Synribo

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SYNRIBO 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).

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Medicines can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of Synribo there are no specific foods that you must exclude from your diet when receiving this medication.

The recommended starting schedule for induction is 1.25 mg/m² administered subcutaneously twice daily for 14 consecutive days every 28 days, over a 28-day cycle. Cycles should be repeated every 28 days.

The recommended maintenance schedule is 1.25 mg/m² administered subcutaneously twice daily for 7 consecutive days every 28 days, over a 28-day cycle. Treatment should continue as long as patients are clinically benefiting from therapy.

Omacetaxine is a cancer medicine that interferes with the growth and spread of cancer cells in the body.

Omacetaxine is used to treat chronic myeloid leukemia (CML).

Omacetaxine is usually given after other cancer medications have been tried without success.

Omacetaxine may also be used for purposes not listed in this medication guide.

• 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.)

Myelosuppression

In uncontrolled trials with Synribo, patients with chronic phase and accelerated phase CML experienced NCI CTC (version 3.0) Grade 3 or 4 thrombocytopenia (85%, 88%), neutropenia (81%, 71%), and anemia (62%, 80%), respectively. Fatalities related to myelosuppression occurred in 3% of patients in the safety population (N=163). Patients with neutropenia are at increased risk for infections, and should be monitored frequently and advised to contact a physician if they have symptoms of infection or fever.

Monitor complete blood counts weekly during induction and initial maintenance cycles and every two weeks during later maintenance cycles, as clinically indicated. In clinical trials myelosuppression was generally reversible and usually managed by delaying next cycle and/or reducing days of treatment with Synribo [see Dosage and Administration (2.3) and Adverse Reactions (6.1)].

Bleeding

Synribo causes severe thrombocytopenia which increases the risk of hemorrhage. In clinical trials with CP and AP CML patients, a high incidence of Grade 3 and 4 thrombocytopenia (85% and 88%, respectively) was observed. Fatalities from cerebral hemorrhage occurred in 2% of patients treated with Synribo in the safety population. Severe, non-fatal, gastrointestinal hemorrhages occurred in 2% of patients in the same population. Most bleeding events were associated with severe thrombocytopenia.

Monitor platelet counts as part of the CBC monitoring as recommended [see Warnings and Precautions (5.1)]. Avoid anticoagulants, aspirin, and non-steroidal anti-inflammatory drugs (NSAIDs) when the platelet count is less than 50,000/µL as they may increase the risk of bleeding.

Hyperglycemia

Synribo can induce glucose intolerance. Grade 3 or 4 hyperglycemia was reported in 11% of patients in the safety population. Hyperosmolar non-ketotic hyperglycemia occurred in 1 patient treated with Synribo in the safety population. Monitor blood glucose levels frequently, especially in patients with diabetes or risk factors for diabetes. Avoid Synribo in patients with poorly controlled diabetes mellitus until good glycemic control has been established.

Embryo-Fetal Toxicity

Synribo can cause fetal harm when administered to a pregnant woman. Omacetaxine mepesuccinate caused embryo-fetal death in animals. Females of reproductive potential should avoid becoming pregnant while being treated with Synribo. There are no adequate and well-controlled studies of Synribo in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1)].

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).

Omacetaxine mepesuccinate has the following chemical structure:

The molecular formula is C29H39NO9 with a molecular weight of 545.6 g/mol. Synribo for Injection is a sterile, preservative-free, white to off-white, lyophilized powder in a single-dose 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.

The efficacy of Synribo was evaluated using a combined cohort of adult patients with CML from two trials. The combined cohort consisted of patients who had received 2 or more approved TKIs and had, at a minimum, documented evidence of resistance or intolerance to dasatinib and/or nilotinib. Resistance was defined as one of the following: no complete hematologic response (CHR) by 12 weeks (whether lost or never achieved); or no cytogenetic response by 24 weeks (i.e., 100% Ph positive [Ph+]) (whether lost or never achieved); or no major cytogenetic response (MCyR) by 52 weeks (i.e., ≥35% Ph+) (whether lost or never achieved); or progressive leukocytosis. Intolerance was defined as one of the following: 1) Grade 3-4 non-hematologic toxicity that does not resolve with adequate intervention; or 2) Grade 4 hematologic toxicity lasting more than 7 days; or 3) any Grade ≥ 2 toxicity that is unacceptable to the patient. Patients with NYHA class III or IV heart disease, active ischemia or other uncontrolled cardiac conditions were excluded.

