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  • CLASSES

    Other Antineoplastic Agents
    Other Antineoplastic Plant Alkaloids and Natural Products

    DEA CLASS

    Rx

    DESCRIPTION

    Protein synthesis inhibitor
    FDA approved for the treatment of adult patients with chronic or accelerated phase chronic myeloid leukemia resistant and/or intolerant to 2 or more tyrosine kinase inhibitors
    Severe myelosuppression and fatal hemorrhage have been reported

    COMMON BRAND NAMES

    SYNRIBO

    HOW SUPPLIED

    SYNRIBO Subcutaneous Inj Pwd F/Sol: 3.5mg

    DOSAGE & INDICATIONS

    For the treatment of chronic myelogenous leukemia (CML).
    NOTE: The FDA has designated omacetaxine as an orphan drug for the treatment of CML.
    For the treatment of chronic or accelerated phase CML with resistance and/or intolerance to 2 or more tyrosine kinase inhibitors.
    Subcutaneous dosage
    Adults

    1.25 mg/m2 subcutaneously twice daily (approximately 12 hours apart) for 14 days repeated every 28 days until a hematologic response is achieved, then begin maintenance therapy with omacetaxine 1.25 mg/m2 subcutaneously twice daily (approximately 12 hours apart) for 7 days repeated every 28 days for as long as a clinical benefit is observed. Treatment delays and/or a reduction in the number of doses/cycle may be necessary in patients who develop toxicity. The efficacy of omacetaxine has been evaluated using a combined cohort from 2 studies in patients with chronic phase (CP) or accelerated phase (AP) chronic myelogenous leukemia (CML) who had received prior therapy with 2 or more tyrosine kinase inhibitors and had evidence of resistance or intolerance to dasatinib and/or nilotinib. In this analysis, treatment with omacetaxine resulted in a major cytogenic response (MCyR) rate (primary endpoint) of 18.4% in patients with CP-CML (n = 76); the mean time to MCyR onset was 3.5 months and the median MCyR duration was 12.5 months. In subgroup analyses of patients with CP-CML, the MCyR rate was higher in patients younger than 65 years compared with older patients (23% vs. 9%) and in men compared with women (21% vs. 14%). In patients with CP-CML, the confirmed complete and partial cytogenic response rates were 7.9% and 3.9%, respectively. In patients with AP-CML (n = 35), the composite endpoint (MaHR) of complete hematologic response (CHR, 11.4%) rate or no evidence of leukemia (NEL, 2.9%) was achieved in 14.3% (median duration of 4.7 months); however, none of these patients had a MCyR. The MaHR rate was higher in a subgroup of patients aged 65 years or older (31%) compared with younger patients (0%) with AP-CML.

    MAXIMUM DOSAGE

    Adults

    2.5 mg/m2/day subcutaneously.

    Geriatric

    2.5 mg/m2/day subcutaneously.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available. No studies have been performed to evaluate the impact of hepatic impairment on the pharmacokinetic parameters of omacetaxine.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available. No studies have been performed to evaluate the impact of renal impairment on the pharmacokinetic parameters of omacetaxine.

    ADMINISTRATION

    NOTE: Observe and exercise usual precautions for handling, preparing, administering, and disposing of cytotoxic drugs.

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Subcutaneous Administration

    Omacetaxine is available as a 3.5-mg single-use lyophilized powder vial.
    Syringes for subcutaneous use should be prepared in a healthcare facility.
    A patient or caregiver may administer the injection after being properly trained on handling, storage conditions, administration technique, disposal, and clean-up of accidental spillage of the product. See the Instructions for Use provided by the manufacturer.
    Reconstitution:
    Add 1 mL of 0.9% Sodium Chloride injection to the vial for a final omacetaxine concentration of 3.5 mg/mL.
    Gently swirl the vial until the solution is clear and completely dissolved (approximately 1 minute).
    Storage following reconstitution: use within 12 hours when stored at room temperature (20 to 25 degrees C; 68 to 77 degrees F) or within 6 days (144 hours) when stored in the refrigerator (2 to 8 degrees C; 36 to 46 degrees F).
    Subcutaneous Injection:
    Withdraw the calculated volume for the patient dose into a syringe; discard any unused portion of the vial.
    Inject subcutaneously in a recommended injection site (i.e., thigh or stomach-area (abdomen)).
    Ensure that necessary supplies for home administration are provided including reconstituted omacetaxine syringe with patient-specific dose, protective eyewear, gloves, biohazard container, absorbent pad(s) for placement of administration materials and accidental spillage, alcohol swabs, gauze pads, ice packs or cooler for transportation of syringes.[52213]

