Synribo

Generic Name: Omacetaxine Mepesuccinate
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 Synribo

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

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Synribo 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.)

Cautions for Synribo

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

Interactions for Synribo

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

Drug

Interaction

Comments

Aspirin

Possible bleeding1

Avoid concomitant use if platelet count <50,000/mm31

Anticoagulants

Possible bleeding1

Avoid concomitant use if platelet count <50,000/mm31

NSAIAs

Possible bleeding1

Avoid concomitant use if platelet count <50,000/mm31

Synribo 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 Clcr 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 nilotinib2 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.

Omacetaxine Mepesuccinate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For Injection, for subcutaneous use

3.5 mg

Synribo

Teva

AHFS DI Essentials. © Copyright, 2004-2013, Selected Revisions September 23, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Teva Pharmaceuticals. Synribo (omacetaxine mepesuccinate) for injection prescribing information. North Wales, PA; 2012 Oct.

2. Cortes J, Lipton JH, Rea D et al. Phase 2 study of subcutaneous omacetaxine mepesuccinate after TKI failure in patients with chronic-phase CML with T315I mutation. Blood. 2012; 120:2573-80. [PubMed 22896000]

3. Cortes J, Digumarti R, Parikh PM et al. Phase 2 study of subcutaneous omacetaxine mepesuccinate for chronic-phase chronic myeloid leukemia patients resistant to or intolerant of tyrosine kinase inhibitors. Am J Hematol. 2013; :. [PubMed 23468307]

4. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414). Rockville, MD; [April 4, 2013]. From FDA web site .

5. National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology: chronic myelogenous leukemia. Version 4.2013. Accessed from the NCCN website.

6. Cortes J, Goldman JM, Hughes T. Current issues in chronic myeloid leukemia: monitoring, resistance, and functional cure. J Natl Compr Canc Netw. 2012; 10 Suppl 3:S1-S13. [PubMed 23055247]

7. Food and Drug Administration. Center for Drug Evaluation and Research: Application number 203585Orig1s000Orig1s000: Medical Review. From FDA website.

8. Kim TD, Frick M, le Coutre P. Omacetaxine mepesuccinate for the treatment of leukemia. Expert Opin Pharmacother. 2011; 12:2381-92. [PubMed 21916787]

9. Quintás-Cardama A, Cortes J. Homoharringtonine for the treatment of chronic myelogenous leukemia. Expert Opin Pharmacother. 2008; 9:1029-37. [PubMed 18377344]

10. Quintás-Cardama A, Kantarjian H, Cortes J. Homoharringtonine, omacetaxine mepesuccinate, and chronic myeloid leukemia circa 2009. Cancer. 2009; 115:5382-93. [PubMed 19739234]

11. Wetzler M, Segal D. Omacetaxine as an anticancer therapeutic: what is old is new again. Curr Pharm Des. 2011; 17:59-64. [PubMed 21294709]

12. Coude MM, Luycx O, Cariou ME et al. Undetectable molecular residual disease after omacetaxine and nilotinib combination therapy in an imatinib-resistant chronic myeloid leukaemia patient harbouring the BCR-ABL1 T315I gatekeeper mutation. Br J Haematol. 2012; 157:407-10. [PubMed 22225474]

13. Nicolini FE, Chomel JC, Roy L et al. The durable clearance of the T315I BCR-ABL mutated clone in chronic phase chronic myelogenous leukemia patients on omacetaxine allows tyrosine kinase inhibitor rechallenge. Clin Lymphoma Myeloma Leuk. 2010; 10:394-9. [PubMed 21030353]

14. Cortes J, Kantarjian H. How I treat newly diagnosed chronic phase CML. Blood. 2012; 120:1390-7. [PubMed 22613793]

15. Cortes J, Hochhaus A, Hughes T et al. Front-line and salvage therapies with tyrosine kinase inhibitors and other treatments in chronic myeloid leukemia. J Clin Oncol. 2011; 29:524-31. [PubMed 21220597]

16. Allan EK, Holyoake TL, Craig AR et al. Omacetaxine may have a role in chronic myeloid leukaemia eradication through downregulation of Mcl-1 and induction of apoptosis in stem/progenitor cells. Leukemia. 2011; 25:985-94. [PubMed 21468038]

17. Chen Y, Hu Y, Michaels S et al. Inhibitory effects of omacetaxine on leukemic stem cells and BCR-ABL-induced chronic myeloid leukemia and acute lymphoblastic leukemia in mice. Leukemia. 2009; 23:1446-54. [PubMed 19322212]

18. Nemunaitis J, Mita A, Stephenson J et al. Pharmacokinetic study of omacetaxine mepesuccinate administered subcutaneously to patients with advanced solid and hematologic tumors. Cancer Chemother Pharmacol. 2013; 71:35-41. [PubMed 23053254]

20. Teva Pharmaceuticals. North Wales, PA: Personal communication.

21. Nicolini FE, Khoury HJ, Akard L et al. Omacetaxine mepesuccinate for patients with accelerated-phase chronic myeloid leukemia with resistance or intolerance to two or more tyrosine kinase inhibitors. Haematologica. 2013; :. [PubMed 23753022]

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