Medication Guide App

Synribo

Generic Name: omacetaxine mepesuccinate
Dosage Form: injection, powder, lyophilized, for solution

Indications and Usage for Synribo

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).

Synribo Dosage and Administration

Induction Schedule

The recommended starting schedule for induction is 1.25 mg/m2 administered subcutaneously twice daily at approximately 12 hour intervals for 14 consecutive days every 28 days, over a 28-day cycle. Cycles should be repeated every 28 days until patients achieve a hematologic response.

Maintenance Dosing

The recommended maintenance schedule is 1.25 mg/m2 administered subcutaneously twice daily approximately 12 hour intervals for 7 consecutive days every 28 days, over a 28-day cycle. Treatment should continue as long as patients are clinically benefiting from therapy.

Dose Adjustments and Modifications

Hematologic Toxicity:

Synribo treatment cycles may be delayed and/or the number of days of dosing during the cycle reduced for hematologic toxicities (e.g. neutropenia, thrombocytopenia) [see Warnings and Precautions (5.1)].

Complete blood counts (CBCs) should be performed weekly during induction and initial maintenance cycles. After initial maintenance cycles, monitor CBCs every two weeks or as clinically indicated. If a patient experiences Grade 4 neutropenia (absolute neutrophil count (ANC) less than 0.5 x 109/L) or Grade 3 thrombocytopenia (platelet counts less than 50 x 109/L) during a cycle, delay starting the next cycle until ANC is greater than or equal to 1.0 x 109/L and platelet count is greater than or equal to 50 x 109/L. Also, for the next cycle, reduce the number of dosing days by 2 days (e.g. to 12 or 5 days).

Non-Hematologic Toxicity:

Manage other clinically significant non-hematologic toxicity symptomatically. Interrupt and/or delay Synribo until toxicity is resolved.

Reconstitution Instructions and Handling Precautions

Synribo should be prepared in a healthcare facility and must be reconstituted by a healthcare professional.

Reconstitute Synribo with one mL of 0.9% Sodium Chloride Injection, USP, prior to subcutaneous injection. After addition of the diluent, gently swirl until a clear solution is obtained. The lyophilized powder should be completely dissolved in less than one minute. The resulting solution is clear and colorless and contains 3.5 mg/mL Synribo. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Synribo does not contain antimicrobial preservatives. Therefore care must be taken to ensure that the solution for injection is not contaminated during preparation.

Synribo is a cytotoxic drug. Follow special handling and disposal procedures1. Wear protective eyewear and gloves during handling and administration of the product. Proper aseptic technique should be used. Avoid skin and eye contact. If Synribo comes into contact with skin, immediately and thoroughly wash affected area with soap and water. If contact with the eyes occurs, thoroughly flush the eyes with water.

Storage Conditions and Storage Time after Preparation of Syringes

If Synribo is not used immediately after reconstitution, follow in-use storage conditions and allowable storage times prior to use as instructed in Table 1. Do not administer Synribo outside of the storage conditions and timeframes listed in Table 1.

Table 1: Storage Conditions and Storage Time after Preparation of Syringes

Storage Conditions

Storage Time

Room temperature (20°C to 25°C [68°F to 77°F])

Use within 12 hours of reconstitution

Refrigerated (2°C to 8°C [36oF to 46oF])

Use within 6 days (144 hours) of reconstitution

Considerations for Home Administration

Before a decision is made to allow Synribo to be administered by someone other than a healthcare professional, ensure that the patient is an appropriate candidate for self-administration or for administration by a caregiver. Provide training on proper handling, storage conditions, administration, disposal, and clean-up of accidental spillage of the product. Ensure that patients receive the necessary supplies for home administration. At minimum these should include:

Reconstituted Synribo in syringe with a capped needle for subcutaneous injection. Syringe(s) should be filled to the patient-specific dose.
Protective eyewear
Gloves
An appropriate biohazard container
Absorbent pad(s) for placement of administration materials and for accidental spillage
Alcohol swabs
Gauze pads
Ice packs or cooler for transportation of reconstituted Synribo syringes

If a patient or caregiver cannot be trained for any reason, then in such patients, Synribo should be administered by a healthcare professional.

Disposal and Accidental Spillage Procedures

After administration, any unused solution should be discarded properly1. Instruct patients planning home administration on the following: do not recap or clip the used needle, and do not place used needles, syringes, vials, and other used supplies in a household trash or recycling bin. Used needles, syringes, vials, and other used supplies should be disposed of in an appropriate biohazard container.

If accidental spillage occurs, continue to use protective eyewear and gloves, wipe the spilled liquid with the absorbent pad, and wash the area with water and soap. Then, place the pad and gloves into the biohazard container and wash hands thoroughly. Return the biohazard container to the clinic or pharmacy for final disposal.

