Omacetaxine (Monograph)

Brand name: Synribo
Drug class: Antineoplastic Agents
Chemical name: 4-Methyl (2R)-2-hydroxy-2-(4-hydroxy-4-methylpentyl)butanedioate cephalotaxine (ester)
Molecular formula: C₂₉H₃₉NO₉
CAS number: 26833-87-4

Introduction

Antineoplastic agent; protein synthesis inhibitor.^{1 5 8 16 17}

Uses for Omacetaxine

Chronic Myelogenous Leukemia (CML)

Treatment of CML in adults in the chronic or accelerated phase of the disease after failure (secondary to resistance and/or intolerance) of prior therapy with ≥2 tyrosine kinase inhibitors (designated an orphan drug by FDA for treatment of CML⁴ ).^{1 2 3 21}

Omacetaxine Dosage and Administration

General

• Monitor CBCs weekly during induction and initial maintenance cycles, then every 2 weeks thereafter or as clinically indicated.¹

• Healthcare professional should prepare and administer the drug.¹

• Consult specialized references for procedures for proper handling and disposal of antineoplastics.¹

Administration

Sub-Q Administration

Administer by sub-Q injection.¹

Handle cautiously; use protective equipment (e.g., gloves, protective clothing).¹ If contact with the skin occurs, wash affected area immediately and thoroughly with soap and water.¹

Reconstitution

Reconstitute vial containing 3.5 mg of omacetaxine mepesuccinate powder with 1 mL of 0.9% sodium chloride injection to provide a solution containing 3.5 mg/mL.¹ Gently swirl vial until a clear solution is obtained; complete dissolution usually occurs in <1 minute.¹

Dosage

Available as omacetaxine mepesuccinate; dosage expressed in terms of the salt.¹

Adults

CML

Chronic or Accelerated Phase

Sub-Q

Induction therapy: 1.25 mg/m² twice daily for 14 consecutive days of a 28-day treatment cycle.¹ Repeat cycles until a hematologic response is achieved.¹

Maintenance therapy: 1.25 mg/m² twice daily for 7 consecutive days of a 28-day treatment cycle.¹

Optimal duration of therapy not established; may continue therapy for as long as the patient derives clinical benefit.¹ In clinical trials, median duration of therapy was 7.4 months (median of 6 treatment cycles) in patients with chronic phase CML and 1.9 months (median of 2 treatment cycles) in those with accelerated phase CML.¹

Dosage Modification for Toxicity

Hematologic Toxicity

If grade 4 neutropenia (ANC <500/mm³) or grade 3 thrombocytopenia (platelet count <50,000/mm³) occurs, delay the next treatment cycle until ANC is ≥1000/mm³ and platelet count is ≥50,000/mm³.^{1 5} In addition, reduce the number of consecutive dosing days by 2 in the next treatment cycle (e.g., to 12 days in patients receiving an induction dosage or to 5 days in those receiving a maintenance dosage).^{1 5}

Nonhematologic Toxicity

If clinically important nonhematologic toxicities (e.g., diarrhea, hyperglycemia) occur, manage symptomatically; in addition, interrupt and/or delay omacetaxine mepesuccinate therapy until such toxicities have resolved.^{1 5}

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.¹

Renal Impairment

Some clinicians suggest dosage adjustment may not be necessary, since only limited amounts of the drug are excreted unchanged in urine.¹⁸ Manufacturer makes no specific dosage recommendations at this time.¹

Geriatric Patients

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

Related/similar drugs

cyclophosphamide, hydroxyurea, Gleevec, Sprycel, Tasigna, Bosulif

Cautions for Omacetaxine

Contraindications

• None.¹

Warnings/Precautions

Warnings

Myelosuppression

Major dose-limiting toxicity.^{1 2 3 8 20 21} Grade 3 or 4 thrombocytopenia (85–88% of patients), neutropenia (71–81%), and anemia (62–80%) reported frequently; fatal in 3% of patients in clinical trials.¹

Myelosuppression generally reversible and managed with treatment delays and/or reduction in number of dosing days.^{1 2 20}

Monitor CBCs routinely (i.e., every week during induction and initial maintenance cycles, then every 2 weeks or as clinically indicated thereafter).^{1 5} Dosage adjustments may be required if severe hematologic toxicities occur.^{1 5} (See Hematologic Toxicity under Dosage and Administration.)