    STORAGE

    SYNRIBO:
    - Discard unused portion. Do not store for later use.
    - Protect from light
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    - Store in carton until time of use

    CONTRAINDICATIONS / PRECAUTIONS

    Anemia, bleeding, GI bleeding, infection, intracranial bleeding, neutropenia, thrombocytopenia

    Myelosuppression (e.g., anemia, thrombocytopenia, neutropenia) has been reported commonly with omacetaxine use. Additionally, bleeding associated with severe thrombocytopenia has been reported in patients who received omacetaxine in clinical trials, including fatal intracranial bleeding and severe GI bleeding. Obtain a complete blood count (CBC) panel weekly during induction and initial maintenance cycles, then monitor CBC panels every 2 weeks as clinically indicated. Monitor patients with neutropenia for symptoms of infection or fever. Delaying the next cycle of therapy and/or reducing the number of dosing days/cycle may be necessary in patients who develop hematologic toxicity.

    Diabetes mellitus, hyperglycemia, hyperosmolar hyperglycemic state (HHS)

    Impaired glucose tolerance and severe hyperglycemia have been reported with omacetaxine use. Hyperosmolar hyperglycemic state (HHS) (hyperosmolar non-ketotic hyperglycemia) occurred in 1 patient who received omacetaxine in a clinical trial. Avoid omacetaxine therapy in patients with poorly controlled diabetes mellitus until good glycemic control is achieved. Monitor blood glucose levels frequently, particularly in patients with diabetes or risk factors for diabetes.

    Geriatric

    A higher incidence of toxicity, including hematologic toxicity, was experienced in geriatric patients aged 65 years and older compared with younger patients in clinical studies in patients with chronic myelogenous leukemia who received omacetaxine.

    Infertility, pregnancy

    Omacetaxine is classified as FDA pregnancy risk category D. Fetal harm may occur if omacetaxine is administered to a pregnant women, based on animal studies. Females of reproductive potential should avoid becoming pregnant during omacetaxine therapy. Woman who become pregnant while receiving omacetaxine should be apprised of the potential hazard to the fetus. Embryo-fetal toxicity including embryotic death, increase in unossified bones/reduced bone ossification, and a decrease in fetal weight was observed in pregnant mice who received omacetaxine doses (0.41 mg/kg/day) that were about half the recommended daily human dose based on body surface area. Male infertility may occur with omacetaxine use. In mice, bilateral degeneration of the seminiferous tubular testicular epithelium and hypospermia/aspermia in the epididymides were reported following doses that were 2- to 3-times the recommended omacetaxine human daily dosage given for 6 cycles over 6 months.

    Breast-feeding

    According to the manufacturer, omacetaxine or breast-feeding should be discontinued because of the potential for serious adverse reactions in nursing infants from omacetaxine. It is not known if omacetaxine is excreted into human milk. Consider the benefits of breast-feeding, the risk of infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    ADVERSE REACTIONS