Dosage Forms and Strengths

Synribo for Injection contains 3.5 mg omacetaxine mepesuccinate; as a sterile, preservative-free, white to off-white lyophilized powder in a single-use vial.

Contraindications

None.

Warnings and Precautions

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)].

Adverse Reactions

The following serious adverse reactions have been associated with Synribo in clinical trials and are discussed in greater detail in other sections of the label.

Myelosuppression [see Warnings and Precautions (5.1)]
Bleeding [see Warnings and Precautions (5.2)]
Hyperglycemia [see Warnings and Precautions (5.3)]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety data for Synribo are from 3 clinical trials which enrolled a total of 163 adult patients with TKI resistant and/or intolerant chronic phase (N=108) and accelerated phase (N=55) CML. All patients were treated with initial induction therapy consisting of 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 a twice daily schedule for 7 consecutive days every 28 days (maintenance cycle).

Clinical Trials Experience

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 reaction (Table 2).

Table 2: Adverse Reactions Occurring* in at Least 10% of Patients (Chronic Myeloid Leukemia - Chronic Phase)
*
Occurred in the period between the first dose and 30 days after the last dose.
Includes infusion related reaction, injection site erythema, injection site hematoma, injection site hemorrhage, injection site hypersensitivity, injection site induration, injection site inflammation, injection site irritation, injection site mass, injection site edema, injection site pruritus, injection site rash, and injection site reaction.
Infection includes bacterial, viral, fungal, and non-specified.

Number (%) of Patients
(N=108)

Adverse reactions

All reactions

Grade 3 or 4 reactions

Patients with at least 1 commonly occurring adverse reaction

107 (99)

94 (87)

Blood and Lymphatic System Disorders

 
Thrombocytopenia

82 (76)

73 (68)

 
Anemia

66 (61)

39 (36)

 
Neutropenia

57 (53)

51 (47)

 
Lymphopenia

18 (17)

17 (16)

 
Bone Marrow Failure

11 (10)

11 (10)

 
Febrile Neutropenia

11 (10)

11 (10)

Gastrointestinal Disorders

 
Diarrhea

44 (41)

1 (1)

 
Nausea

38 (35)

1 (1)

 
Constipation

15 (14)

0

 
Abdominal Pain/Upper Abdominal Pain

25 (23)

0

 
Vomiting

13 (12)

0

General Disorders and Administration Site Conditions

 
Fatigue

31 (29)

5 (5)

 
Pyrexia

27 (25)

1 (1)

 
Asthenia

25 (23)

1 (1)

 
Edema Peripheral

17 (16)

0

 
Infusion and injection site related reactions

38 (35)

0

Infections and Infestations

52 (48)

12 (11)

Metabolism and Nutrition Disorders

 
Anorexia

11 (10)

1 (1)

Musculoskeletal and Connective Tissue Disorders

 
Arthralgia

20 (19)

1 (1)

 
Pain in Extremity

14 (13)

1 (1)

 
Back Pain

13 (12)

2 (2)

 
Myalgia

12 (11)

1 (1)

Nervous System Disorders

 
Headache

22 (20)

1 (1)

Psychiatric Disorders

 
Insomnia

13 (12)

1 (1)

Respiratory, Thoracic and Mediastinal Disorders

 
Cough

17 (16)

1 (1)

 
Epistaxis

18 (17)

1 (1)

Skin and Subcutaneous Tissue Disorders

 
Alopecia

16 (15)

0

 
Rash

12 (11)

0

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 (Table 3).

Table 3: Adverse Reactions Occurring* in at Least 10% of Patients (Chronic Myeloid Leukemia - Accelerated Phase)
*
Occurred in the period between the first dose and 30 days after the last dose.
Includes infusion related reaction, injection site erythema, injection site hematoma, injection site hemorrhage, injection site hypersensitivity, injection site induration, injection site inflammation, injection site irritation, injection site mass, injection site edema, injection site pruritus, injection site rash, and injection site reaction.
Infection includes bacterial, viral, fungal, and non-specified.