Patients were treated with omacetaxine mepesuccinate at a dose of 1.25 mg/m2 administered subcutaneously twice daily for 14 consecutive days every 28 days (induction cycle). Responding patients were then treated with the same dose and twice daily schedule for 7 consecutive days every 28 days (maintenance cycle). Patients were allowed to continue to receive maintenance treatment for up to 24 months. Responses were adjudicated by an independent Data Monitoring Committee (DMC).

Chronic Phase CML (CP CML)

A total of 76 patients with chronic phase CML were included in the efficacy analysis. The demographics were: median age 59 years, 62% were male, 30% were 65 years of age or older, 80% were Caucasian, 5% were African-American, 4% were Asian and 4% were Hispanic. Thirty-six (47%) patients had failed treatment with imatinib, dasatinib, and nilotinib. Most patients had also received prior non-TKI treatments, most commonly hydroxyurea (54%), interferon (30%), and/or cytarabine (29%). The efficacy endpoint was based on MCyR (adjudicated by a DMC).

  Table 5: Efficacy Results Evaluated by DMC for Patients with CP CML

	Patients (N=76)
Primary Response – MCyR
Total with MCyR, n (%)	14 (18.4)
95% confidence interval	(10.5% – 29.0%)
Cytogenetic Response, n (%)
Confirmed complete	6 (7.9)
Confirmed partial	3 (3.9)

  Cytogenetic response evaluation is based on standard cytogenetic analysis (at least 20 metaphases).
Complete: 0% Ph+ cells, Partial > 0% to 35% Ph+ cells

The mean time to MCyR onset in the 14 patients was 3.5 months. The median duration of MCyR for the 14 patients was 12.5 months (Kaplan-Meier estimate).

Accelerated Phase CML (AP CML)

A total of 35 patients with accelerated phase CML were included in the efficacy analysis. The demographics were: median age was 63 years, 57% were male, 46% were 65 years of age or older, 68% were Caucasian, 23% were African-American, 3% were Asian and 3% were Hispanic. Twenty-two (63%) of 35 patients with accelerated phase had failed treatment with imatinib, dasatinib, and nilotinib. Most patients had also received prior non-TKI treatments, most commonly hydroxyurea (43%), interferon (31%), and/or cytarabine (29%). The efficacy endpoint was assessed based on MCyR and MaHR (complete hematologic response [CHR] or no evidence of leukemia [NEL]). The efficacy results for the patients with accelerated phase as adjudicated by the DMC are shown in Table 6.

  Table 6: Efficacy Results Evaluated by DMC for Patients with AP CML

	Patients (N=35)
Primary Response – MaHR
Total with MaHR, n (%)	5 (14.3)
95% confidence interval	(4.5% - 30.3%)
CHR	4 (11.4)
NEL	1 (2.9)
Primary Response – MCyR
Total with MCyR, n (%)	0

  MaHR is defined as complete hematologic response (CHR) or no evidence of leukemia (NEL): CHR - absolute neutrophil count ≥ 1.5 × 109/liter, platelets ≥ 100 × 109/liter, no blood blasts, bone marrow blasts < 5%, no extramedullary disease; NEL - Morphologic leukemia-free state, defined as <5% bone marrow blasts.

The mean time to response onset in the 5 patients was 2.3 months. The median duration of MaHR for the 5 patients was 4.7 months (Kaplan-Meier estimate).

Synribo® (sin-RYE-bo)
(omacetaxine mepesuccinate)
for injection, for subcutaneous use

Read this Instructions for Use before you inject Synribo for the first time and each time you get a refill. Also read the Medication Guide for Synribo.

Before you or your caregiver injects Synribo, your healthcare provider will show you how to properly:

• handle syringes and inject Synribo • dispose of used supplies for injecting Synribo • clean up any spilled Synribo

Important:

• Be sure that you store Synribo exactly as your healthcare provider tells you to. See the section “How should I store Synribo?” in the Medication Guide. • Never try to re-cap the needle. This could cause a needle-stick injury. • If Synribo comes into contact with your skin, wash the area well with soap and water.

Your healthcare provider will arrange for you to receive all of the supplies that you will need for each injection of Synribo:

• syringe with attached needle, containing Synribo for injection • protective eyewear, such as protective eyeglasses (not regular eyeglasses) or face shield • gloves • disposal biohazard container • absorbent pads for use to clean up an accidental spill of Synribo • alcohol swabs • gauze pads

You may also need an adhesive bandage.

