Omacetaxine mepesuccinate
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Edzel Lorraine Co, DMD, MD[2]
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Overview
Omacetaxine mepesuccinate is an injection that is FDA approved for the treatment of adult patients with chronic or accelerated phase chronic myeloid leukemia (CML) with resistance and/or intolerance to two or more tyrosine kinase inhibitors (TKI). Common adverse reactions include {{{adverseReactions}}}.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
- Induction Dose: 1.25 mg/m2 administered by subcutaneous injection twice daily for 14 consecutive days of a 28-day cycle.
- Maintenance Dose: 1.25 mg/m2 administered by subcutaneous injection twice daily for 7 consecutive days of a 28-day cycle.
- Dose modifications are needed for toxicity.
- Single-use vial containing 3.5 mg of omacetaxine mepesuccinate as a lyophilized powder.
Off-Label Use and Dosage (Adult)
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Omacetaxine mepesuccinate FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
Off-Label Use and Dosage (Pediatric)
Contraindications
- None
Warnings
- Myelosuppression: severe and fatal thrombocytopenia, neutropenia and anemia. Monitor hematologic parameters frequently.
- Bleeding: severe thrombocytopenia and increased risk of hemorrhage. Fatal cerebral hemorrhage and severe, non-fatal gastrointestinal hemorrhage.
- Hyperglycemia: glucose intolerance and hyperglycemia including hyper-osmolar non-ketotic hyperglycemia.
- Embryo-fetal toxicity: Can cause fetal harm. Advise females of reproductive potential to avoid pregnancy.
Adverse Reactions
Clinical Trials Experience
CML-Chronic Phase and Accelerated Phase: Most common adverse reactions (frequency 20%): thrombocytopenia, anemia, neutropenia, diarrhea, nausea, fatigue, asthenia, injection site reaction, pyrexia, infection, and lymphopenia.
Postmarketing Experience
There is limited information regarding Omacetaxine mepesuccinate Postmarketing Experience in the drug label.
Drug Interactions
Based on the findings from in vitro drug interaction studies with SYNRIBO, no clinical drug interaction trials were warranted.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA): D
Based on its mechanism of action and findings from animal studies, SYNRIBO can cause fetal harm when administered to pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
In an embryo-fetal development study, pregnant mice were administered omacetaxine mepesuccinate subcutaneously during the period of organogenesis at doses of 0.21 or 0.41 mg/kg/day. Drug-related adverse effects included embryonic death, an increase in unossified bones/reduced bone ossification and decreased fetal body weights. Fetal toxicity occurred at doses of 0.41 mg/kg (1.23 mg/m2) which is approximately half the recommended daily human dose on a body surface area basis.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Omacetaxine mepesuccinate in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Omacetaxine mepesuccinate during labor and delivery.
Nursing Mothers
It is not known whether omacetaxine mepesuccinate is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reaction in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
The safety and effectiveness of SYNRIBO in pediatric patients have not been established
Geriatic Use
In the chronic and accelerated phase CML efficacy populations 23 (30%) and 16 (46%) patients were ≥65 years of age. For the age subgroups of <65 years of age and ≥65 years of age, there were differences between the subgroups, with higher rates of major cytogenetic responses (MCyRs) in younger patients with CP CML compared with older patients (23% vs. 9%, respectively) and higher rates of major hematologic responses (MaHRs) in older patients with AP CML compared with younger patients (31% vs. 0%, respectively). Patients ≥65 years of age were more likely to experience toxicity, most notably hematologic toxicity.
Gender
Of the 76 patients included in the chronic phase CML population efficacy analysis, 47 (62%) of the patients were men and 29(38%) were women. For patients with chronic phase CML, the MCyR rate in men was higher than in women (21% vs. 14%,respectively). There were differences noted in the safety profile of omacetaxine mepesuccinate in men and women with chronic phase CML although the small number of patients in each group prevents a definitive assessment. There were inadequate patient numbers in the accelerated phase subset to draw conclusions regarding a gender effect on efficacy.
Race
There is no FDA guidance on the use of Omacetaxine mepesuccinate with respect to specific racial populations.
Renal Impairment
No formal studies assessing the impact of renal impairment on the pharmacokinetics of omacetaxine mepesuccinate have been conducted.
Hepatic Impairment
No formal studies assessing the impact of hepatic impairment on the pharmacokinetics of omacetaxine mepesuccinate have beenconducted.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Omacetaxine mepesuccinate in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Omacetaxine mepesuccinate in patients who are immunocompromised.
