Synribo

Generic Name: omacetaxine mepesuccinate
Date of Approval: October 26, 2012
Company: Teva Pharmaceutical Industries Ltd.

Treatment for: Chronic Myeloid Leukemia

FDA Approves Synribo

The U.S. Food and Drug Administration (FDA) has approved Synribo (omacetaxine mepesuccinate) for Injection to treat adult patients with chronic phase (CP) or accelerated phase (AP) chronic myeloid leukemia (CML) with resistance and/or intolerance to two or more tyrosine kinase inhibitors (TKIs).

The mechanism of action of Synribo has not been fully elucidated but includes inhibition of protein synthesis. It acts independently of direct Bcr-Abl binding to reduce protein levels of both the Bcr-Abl oncoprotein and Mcl-1 which inhibits apoptosis, in vitro. SYNRIBO also showed activity in mouse models of wild-type and T315I mutated Bcr-Abl CML. It is the first protein synthesis inhibitor for the treatment of CML.

Synribo received an accelerated approval that allows the FDA to approve a drug to treat a serious disease based on clinical data showing that the drug has an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients. The program is designed to provide patients with earlier access to promising new drugs. Full approval is expected following submission of more mature data from pivotal analysis.

The approval is based on an analysis of combined data subsets from two Phase II, open-label, multicenter studies. The pooled analysis included patients who had received 2 or more approved TKIs and, at a minimum, had evidence of resistance or intolerance to dasatinib and/or nilotinib. 47% of CP patients and 63% of AP patients had failed treatment with imatinib, dasatinib, and nilotinib. The majority of patients had also received other treatments including hydroxyurea, interferon, and cytarabine.

Most common adverse reactions (frequency ≥20%) in chronic and accelerated phase patients: thrombocytopenia, anemia, neutropenia, diarrhea, nausea, fatigue, asthenia, injection site reaction, pyrexia, infection, and lymphopenia.

Administered subcutaneously, Synribo will be dosed twice daily for 14 consecutive days of a 28-day cycle at treatment induction, and twice daily for seven consecutive days of a 28-day cycle during maintenance therapy once a response is achieved.

Important Safety Information

• Serious adverse reactions, including myelosuppression, bleeding, and hyperglycemia, have been associated with Synribo. Some reactions, such as myelosuppression and cerebral hemorrhage, have been fatal. Patients should be monitored closely for these reactions. Consider dose modifications for toxicities
• Women should be advised to avoid becoming pregnant while using Synribo
• Most common adverse reactions (frequency ≥20%) in chronic and accelerated phase patients: thrombocytopenia, anemia, neutropenia, diarrhea, nausea, fatigue, asthenia, injection site reaction, pyrexia, infection, and lymphopenia

Highlights of Prescribing Information

These highlights do not include all the information needed to use Synribo safely and effectively. See full prescribing information for Synribo.

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Indications and Usage

Synribo for Injection is indicated 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). This indication is based upon response rate. There are no trials verifying an improvement in disease-related symptoms or increased survival with Synribo.

Dosage and Administration

• 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.

Dosage Forms and Strengths

Single-use vial containing 3.5 mg of omacetaxine mepesuccinate as a lyophilized powder.

Contraindications

None.

Warnings and Precautions

• 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 hyperosmolar non-ketotic hyperglycemia.
• Embryo-fetal toxicity: Can cause fetal harm. Advise females of reproductive potential to avoid pregnancy.

Synribo side effects

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.

To report SUSPECTED ADVERSE REACTIONS, contact Teva Pharmaceutical USA, Inc. at 1-800-896-5855 or FDA at 1-800- FDA-1088 or www.fda.gov/medwatch.

See also: Synribo side effects (in more detail)

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.