Number (%) of Patients
(N=55)

Adverse reactions

All reactions

Grade 3 or 4 reactions

Patients with at least 1 commonly occurring adverse reaction

55 (100)

47 (86)

Blood and Lymphatic System Disorders

 
Anemia

28 (51)

21 (38)

 
Febrile Neutropenia

11 (20)

9 (16)

 
Neutropenia

11 (20)

10 (18)

 
Thrombocytopenia

32 (58)

27 (49)

Gastrointestinal Disorders

 
Diarrhea

19 (35)

4 (7)

 
Nausea

16 (29)

2 (4)

 
Vomiting

9 (16)

1 (2)

 
Abdominal Pain/Upper Abdominal Pain

9 (16)

0

General Disorders and Administration Site Conditions

 
Fatigue

17 (31)

5 (9)

 
Pyrexia

16 (29)

1 (2)

 
Asthenia

13 (24)

1 (2)

 
Chills

7 (13)

0

 
Infusion and injection site related reactions

12 (22)

0

Infections and Infestations

31 (56)

11 (20)

Metabolism and Nutrition Disorders

 
Anorexia

7 (13)

1 (2)

Musculoskeletal and Connective Tissue Disorders

 
Pain in Extremity

6 (11)

1 (2)

Nervous System Disorders

 
Headache

7 (13)

0

Respiratory, Thoracic and Mediastinal Disorders

 
Cough

8 (15)

0

 
Dyspnea

6 (11)

1 (2)

 
Epistaxis

6 (11)

1 (2)

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%), and diarrhea (6%). 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 4. 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.

Table 4: Grade 3/4 Laboratory Abnormalities in Clinical Studies in Patients with Chronic Phase and Accelerated Phase CML

Chronic Phase

Accelerated Phase

%

%

Hematology Parameters

Hemoglobin Decreased

62

72

80

Leukocytes Decreased

61

 

Neutrophils Decreased

81

85

71

Platelets Decreased

88

 

Biochemistry Parameters

Alanine aminotransferase (ALT) Increased

6

2

Bilirubin Increased

Creatinine Increased

9

9

6

16

Glucose Increased

10

15

Uric Acid Increased

56

57

Glucose Decreased

8

6

Additional Data From Safety Population

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.

Vascular Disorders: hematoma, hypertension, hot flush, hypotension.

Drug Interactions

Based on the findings from in vitro drug interaction studies with Synribo, no clinical drug interaction trials were warranted [see Clinical Pharmacology (12.3)].

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category D [see Warnings and Precautions (5.4)]

Risk Summary

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.

Animal Data

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.

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.

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.

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 been conducted.

Effect of 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.

Overdosage

A patient in the clinical expanded access program received an overdose of 2.5 mg/m2 twice daily for 5 days in the 16th cycle. The patient presented with gastrointestinal disorders, gingival hemorrhage, alopecia, and Grade 4 thrombocytopenia and neutropenia. When Synribo treatment was temporarily interrupted the gastrointestinal disorders and hemorrhagic syndrome resolved, and neutrophil values returned to within normal range. The alopecia and thrombocytopenia (Grade 1) improved, and Synribo was restarted.

No specific antidote for Synribo overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters.

Synribo Description

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-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.

Synribo - Clinical Pharmacology

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 Bcr-Abl 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.

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.

Drug Interactions

Cytochrome P450 Enzymes (CYPs): Omacetaxine mepesuccinate is not a substrate of CYP450 enzymes in vitro. Omacetaxine mepesuccinate and 4′-DMHHT do not inhibit major CYPs in vitro at concentrations that can be expected clinically. The potential for omacetaxine mepesuccinate or 4′-DMHHT to induce CYP450 enzymes has not been determined.

Transporter Systems: Omacetaxine mepesuccinate is a P-glycoprotein (P-gp) substrate in vitro. Omacetaxine mepesuccinate and 4′-DMHHT do not inhibit P-gp mediated efflux of loperamide in vitro at concentrations that can be expected clinically.

Assessment for Risk of QT Prolongation

In an uncontrolled pharmacokinetic study there were no reports of QTcF > 480 ms or ΔQTcF > 60 ms in 21 treated patients who received omacetaxine mepesuccinate 1.25 mg/m2 BID for 14 consecutive days. There was no evidence for concentration-dependent increases in QTc for omacetaxine mepesuccinate or 4’-DMHHT. Although the mean effect on QTc was 4.2 ms (upper 95% CI: 9.5 ms), QTc effects less than 10 ms cannot be verified due to the absence of a placebo and positive controls.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

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

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

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)

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
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.

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

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).

REFERENCES

1.
OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html.

How Supplied/Storage and Handling

16.1 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 and Handling

Store unopened vials at 20oC to 25ºC (68o F to 77ºF); excursions permitted from 15ºC to 30ºC (59ºF to 86ºF) [see USP Controlled Room Temperature]. Prior to re-constitution, keep product in carton to protect from light.

Omacetaxine mepesuccinate is a cytotoxic drug. Follow special handling and disposal procedures1.

Patient Counseling Information

Availability of Medication Guide and Instructions for Use

Advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). Assist patients and caregivers in understanding their contents and give them the opportunity to discuss the contents of the Medication Guide and Instructions for Use and to obtain answers to any questions they may have prior to initiating therapy. The complete text of the Medication Guide and Instructions for Use are attached to the prescribing information.