    Severe

    thrombocytopenia / Delayed / 49.0-88.0
    neutropenia / Delayed / 18.0-81.0
    anemia / Delayed / 36.0-80.0
    leukopenia / Delayed / 61.0-72.0
    hyperuricemia / Delayed / 56.0-57.0
    infection / Delayed / 11.0-20.0
    lymphopenia / Delayed / 16.0-16.0
    hyperglycemia / Delayed / 10.0-15.0
    seizures / Delayed / 1.0-10.0
    bradycardia / Rapid / 1.0-10.0
    ocular hemorrhage / Delayed / 1.0-10.0
    fatigue / Early / 5.0-9.0
    hyperbilirubinemia / Delayed / 6.0-9.0
    hypoglycemia / Early / 6.0-8.0
    diarrhea / Early / 1.0-7.0
    elevated hepatic enzymes / Delayed / 2.0-6.0
    nausea / Early / 1.0-4.0
    intracranial bleeding / Delayed / 2.0-2.0
    GI bleeding / Delayed / 2.0-2.0
    anorexia / Delayed / 2.0-2.0
    vomiting / Early / 0-2.0
    back pain / Delayed / 2.0-2.0
    dyspnea / Early / 2.0-2.0
    epistaxis / Delayed / 1.0-2.0
    fever / Early / 1.0-2.0
    asthenia / Delayed / 1.0-2.0
    arthralgia / Delayed / 1.0-1.0
    cough / Delayed / 0-1.0
    headache / Early / 0-1.0

    Moderate

    infusion-related reactions / Rapid / 22.0-34.0
    constipation / Delayed / 15.0-15.0
    peripheral edema / Delayed / 13.0-13.0
    hematoma / Early / 1.0-10.0
    diabetes mellitus / Delayed / 1.0-10.0
    gastritis / Delayed / 1.0-10.0
    dysphagia / Delayed / 1.0-10.0
    oral ulceration / Delayed / 1.0-10.0
    hemorrhoids / Delayed / 1.0-10.0
    stomatitis / Delayed / 1.0-10.0
    bone pain / Delayed / 1.0-10.0
    dysphonia / Delayed / 1.0-10.0
    hemoptysis / Delayed / 1.0-10.0
    skin ulcer / Delayed / 1.0-10.0
    erythema / Early / 1.0-10.0
    edema / Delayed / 1.0-10.0
    depression / Delayed / 1.0-10.0
    confusion / Early / 1.0-10.0
    dysuria / Early / 1.0-10.0
    dehydration / Delayed / 1.0-10.0
    gout / Delayed / 1.0-10.0
    hypotension / Rapid / 1.0-10.0
    angina / Early / 1.0-10.0
    hypertension / Early / 1.0-10.0
    palpitations / Early / 1.0-10.0
    chest pain (unspecified) / Early / 1.0-10.0
    sinus tachycardia / Rapid / 1.0-10.0
    blurred vision / Early / 1.0-10.0
    conjunctivitis / Delayed / 1.0-10.0
    cataracts / Delayed / 1.0-10.0
    hyperthermia / Delayed / 1.0-10.0
    hot flashes / Early / 1.0-10.0
    bleeding / Early / Incidence not known

    Mild

    injection site reaction / Rapid / 22.0-34.0
    alopecia / Delayed / 15.0-15.0
    abdominal pain / Early / 13.0-14.0
    chills / Rapid / 13.0-13.0
    gingivitis / Delayed / 1.0-10.0
    xerostomia / Early / 1.0-10.0
    gastroesophageal reflux / Delayed / 1.0-10.0
    dyspepsia / Early / 1.0-10.0
    weakness / Early / 1.0-10.0
    myalgia / Early / 1.0-10.0
    musculoskeletal pain / Early / 1.0-10.0
    nasal congestion / Early / 1.0-10.0
    rhinorrhea / Early / 1.0-10.0
    purpura / Delayed / 1.0-10.0
    petechiae / Delayed / 1.0-10.0
    night sweats / Early / 1.0-10.0
    ecchymosis / Delayed / 1.0-10.0
    pruritus / Rapid / 1.0-10.0
    rash / Early / 10.0-10.0
    skin hyperpigmentation / Delayed / 1.0-10.0
    xerosis / Delayed / 1.0-10.0
    hyperhidrosis / Delayed / 1.0-10.0
    malaise / Early / 1.0-10.0
    influenza / Delayed / 1.0-10.0
    anxiety / Delayed / 1.0-10.0
    agitation / Early / 1.0-10.0
    insomnia / Early / 10.0-10.0
    tremor / Early / 1.0-10.0
    paresthesias / Delayed / 1.0-10.0
    dizziness / Early / 1.0-10.0
    dysgeusia / Early / 1.0-10.0
    lethargy / Early / 1.0-10.0
    hypoesthesia / Delayed / 1.0-10.0
    tinnitus / Delayed / 1.0-10.0
    diplopia / Early / 1.0-10.0
    xerophthalmia / Early / 1.0-10.0
    lacrimation / Early / 1.0-10.0
    ocular pain / Early / 1.0-10.0