Never mix Synribo yourself. If you don’t receive syringes already filled with Synribo, contact your doctor or pharmacy.

Step 1. Preparing to give an injection of Synribo.

• Find a clean flat work surface. • Wash your hands well with soap and water. • Put on a pair of gloves and your protective eyewear before you handle the syringe containing Synribo. Wearing gloves and protective eyewear protects you from splashes or spills. See Figure A. • Look at the date printed on the syringe label to make sure that the expiration date has not passed. Do not use if the expiration date has passed and contact your doctor or pharmacy immediately. • Gather the rest of your supplies and place them on your work surface.

Figure A

Step 2. Choose an injection site.

• You may inject Synribo into your thigh or stomach-area (abdomen). See Figure B. The injection can be given in the back of your arm if a caregiver is giving the injection. See Figure C. • Use a different site for each injection to help decrease tenderness at the injection site. Each injection site should be at least 1 inch away from any recently used injection site. • Do not inject Synribo into areas of your skin that are tender, red, bruised, hard, or that have scars or stretch marks.   Figure B Figure C

Step 3. Prepare the injection site.

• Clean the injection site well with an alcohol wipe and allow it to air dry. See Figure D.

Figure D

Step 4. Inject Synribo.

• Carefully remove the needle cap by pulling, taking care not to stick yourself. See Figure E. • Do not press down on the plunger.

Figure E

• With one hand, pinch skin of injection site between your thumb and forefinger. See Figure F.

Figure F

• With your other hand, hold the syringe at a 45 degree or 90 degree angle to your skin. Use a quick dart-like motion to insert the needle through the skin at the injection site. See Figures G and H. The needle should go through the skin but not into your muscle.   Figure G Figure H • Slowly push down on the plunger with your thumb until syringe is empty. See Figure I.

Figure I

• Stop pinching your skin. Quickly remove needle and then apply pressure on injection site with a dry gauze pad. You can put a small adhesive bandage over the injection site if there is bleeding. See Figure J.

Figure J

• Follow the instructions below for how to dispose of the syringe, needle, and other supplies used to give your injection. Never try to re-cap the needle. This could cause a needle-stick injury. • Remove your gloves. Wash your hands right away with soap and water, and then remove your protective eyewear.

How should I throw away (dispose of) used Synribo syringes, needles, and other supplies?

• Throw away (dispose of) used Synribo syringes, needles, and other used supplies in an appropriate biohazard container. • Return the biohazard container to your healthcare provider for disposal. • Do not place used syringes, needles, or other supplies in a household trash or recycle container. Do not re-cap or clip the used needle. This could cause a needle-stick injury. • Do not throw away the protective eyewear. You will need them for each dose of Synribo.

What should I do in case of an accidental Synribo spill?

• Your healthcare provider will arrange for you to receive supplies to use in case you spill Synribo. • Follow your healthcare provider’s instructions about how to clean up a Synribo spill. • Do not touch a spill unless you are wearing gloves and protective eyewear. • Use an absorbent pad to wipe up the spill. Wash the area with soap and water. Use an extra absorbent pad or paper towel to dry the area. • Place the pad, gloves, and other supplies that were used to clean the spill in the biohazard container. • Call your healthcare provider right away to report the spill.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

  Distributed by:

Teva Pharmaceuticals USA, Inc.

North Wales, PA 19454

SYNIFU-002

Issued: December 2015

Use the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not use extra medicine to make up the missed dose.

If you are receiving this medicine in a clinic or cancer center, call your doctor for instructions if you miss an appointment for your Synribo injection.

If Synribo gets in your eyes, rinse with water and call your doctor right away.

Avoid being near people who are sick or have infections. Tell your doctor at once if you develop signs of infection. Avoid activities that may increase your risk of bleeding or injury. Use extra care to prevent bleeding while shaving or brushing your teeth.

Synribo may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

This medicine can pass into body fluids (urine, feces, vomit). For at least 48 hours after you receive a dose, avoid allowing your body fluids to come into contact with your hands or other surfaces. Caregivers should wear rubber gloves while cleaning up a patient's body fluids, handling contaminated trash or laundry or changing diapers. Wash hands before and after removing gloves. Wash soiled clothing and linens separately from other laundry.