Monitor neutropenic patients frequently for symptoms of infection and fever.¹

Bleeding

Risk of bleeding, including potentially fatal CNS or GI hemorrhage; usually associated with severe thrombocytopenia.^{1 2 7 20} (See Myelosuppression under Cautions.)

Monitor platelet counts routinely as part of the recommended CBC monitoring schedule.^{1 5} (See Interactions.)

Hyperglycemia

Risk of glucose intolerance and hyperglycemia.^{1 8} Grade 3 or 4 hyperglycemia reported in clinical trials; at least 1 case of hyperosmolar nonketotic hyperglycemia was observed.^{1 7}

Monitor blood glucose concentrations frequently, particularly in patients with preexisting diabetes mellitus or risk factors for diabetes mellitus.^{1 5} Avoid use in patients with poorly controlled diabetes mellitus until good glycemic control is established.^{1 5}

Fetal /Neonatal Morbidity and Mortality

May cause fetal harm; fetotoxicity and embryolethality demonstrated in animals.¹

If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.¹

Specific Populations

Pregnancy

Category D.¹ (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether omacetaxine mepesuccinate is distributed into milk; discontinue nursing or the drug.¹

Pediatric Use

Safety and efficacy not established in pediatric patients.^{1 7} Has been used in a limited number of acutely ill children with refractory or recurrent leukemia; however, long-term effects on growth and development not known.⁷

Geriatric Use

In chronic phase CML, rate of major cytogenetic response with omacetaxine mepesuccinate following failure of ≥2 tyrosine kinase inhibitors was lower in geriatric patients compared with younger adults.¹

In accelerated phase CML, rate of hematologic response with omacetaxine mepesuccinate following failure of ≥2 tyrosine kinase inhibitors was higher in geriatric patients compared with younger adults.¹

Risk of toxicity, particularly hematologic toxicity, is increased in geriatric patients ≥65 years of age.¹

Hepatic Impairment

Not formally evaluated in patients with hepatic impairment.¹ (See Special Populations under Pharmacokinetics.)

Renal Impairment

Not formally evaluated in patients with renal impairment.¹ (See Special Populations under Pharmacokinetics.)

Common Adverse Effects

Thrombocytopenia,^{1 2 3 18 21} anemia,^{1 2 3 18 21} neutropenia,^{1 2 3 18 21} leukopenia,^{1 2 3} bone marrow failure,¹ febrile neutropenia,^{1 3 21} lymphopenia,^{1 2} diarrhea,^{1 2 3 18 21} nausea,^{1 2 3 18 21} vomiting,^{1 3 18} constipation,^{1 2 18} abdominal pain,^{1 2 18} fatigue,^{1 2 3 18 21} asthenia,^{1 2 3 21} anorexia,^{1 18} extremity pain,^{1 2 3} back pain,^{1 2} headache,^{1 2 3} insomnia,^{1 2} arthralgia,^{1 2} peripheral edema,^{1 2 3} injection site reaction,^{1 2 3 18} pyrexia,^{1 2 3 21} infection,^{1 2 21} chills,¹ cough,^{1 2} dyspnea,^{1 18} epistaxis,^{1 2 3} alopecia,^{1 2} rash,^{1 2} increased serum concentrations of glucose,¹ uric acid,¹ and creatinine.¹

Drug Interactions

No formal drug interaction studies to date.¹

Not a substrate of CYP isoenzymes in vitro; does not inhibit major CYP isoenzymes in vitro at clinically relevant concentrations.¹