    DRUG INTERACTIONS

    Acetaminophen; Aspirin, ASA; Caffeine: (Major) Avoid the concomitant use of omacetaxine and aspirin, ASA when the platelet count is less than 50,000 cells/microliter due to an increased risk of bleeding. Also, aspirin may mask signs of infection such as fever and pain in patients following treatment with antineoplastic agents or immunosuppressives. Aspirin, ASA should be used with caution in patients receiving immunosuppressive therapy. Special consideration should be given to myelosuppressed patients prior to receiving aspirin.
    Anticoagulants: (Major) Avoid the concomitant use of omacetaxine and anticoagulants when the platelet count is less than 50,000 cells/microliter due to an increased risk of bleeding.
    Aspirin, ASA: (Major) Avoid the concomitant use of omacetaxine and aspirin, ASA when the platelet count is less than 50,000 cells/microliter due to an increased risk of bleeding. Also, aspirin may mask signs of infection such as fever and pain in patients following treatment with antineoplastic agents or immunosuppressives. Aspirin, ASA should be used with caution in patients receiving immunosuppressive therapy. Special consideration should be given to myelosuppressed patients prior to receiving aspirin.
    Aspirin, ASA; Butalbital; Caffeine: (Major) Avoid the concomitant use of omacetaxine and aspirin, ASA when the platelet count is less than 50,000 cells/microliter due to an increased risk of bleeding. Also, aspirin may mask signs of infection such as fever and pain in patients following treatment with antineoplastic agents or immunosuppressives. Aspirin, ASA should be used with caution in patients receiving immunosuppressive therapy. Special consideration should be given to myelosuppressed patients prior to receiving aspirin.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Avoid the concomitant use of omacetaxine and aspirin, ASA when the platelet count is less than 50,000 cells/microliter due to an increased risk of bleeding. Also, aspirin may mask signs of infection such as fever and pain in patients following treatment with antineoplastic agents or immunosuppressives. Aspirin, ASA should be used with caution in patients receiving immunosuppressive therapy. Special consideration should be given to myelosuppressed patients prior to receiving aspirin.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Major) Avoid the concomitant use of omacetaxine and aspirin, ASA when the platelet count is less than 50,000 cells/microliter due to an increased risk of bleeding. Also, aspirin may mask signs of infection such as fever and pain in patients following treatment with antineoplastic agents or immunosuppressives. Aspirin, ASA should be used with caution in patients receiving immunosuppressive therapy. Special consideration should be given to myelosuppressed patients prior to receiving aspirin.
    Aspirin, ASA; Carisoprodol: (Major) Avoid the concomitant use of omacetaxine and aspirin, ASA when the platelet count is less than 50,000 cells/microliter due to an increased risk of bleeding. Also, aspirin may mask signs of infection such as fever and pain in patients following treatment with antineoplastic agents or immunosuppressives. Aspirin, ASA should be used with caution in patients receiving immunosuppressive therapy. Special consideration should be given to myelosuppressed patients prior to receiving aspirin.
    Aspirin, ASA; Carisoprodol; Codeine: (Major) Avoid the concomitant use of omacetaxine and aspirin, ASA when the platelet count is less than 50,000 cells/microliter due to an increased risk of bleeding. Also, aspirin may mask signs of infection such as fever and pain in patients following treatment with antineoplastic agents or immunosuppressives. Aspirin, ASA should be used with caution in patients receiving immunosuppressive therapy. Special consideration should be given to myelosuppressed patients prior to receiving aspirin.
    Aspirin, ASA; Dipyridamole: (Major) Avoid the concomitant use of omacetaxine and aspirin, ASA when the platelet count is less than 50,000 cells/microliter due to an increased risk of bleeding. Also, aspirin may mask signs of infection such as fever and pain in patients following treatment with antineoplastic agents or immunosuppressives. Aspirin, ASA should be used with caution in patients receiving immunosuppressive therapy. Special consideration should be given to myelosuppressed patients prior to receiving aspirin.
