SYNRIBO

Other Antineoplastic Agents
Other Antineoplastic Plant Alkaloids and Natural Agents

Hazardous Drugs Classification
NIOSH 2016 List: Group 1
NIOSH (Draft) 2020 List: Table 1
Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.

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

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]

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

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

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

SYNRIBO

Rx

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

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.

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.

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.

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.
Acetaminophen; Aspirin: (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.
Acetaminophen; Aspirin; Diphenhydramine: (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.
Acetaminophen; 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.
Amlodipine; 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.
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; 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; Caffeine; Orphenadrine: (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; Citric Acid; Sodium Bicarbonate: (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.
Bupivacaine; 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.
Butalbital; Aspirin; 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.
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.
Celecoxib; Tramadol: (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.
Chlorpheniramine; 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.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
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.
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.
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; Famotidine: (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.
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; Esomeprazole: (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.
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.
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.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
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.
Sumatriptan; 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.
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.

SYNRIBO Subcutaneous Inj Pwd F/Sol: 3.5mg

2.5 mg/m2/day subcutaneously.

2.5 mg/m2/day subcutaneously.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

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.

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.

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.

Omacetaxine may cause fetal harm if used during pregnancy, based on its mechanism of action and data from 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 (1.23 mg/m2/day) that were about half the recommended daily human dose based on body surface area.

Counsel patients about the reproductive risk and contraception requirements during omacetaxine treatment. Pregnancy testing should be performed in women of reproductive potential prior to initiating therapy. These women should use an effective method of contraception during omacetaxine therapy and for 6 months after the last dose. Woman who become pregnant while receiving omacetaxine should be apprised of the potential hazard to the fetus. Due to a risk of male-mediated teratogenicity, male patients with female partners of reproductive potential should use effective contraception during omacetaxine therapy and for 3 months after the last dose. Based on data from animal studies, male infertility may occur with omacetaxine use; it is not known if fertility effects are reversible.