Substrate of P-glycoprotein (P-gp) in vitro, but does not appear to inhibit P-gp at clinically relevant concentrations.¹

Drugs Affecting Hemostasis

Potential risk of bleeding.¹

Specific Drugs

Omacetaxine Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations achieved approximately 30 minutes after sub-Q administration.^{1 18}

Distribution

Extent

Not known whether omacetaxine mepesuccinate is distributed into milk.¹

Plasma Protein Binding

≤50%.¹

Elimination

Metabolism

Primarily hydrolyzed by plasma esterases to an inactive 4'-desmethyl metabolite; undergoes minimal hepatic microsomal oxidation and/or esterase-mediated metabolism in vitro.^{1 18}

Elimination Route

Major route of elimination not known; following sub-Q administration, approximately 12–15% of a dose is excreted unchanged in urine.^{1 18}

Half-life

Approximately 6–7 hours following sub-Q administration.^{1 18}

Special Populations

Effect of hepatic impairment on pharmacokinetic disposition not formally evaluated;¹ results of population pharmacokinetic analysis indicate that mild hepatic impairment (total bilirubin concentration ≤1.5 times the ULN and AST >ULN) does not appear to affect pharmacokinetics.²⁰

Effect of renal impairment on pharmacokinetic disposition not formally evaluated;¹ results of population pharmacokinetic analysis indicate that Cl_cr of 50–80 or <50 mL/minute does not appear to affect pharmacokinetics.²⁰

Stability

Storage

Parenteral

Powder for Injection

20–25°C (may be exposed to 15–30°C); protect from light and retain in original carton until use.¹

Reconstituted solution: May store at room temperature for ≤12 hours or at 2–8°C for ≤24 hours; protect from light.¹

Actions

• Semisynthetic form of a natural cephalotaxine alkaloid found in the leaves of various species of Cephalotaxus evergreen trees native to Asia.^{1 8 9 10 16 20}

• Although exact mechanism of action not fully elucidated, the drug inhibits protein synthesis at the point of early protein translation by interfering with peptide elongation.^{1 8 9 11 16} Thought to induce apoptosis by causing rapid loss of short-lived proteins (e.g., myeloid cell leukemia-1 [Mcl-1]) that are upregulated in leukemic cells and act to regulate proliferation and survival of those cells.^{1 3 8 9 11 16}

• Shown in vitro to reduce levels of Mcl-1 as well as Bcr-Abl tyrosine kinase (an abnormal protein associated with development of CML).^{1 5 8 11 17}

• Unlike tyrosine kinase inhibitors, omacetaxine mepesuccinate does not depend on direct Bcr-Abl binding for its antileukemic activity.^{1 2 8 9 17 20}

• Has shown activity against CML in the presence of the Bcr-Abl T315I mutation (which confers resistance to the tyrosine kinase inhibitors bosutinib, dasatinib, imatinib, and nilotinib^{2 5 6 8 10 11 13} ) in vivo in murine models and in early clinical studies.^{1 2 8 10 13 17}

Advice to Patients

• Necessity of routine monitoring of blood cell counts.¹ Importance of informing a clinician immediately if signs or symptoms of infection (e.g., fever), anemia (e.g., shortness of breath, substantial fatigue), or bleeding (e.g., unusual bleeding or bruising, confusion, slurred speech, altered vision) occur.¹

• Importance of advising patients with diabetes mellitus about the increased risk of hyperglycemia and the need for careful blood glucose monitoring during therapy.¹

• Risk of adverse GI effects (e.g., nausea, diarrhea, abdominal pain, constipation, vomiting); importance of notifying a clinician if such manifestations persist.¹

• Importance of advising patients to avoid driving or operating dangerous machinery if fatigue occurs.¹

• Risk of rash or hair loss; importance of immediately reporting severe or worsening rash or itching.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 women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹ Importance of advising women of childbearing age about the potential for fetotoxic effects, and to avoid pregnancy and nursing while receiving the drug.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.

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