    Aspirin, ASA; Omeprazole: (Major) Avoid the concomitant use of omacetaxine and aspirin, ASA when the platelet count is less than 50,000 cells/microliter due to an increased risk of bleeding. Also, aspirin may mask signs of infection such as fever and pain in patients following treatment with antineoplastic agents or immunosuppressives. Aspirin, ASA should be used with caution in patients receiving immunosuppressive therapy. Special consideration should be given to myelosuppressed patients prior to receiving aspirin.
    Aspirin, ASA; Oxycodone: (Major) Avoid the concomitant use of omacetaxine and aspirin, ASA when the platelet count is less than 50,000 cells/microliter due to an increased risk of bleeding. Also, aspirin may mask signs of infection such as fever and pain in patients following treatment with antineoplastic agents or immunosuppressives. Aspirin, ASA should be used with caution in patients receiving immunosuppressive therapy. Special consideration should be given to myelosuppressed patients prior to receiving aspirin.
    Aspirin, ASA; Pravastatin: (Major) Avoid the concomitant use of omacetaxine and aspirin, ASA when the platelet count is less than 50,000 cells/microliter due to an increased risk of bleeding. Also, aspirin may mask signs of infection such as fever and pain in patients following treatment with antineoplastic agents or immunosuppressives. Aspirin, ASA should be used with caution in patients receiving immunosuppressive therapy. Special consideration should be given to myelosuppressed patients prior to receiving aspirin.
    Celecoxib: (Major) Avoid the concomitant use of omacetaxine and nonsteroidal antiinflammatory drugs (NSAIDs) when the platelet count is less than 50,000 cells/microliter due to an increased risk of bleeding.
    Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Diclofenac: (Major) Avoid the concomitant use of omacetaxine and nonsteroidal antiinflammatory drugs (NSAIDs) when the platelet count is less than 50,000 cells/microliter due to an increased risk of bleeding.
    Diclofenac; Misoprostol: (Major) Avoid the concomitant use of omacetaxine and nonsteroidal antiinflammatory drugs (NSAIDs) when the platelet count is less than 50,000 cells/microliter due to an increased risk of bleeding.
    Diflunisal: (Major) Avoid the concomitant use of omacetaxine and nonsteroidal antiinflammatory drugs (NSAIDs) when the platelet count is less than 50,000 cells/microliter due to an increased risk of bleeding.
    Diphenhydramine; Ibuprofen: (Major) Avoid the concomitant use of omacetaxine and nonsteroidal antiinflammatory drugs (NSAIDs) when the platelet count is less than 50,000 cells/microliter due to an increased risk of bleeding.
    Diphenhydramine; Naproxen: (Major) Avoid the concomitant use of omacetaxine and nonsteroidal antiinflammatory drugs (NSAIDs) when the platelet count is less than 50,000 cells/microliter due to an increased risk of bleeding.
    Esomeprazole; Naproxen: (Major) Avoid the concomitant use of omacetaxine and nonsteroidal antiinflammatory drugs (NSAIDs) when the platelet count is less than 50,000 cells/microliter due to an increased risk of bleeding.
    Etodolac: (Major) Avoid the concomitant use of omacetaxine and nonsteroidal antiinflammatory drugs (NSAIDs) when the platelet count is less than 50,000 cells/microliter due to an increased risk of bleeding.
    Famotidine; Ibuprofen: (Major) Avoid the concomitant use of omacetaxine and nonsteroidal antiinflammatory drugs (NSAIDs) when the platelet count is less than 50,000 cells/microliter due to an increased risk of bleeding.
    Fenoprofen: (Major) Avoid the concomitant use of omacetaxine and nonsteroidal antiinflammatory drugs (NSAIDs) when the platelet count is less than 50,000 cells/microliter due to an increased risk of bleeding.
    Flurbiprofen: (Major) Avoid the concomitant use of omacetaxine and nonsteroidal antiinflammatory drugs (NSAIDs) when the platelet count is less than 50,000 cells/microliter due to an increased risk of bleeding.
    Hydrocodone; Ibuprofen: (Major) Avoid the concomitant use of omacetaxine and nonsteroidal antiinflammatory drugs (NSAIDs) when the platelet count is less than 50,000 cells/microliter due to an increased risk of bleeding.
    Ibuprofen: (Major) Avoid the concomitant use of omacetaxine and nonsteroidal antiinflammatory drugs (NSAIDs) when the platelet count is less than 50,000 cells/microliter due to an increased risk of bleeding.