Geriatric Use
In the chronic and accelerated phase CML efficacy populations 23 (30%) and 16 (46%) patients were ≥65 years of age. For the age subgroups of <65 years of age and ≥65 years of age, there were differences between the subgroups, with higher rates of major cytogenetic responses (MCyRs) in younger patients with CP CML compared with older patients (23% vs. 9%, respectively) and higher rates of major hematologic responses (MaHRs) in older patients with AP CML compared with younger patients (31% vs. 0%, respectively). Patients ≥65 years of age were more likely to experience toxicity, most notably hematologic toxicity.
Administration and Monitoring
Administration
There is limited information regarding Omacetaxine mepesuccinate Administration in the drug label.
Monitoring
There is limited information regarding Omacetaxine mepesuccinate Monitoring in the drug label.
IV Compatibility
There is limited information regarding the compatibility of Omacetaxine mepesuccinate and IV administrations.
Overdosage
There is limited information regarding Omacetaxine mepesuccinate overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
Pharmacology
SYNRIBO contains the active ingredient omacetaxine mepesuccinate, a cephalotaxine ester. It is a protein synthesis inhibitor. Omacetaxine mepesuccinate is prepared by a semi-synthetic process from cephalotaxine, an extract from the leaves of Cephalotaxus sp. The chemical name of omacetaxine mepesuccinate is cephalotaxine, 4-methyl (2R)-hydroxyl-2-(4-hydroxyl-4-methylpentyl) butanedioate (ester).
Mechanism of Action
The mechanism of action of omacetaxine mepesuccinate has not been fully elucidated but includes inhibition of protein synthesis and is independent of direct Bcr-Abl binding. Omacetaxine mepesuccinate binds to the A-site cleft in the peptidyl-transferase center of the large ribosomal subunit from a strain of archaeabacteria. In vitro, omacetaxine mepesuccinate reduced protein levels of the BcrAbl oncoprotein and Mcl-1, an anti-apoptotic Bcl-2 family member. Omacetaxine mepesuccinate showed activity in mouse models of wild-type and T315I mutated Bcr-Abl CML.
Structure
The molecular formula is C29H39NO9 with a molecular weight of 545.6 g/mol. SYNRIBO for injection is a sterile, preservativefree, white to off-white, lyophilized powder in a single-use vial. Each vial contains 3.5 mg omacetaxine mepesuccinate and mannitol. SYNRIBO is intended for subcutaneous administration after reconstitution with 1.0 mL of 0.9% Sodium Chloride Injection, USP. The pH of the reconstituted solution is between 5.5 and 7.0.
Pharmacodynamics
There is limited information regarding Omacetaxine mepesuccinate Pharmacodynamics in the drug label.
Pharmacokinetics
The dose proportionality of omacetaxine mepesuccinate is unknown. A 90% increase in systemic exposure to omacetaxine mepesuccinate was observed between the first dose and steady state.
Absorption The absolute bioavailability of omacetaxine mepesuccinate has not been determined. Omacetaxine mepesuccinate is absorbed following subcutaneous administration, and maximum concentrations are achieved after approximately 30 minutes.
Distribution The steady-state (mean ± SD) volume of distribution of omacetaxine mepesuccinate is approximately 141 93.4 L following subcutaneous administration of 1.25 mg/m2 twice daily for 11 days . The plasma protein binding of omacetaxine mepesuccinate is less than or equal to 50%.
Metabolism Omacetaxine mepesuccinate is primarily hydrolyzed to 4′-DMHHT via plasma esterases with little hepatic microsomal oxidative and/or esterase-mediated metabolism in vitro.
Elimination The major elimination route of omacetaxine mepesuccinate is unknown. The mean percentage of omacetaxine mepesuccinate excreted unchanged in the urine is less than 15%. The mean half-life of omacetaxine mepesuccinate following subcutaneous administration is approximately 6 hours.
Nonclinical Toxicology
No carcinogenicity studies have been conducted with omacetaxine mepesuccinate. Omacetaxine mepesuccinate was genotoxic in an in vitro chromosomal aberration test system in Chinese hamster ovary (CHO) cells, but was not mutagenic when tested in an in vitro bacterial cell assay (Ames test), and it did not induce genetic damage using an in vivo mouse micronucleus assay. SYNRIBO may impair male fertility. Studies in mice demonstrated adverse effects on male reproductive organs. Bilateral degeneration of the seminiferous tubular epithelium in testes and hypospermia/aspermia in the epididymides were reported in the highest dose group (2.33 mg/kg/day reduced to 1.67 mg/kg/day; 7 to 5 mg/m2 /day) following subcutaneous injection of omacetaxine mepesuccinate for six cycles over six months. The doses used in the mice were approximately two to three times the clinical dose (2.5 mg/m2/day) based on body surface area.
