells of neuroectodermal origin, including central neurons, peripheral nerve fibers, and melanocytes.1 2 5 8 11 GD2 overexpression identified in several malignancies (e.g., neuroblastoma, most melanomas).1 2 5 6 8 11

  • Cell lysis occurs through complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC).1 5 6 7

  • In the presence of human effector cells, including peripheral blood mononuclear cells (PBMCs) and granulocytes, causes dose-dependent cytotoxicity of neuroblastoma cells; addition of GM-CSF and IL-2 enhances cell lysis.5 7 11

  • Peripheral neuropathy may result from binding of the drug to antigen GD2 on the surface of peripheral nerve fibers and/or myelin.1 5 7 8 Decreased mechanical pain thresholds demonstrated in animal studies following administration of anti-GD2 monoclonal antibodies, including dinutuximab; lower thresholds persisted for up to 48 hours after completion of drug administration.7

Advice to Patients

  • Risk of serious infusion-related reactions and anaphylaxis.1 Importance of informing clinician immediately if signs and symptoms of such reactions (e.g., facial swelling, urticaria, breathing difficulty, lightheadedness or dizziness) occur during or within 24 hours of dinutuximab infusion.1

  • Risk of severe pain and peripheral sensory and motor neuropathy.1 Importance of promptly informing clinician if severe or worsening pain or signs and symptoms of neuropathy (e.g., numbness, tingling, burning, weakness) occur.1

  • Risk of capillary leak syndrome.1 Importance of informing clinician immediately if signs and symptoms of capillary leak syndrome (e.g., hypotension, generalized edema, dyspnea) occur.1 5

  • Risk of hypotension during dinutuximab infusion.1 Importance of informing clinician immediately if signs and symptoms of hypotension occur.1

  • Risk of infection.1 Importance of informing clinician immediately if signs and symptoms of infection occur.1

  • Risk of adverse ocular effects.1 Importance of promptly informing clinician if signs and symptoms of ocular toxicity (e.g., blurred vision, photophobia, ptosis, diplopia, unequal pupil size) occur.1

  • Risk of myelosuppression.1 Importance of promptly informing clinician if signs and symptoms of anemia, thrombocytopenia, or infection occur.1

  • Risk of electrolyte abnormalities (i.e., hypokalemia, hyponatremia, hypocalcemia).1 Importance of informing clinician if signs and symptoms of electrolyte abnormalities (e.g., seizures, palpitations, muscle cramping) occur.1

  • Risk of atypical hemolytic uremic syndrome.1 Importance of informing clinician if signs and symptoms of hemolytic uremic syndrome (e.g., fatigue, dizziness, fainting, pallor, edema, decreased urination, hematuria) occur.1

  • Risk of fetal harm.1 Necessity of advising women of childbearing potential to use an effective method of contraception while receiving the drug and for ≥2 months after discontinuance of therapy.1 If pregnancy occurs, advise pregnant women of potential risk to the fetus.1

  • Importance of not breast-feeding during therapy.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

  • Importance of informing patients of other important precautionary information.1 (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 dinutuximab is restricted.9 (See Restricted Distribution Program under Dosage and Administration.)

Dinutuximab

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection concentrate, for IV infusion

3.5 mg/mL

Unituxin

United Therapeutics

AHFS DI Essentials. © Copyright, 2016, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

Date published: April 04, 2016
Last reviewed: April 04, 2016
Date modified: April 08, 2016

References

1. United Therapeutics. Unituxin (dinutuximab) injection for intravenous infusion prescribing information. Silver Spring, MD; 2015 Mar.

2. Yu AL, Gilman AL, Ozkaynak MF et al. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med. 2010; 363:1324-34. [PubMed 20879881]

3. US Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2015 Oct 27.

4. Simister NE. Placental transport of immunoglobulin G. Vaccine. 2003; 21:3365-9. [PubMed 12850341]

5. United Therapeutics Europe. Unituxin (dinutuximab) injection for intravenous infusion. Annex I: Summary of product characteristics. Surrey, United Kingdom. (undated)

6. Dhillon S. Dinutuximab: first global approval. Drugs. 2015; 75:923-7. [PubMed 25940913]

7. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 125516Orig1s000: Pharmacology Review(s). From FDA website.

8. Mackall CL, Merchant MS, Fry TJ. Immune-based therapies for childhood cancer. Nat Rev Clin Oncol. 2014; 11:693-703. [PubMed 25348789]

9. United Therapeutics. Ordering and distribution information. 2015 Oct. From United Therapeutics for US Healthcare Professionals website.

10. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 125516Orig1s000: Medical Review(s). From FDA website.

11. Gilman AL, Ozkaynak MF, Matthay KK et al. Phase I study of ch14.18 with granulocyte-macrophage colony-stimulating factor and interleukin-2 in children with neuroblastoma after autologous bone marrow transplantation or stem-cell rescue: a report from the Children's Oncology Group. J Clin Oncol. 2009; 27:85-91. [PubMed 19047298]

12. Pitcher-Wilmott RW, Hindocha P, Wood CB. The placental transfer of IgG subclasses in human pregnancy. Clin Exp Immunol. 1980; 41:303-8. [PubMed 7438556]

13. United Therapeutics. Silver Spring, MD: Personal communication.

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