    Ibuprofen; Oxycodone: (Major) Avoid the concomitant use of omacetaxine and nonsteroidal antiinflammatory drugs (NSAIDs) when the platelet count is less than 50,000 cells/microliter due to an increased risk of bleeding.
    Ibuprofen; Pseudoephedrine: (Major) Avoid the concomitant use of omacetaxine and nonsteroidal antiinflammatory drugs (NSAIDs) when the platelet count is less than 50,000 cells/microliter due to an increased risk of bleeding.
    Indomethacin: (Major) Avoid the concomitant use of omacetaxine and nonsteroidal antiinflammatory drugs (NSAIDs) when the platelet count is less than 50,000 cells/microliter due to an increased risk of bleeding.
    Ketoprofen: (Major) Avoid the concomitant use of omacetaxine and nonsteroidal antiinflammatory drugs (NSAIDs) when the platelet count is less than 50,000 cells/microliter due to an increased risk of bleeding.
    Ketorolac: (Major) Avoid the concomitant use of omacetaxine and nonsteroidal antiinflammatory drugs (NSAIDs) when the platelet count is less than 50,000 cells/microliter due to an increased risk of bleeding.
    Lansoprazole; Naproxen: (Major) Avoid the concomitant use of omacetaxine and nonsteroidal antiinflammatory drugs (NSAIDs) when the platelet count is less than 50,000 cells/microliter due to an increased risk of bleeding.
    Meclofenamate Sodium: (Major) Avoid the concomitant use of omacetaxine and nonsteroidal antiinflammatory drugs (NSAIDs) when the platelet count is less than 50,000 cells/microliter due to an increased risk of bleeding.
    Mefenamic Acid: (Major) Avoid the concomitant use of omacetaxine and nonsteroidal antiinflammatory drugs (NSAIDs) when the platelet count is less than 50,000 cells/microliter due to an increased risk of bleeding.
    Meloxicam: (Major) Avoid the concomitant use of omacetaxine and nonsteroidal antiinflammatory drugs (NSAIDs) when the platelet count is less than 50,000 cells/microliter due to an increased risk of bleeding.
    Nabumetone: (Major) Avoid the concomitant use of omacetaxine and nonsteroidal antiinflammatory drugs (NSAIDs) when the platelet count is less than 50,000 cells/microliter due to an increased risk of bleeding.
    Naproxen: (Major) Avoid the concomitant use of omacetaxine and nonsteroidal antiinflammatory drugs (NSAIDs) when the platelet count is less than 50,000 cells/microliter due to an increased risk of bleeding.
    Naproxen; Pseudoephedrine: (Major) Avoid the concomitant use of omacetaxine and nonsteroidal antiinflammatory drugs (NSAIDs) when the platelet count is less than 50,000 cells/microliter due to an increased risk of bleeding.
    Naproxen; Sumatriptan: (Major) Avoid the concomitant use of omacetaxine and nonsteroidal antiinflammatory drugs (NSAIDs) when the platelet count is less than 50,000 cells/microliter due to an increased risk of bleeding.
    Nonsteroidal antiinflammatory drugs: (Major) Avoid the concomitant use of omacetaxine and nonsteroidal antiinflammatory drugs (NSAIDs) when the platelet count is less than 50,000 cells/microliter due to an increased risk of bleeding.
    Oxaprozin: (Major) Avoid the concomitant use of omacetaxine and nonsteroidal antiinflammatory drugs (NSAIDs) when the platelet count is less than 50,000 cells/microliter due to an increased risk of bleeding.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Piroxicam: (Major) Avoid the concomitant use of omacetaxine and nonsteroidal antiinflammatory drugs (NSAIDs) when the platelet count is less than 50,000 cells/microliter due to an increased risk of bleeding.
    Rofecoxib: (Major) Avoid the concomitant use of omacetaxine and nonsteroidal antiinflammatory drugs (NSAIDs) when the platelet count is less than 50,000 cells/microliter due to an increased risk of bleeding.
    Sulindac: (Major) Avoid the concomitant use of omacetaxine and nonsteroidal antiinflammatory drugs (NSAIDs) when the platelet count is less than 50,000 cells/microliter due to an increased risk of bleeding.
    Tolmetin: (Major) Avoid the concomitant use of omacetaxine and nonsteroidal antiinflammatory drugs (NSAIDs) when the platelet count is less than 50,000 cells/microliter due to an increased risk of bleeding.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
    Valdecoxib: (Major) Avoid the concomitant use of omacetaxine and nonsteroidal antiinflammatory drugs (NSAIDs) when the platelet count is less than 50,000 cells/microliter due to an increased risk of bleeding.