Clinical Studies
Chronic Phase CML The median duration of exposure for the 108 patients with chronic phase CML was 7.4 months (range 0 to 43 months). The median total cycles of exposure was 6 (range 1 to 41), and the median total dose delivered during the trials was 131 mg/m2 (range 1.2 to 678). Among the patients with chronic phase CML, 87% received 14 days of treatment during cycle 1. By cycles 2 and 3, the percentage of patients receiving 14 days of treatment decreased to 42% and 16% respectively. Of the 91 patients who received at least 2 cycles of treatment, 79 (87%) had at least 1 cycle delay during the trials. The median number of days of cycle delays was greatest for cycle 2 (17 days) and cycle 3 (25 days) when more patients were receiving induction cycles. Adverse reactions were reported for 99% of the patients with chronic phase CML. A total of 18% of patients had adverse reactions leading to withdrawal. The most frequently occurring adverse reactions leading to discontinuation were pancytopenia, thrombocytopenia, and increased alanine aminotransferase (each 2%). A total of 87% of patients reported at least 1 Grade 3 or Grade 4 treatment emergent adverse reactions.
Serious adverse reactions were reported for 51% of patients. Serious adverse reactions reported for at least 5% of patients were bone marrow failure and thrombocytopenia (each 10%), and febrile neutropenia (6%). Serious adverse reactions of infections were reported for 8% of patients. Deaths occurred while on study in five (5%) patients with CP CML. Two patients died due to cerebral hemorrhage, one due to multi-organ failure, one due to progression of disease, and one from unknown causes. Accelerated Phase CML Median total cycles of exposure was 2 (range 1 to 29), and the median total dose delivered during the trials was 70 mg/m2 . The median duration of exposure for the 55 patients with accelerated phase CML was 1.9 months (range 0 to 30 months). Of the patients with accelerated phase CML, 86% received 14 days of treatment during cycle 1. By cycles 2 and 3, the percentage of patients receiving 14 days of treatment decreased to 55% and 44% respectively. Of the 40 patients who received at least 2 cycles of treatment, 27 (68%) had at least 1 cycle delay during the trials. The median number of days of cycle delays was greatest for cycle 3 (31 days) and cycle 8 (36 days). Adverse reactions regardless of investigator attribution were reported for 100% patients with accelerated phase CML. A total of 33% of patients had adverse reactions leading to withdrawal. The most frequently occurring adverse reactions leading to withdrawal were leukocytosis (6%), and thrombocytopenia (4%). A total of 84% of patients reported at least 1 Grade 3 or Grade 4 treatment emergent adverse reaction
Serious adverse reactions were reported for 60% of patients. Serious adverse reactions reported for at least 5% of patients were febrile neutropenia (18%), thrombocytopenia (9%), anemia (7%), diarrhea and convulsions (6% each). Serious adverse reactions of infections were reported for 11% of patients. Death occurred while on study in 5 (9%) patients with AP CML. Two patients died due to cerebral hemorrhage and three due to progression of disease. Laboratory Abnormalities in Chronic and Accelerated Phase CML Grade 3/4 laboratory abnormalities reported in patients with chronic and accelerated phase CML are described in Table 3. Myelosuppression occurred in all patients treated with SYNRIBO. [see Warnings and Precautions (5.1)] Five patients with chronic phase CML and 4 patients with accelerated phase CML permanently discontinued SYNRIBO due to pancytopenia, thrombocytopenia, febrile neutropenia, or bone marrow necrosis. An event of hyperosmolar non-ketotic hyperglycemia was reported in one patient in the safety population and a similar case has been reported in the literature. Two patients with chronic phase CML permanently discontinued SYNRIBO due to elevated transaminases.