    PREGNANCY AND LACTATION

    Pregnancy

    According to the manufacturer, omacetaxine or breast-feeding should be discontinued because of the potential for serious adverse reactions in nursing infants from omacetaxine. It is not known if omacetaxine is excreted into human milk. Consider the benefits of breast-feeding, the risk of infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Omacetaxine mepesuccinate is a cephalotaxine ester derived from the evergreen tree, Cephalotaxus harringtonia. Omacetaxine inhibits protein synthesis by binding to the A-site in the peptidyl-transferase center of the large ribosomal subunit. It reduces protein levels of Bcr-Abl and Mcl-1 independent of direct Bcr-Abl binding. Omacetaxine may induce apoptosis through mitochondrial disruption and cytochrome c release leading to caspase-9 and caspase-3 activation in certain myeloid leukemia cell lines (i.e., HL60, HL60/MRP). Apoptosis may also be facilitated by a down-regulation of Mcl-1 and activation of PARP and caspase-8. The Bcr-Abl kinase is essential for the initiation, maintenance, and progression of chronic myelogenous leukemia (CML). A Bcr-Abl mutation that exchanges the amino acids threonine and isoleucine at position 315 (T315I mutation) represents a mechanism of resistance for the tyrosine kinase inhibitors (TKI). Omacetaxine has demonstrated activity in wild-type and T315I mutated Bcr-Abl in mice models and efficacy in CML patients with the T315I mutation who had failed previous TKI therapy.

    PHARMACOKINETICS

    Omacetaxine mepesuccinate is administered subcutaneously. It is 50% or less bound to plasma proteins. Following omacetaxine 1.25 mg/m2 subcutaneously twice daily for 11 days, the steady-state volume of distribution was 141 +/- 93.4 L. The terminal elimination half-life in plasma is 14.6 hours. The primary mechanism of omacetaxine metabolism is via hydrolysis to 4'-DMHHT by plasma esterases. It appears that omacetaxine has minimal hepatic microsomal oxidative and/or esterase-mediated metabolism. In vitro, omacetaxine does not inhibit major CYP450 isoenzymes. Additionally, it is a P-gp substrate but not a P-gp inhibitor at therapeutic concentrations in vitro. Approximately 81% of the mean total radioactivity was recovered following a single subcutaneous dose of radiolabeled omacetaxine; about 37% and 44% of the radioactivity was recovered in the urine and feces, respectively.

    Subcutaneous Route

    The absolute bioavailability of omacetaxine mepesuccinate is not known. Following subcutaneous administration, the time to the maximum omacetaxine concentration level (Tmax) is 30 minutes. At steady state, the systemic exposure of omacetaxine increases by 90% from the first dose.