The following adverse reactions were reported in patients in the SYNRIBO clinical studies of patients with chronic phase and accelerated phase CML at a frequency of 1% to less than 10%. Within each category, adverse reactions are ranked on the basis of frequency. Cardiac Disorders: tachycardia, palpitations, acute coronary syndrome, angina pectoris, arrhythmia, bradycardia, ventricular extrasystoles. Ear and Labyrinth Disorders: ear pain, ear hemorrhage, tinnitus. Eye Disorders: cataract, vision blurred, conjunctival hemorrhage, dry eye, lacrimation increased, conjunctivitis, diplopia, eye pain, eyelid edema. Gastrointestinal Disorders: stomatitis, mouth ulceration, abdominal distension, dyspepsia, gastroesophageal reflux disease, gingival bleeding, aphthous stomatitis, dry mouth, hemorrhoids, gastritis, gastrointestinal hemorrhage, melena, mouth hemorrhage, oral pain, anal fissure, dysphagia, gingival pain, gingivitis. General Disorders and Administration Site Conditions: mucosal inflammation, pain, chest pain, hyperthermia, influenza-like illness, catheter site pain, general edema, malaise. Immune System Disorders: hypersensitivity. Injury, Poisoning and Procedural Complications: contusion, transfusion reaction. Metabolism and Nutrition Disorders: decreased appetite, diabetes mellitus, gout, dehydration.
Musculoskeletal and Connective Tissue Disorders: bone pain, myalgia, muscular weakness, muscle spasms, musculoskeletal chest
pain, musculoskeletal pain, musculoskeletal stiffness, musculoskeletal discomfort. Nervous System Disorders: dizziness, cerebral hemorrhage, paresthesia, convulsion, hypoesthesia, lethargy, sciatica, burning sensation, dysgeusia, tremor.
Psychiatric Disorders: anxiety, depression, agitation, confusional state, mental status change. Renal and Urinary Disorders: dysuria.
Respiratory, Thoracic and Mediastinal Disorders: pharyngolaryngeal pain, nasal congestion, dysphonia, productive cough, rales, rhinorrhea, hemoptysis, sinus congestion. Skin and Subcutaneous Tissue Disorders: erythema, pruritus, dry skin, petechiae, hyperhidrosis, night sweats, ecchymosis, purpura, skin lesion, skin ulcer, rash erythematous, rash papular, skin exfoliation, skin hyperpigmentation.
How Supplied
SYNRIBO (omacetaxine mepesuccinate) for Injection is supplied in 8 mL clear glass single-use vial in individual cartons. Each vial contains 3.5 mg of SYNRIBO (omacetaxine mepesuccinate) for Injection (NDC 63459-177-14).
Storage
Store at 20o C to 25ºC (68o C to 77ºF); excursions permitted from 15ºC to 30ºC (59ºF to 86ºF). Until use, keep product in carton to protect from light. Omacetaxine mepesuccinate is an antineoplastic product. Follow special handling and disposal procedures.
Images
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Patient Counseling Information
- Bleeding
Advise patients of the possibility of serious bleeding due to low platelet counts. Instruct patients to report immediately any signs or symptoms suggestive of hemorrhage (unusual bleeding, easy bruising or blood in urine or stool; confusion, slurred speech, or altered vision).
- Myelosuppression
Advise patients of the likelihood that SYNRIBO will cause a decrease in white blood cells, platelets, and red blood cells and that monitoring of these parameters will be needed. Instruct patients to contact a heath care professional if they develop a fever, or other signs/symptoms of infection; shortness of breath, significant fatigue, or bleeding.
- Hyperglycemia
Advise patients with diabetes of the possibility of hyperglycemia and the need for careful monitoring of blood glucose levels. Patients with poorly controlled diabetes mellitus should not be treated with omacetaxine mepesuccinate until good glycemic control has been established.
- Pregnancy and Nursing
Advise patients that omacetaxine mepesuccinate can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential of the potential hazard to the fetus and to avoid becoming pregnant. Advise females to avoid nursing while receiving SYNRIBO.
- Gastrointestinal Complaints
Advise patients that they may experience nausea, diarrhea, abdominal pain, constipation, and vomiting. If these symptoms persist, they should seek medical attention.
- Fatigue
Advise patients that SYNRIBO may cause tiredness and to avoid driving any vehicle or operating any dangerous tools or machinery if they experience this side effect.
- Rash
Advise patients that they may experience skin rash. Advise patients to immediately report severe or worsening rash or itching.
- Alopecia
Advise patients that they may experience hair loss.
Precautions with Alcohol
Alcohol-Omacetaxine mepesuccinate interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
Brand Names
There is limited information regarding Omacetaxine mepesuccinate Brand Names in the drug label.
Look-Alike Drug Names
There is limited information regarding Omacetaxine mepesuccinate Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.