Patient Training

Once it is determined that a patient is an appropriate candidate for self-administration or administration by a caregiver, ensure that patients receive the necessary supplies for home administration of Synribo and train them on the following [see Dosage and Administration (2.4, 2.5, 2.6, 2.7)]:

How to transport reconstituted Synribo in a secure container or packaging and under recommended temperature conditions
Acceptable storage conditions and use times for reconstituted Synribo
o
When stored in a refrigerator (2°C to 8°C [36°F to 46°F]), use within 6 days (144 hours)
o
When stored at room temperature (not to exceed 25°C [77°F]), use within 12 hours
If stored in a refrigerator, keep Synribo from coming into contact with food or drink.
To wear disposable gloves and protective eyewear when handling Synribo.
To wash hands before putting on gloves and after removing gloves.
Not to eat or drink while handling Synribo. To administer Synribo in an area away from food or food preparation areas.
To administer Synribo in a location away from children and pregnant women.
Proper subcutaneous injection technique including acceptable sites.
The importance of body site selection for administering the injection, as well as the importance of alternating the injection sites. Advise patients to not inject Synribo into areas of the skin that are tender, red, bruised, hard, or that have scars or stretch marks.
In the case of a missed dose: If a patient misses an injection, skip the missed dose and the patient should give the next scheduled injection at the next scheduled time. Inform patients NOT to give two injections to make up for a missed injection.
In the case that Synribo comes into contact with a patient’s skin or eyes: Advise patients to wash exposed skin with soap and water and in the case of eye exposure, thoroughly flush the eye with water. After washing or flushing, advise patients to call their healthcare provider immediately.
In the case that too much Synribo is injected or that Synribo is accidentally swallowed: Instruct patients to contact their healthcare provider immediately if they have injected too much Synribo, or if someone has swallowed Synribo.
Disposal procedures, including use of an appropriate biohazard container and return of the container to the clinic or pharmacy for final disposal. Inform patients NOT to recap or clip the used needle and not to place used needles, syringes, vials, and other used supplies in a household trash or recycle container.
Accidental spillage procedures, including wiping the spilled liquid with the absorbent pad (using protective eyewear and gloves), washing the area with water and soap, and proper disposal of materials.

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). Instruct patients to report in advance if they plan to have any dental or surgical procedures.

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 health 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 Distress

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.

SYN-003

Distributed by:

Teva Pharmaceuticals USA, Inc.

North Wales, PA 19454

MEDICATION GUIDE

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

Read this Medication Guide before you start using Synribo and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment.

What is the most important information I should know about Synribo?

Synribo can cause serious side effects including:

Low blood counts. Low blood counts are common when using Synribo, including low red blood cells, white blood cells, and platelets, and can be severe. If your white blood cell count becomes very low, you are at increased risk for infection which can lead to death. Your healthcare provider will check your blood counts regularly during treatment with Synribo. Tell your healthcare provider right away if you get any of the following symptoms:

fever
feeling very tired
chills
shortness of breath
body aches
bleeding (see below)

Bleeding. Synribo causes severe low platelet counts that may increase your risk of severe bleeding. Severe low platelet counts can cause you to have bleeding in your brain or severe stomach bleeding, that can lead to death. Your healthcare provider will check your platelet counts regularly during treatment with Synribo. Tell your healthcare provider right away if you get any of the following symptoms:

unusual bleeding
confusion
easy bruising
slurred speech
blood in urine or stool
vision changes

See “What are the possible side effects of Synribo?” for more information about side effects.

What is Synribo?

Synribo is a prescription medicine used to treat adults with a type of blood cancer (leukemia) called chronic myeloid leukemia (CML):

that is in the chronic phase or accelerated phase, and
who have not responded to (resistant) or cannot tolerate 2 or more medicines called tyrosine kinase inhibitors.

It is not known if Synribo is safe and effective in children.

What should I tell my healthcare provider before using Synribo?

Before using Synribo, tell your healthcare provider if you:

have diabetes or a family history of diabetes
have bleeding problems
plan to have any dental or surgical procedures
have any other medical problems
are pregnant or plan to become pregnant.Synribo can harm your unborn baby. You should not become pregnant during treatment with Synribo. Tell your healthcare provider right away if you become pregnant during treatment with Synribo.
are breastfeeding or plan to breastfeed. It is not known if Synribo passes into your breast milk. You and your healthcare provider should decide if you will take Synribo or breastfeed. You should not do both.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.

How should I use Synribo?

Follow the detailed Instructions for Use at the end of this Medication Guide for information about the right way to:
o
properly handle and inject Synribo
o
dispose of used supplies for injecting Synribo
o
clean up any spilled Synribo
Your healthcare provider will tell you how much Synribo to inject and the timing of when to inject it. Inject Synribo exactly as prescribed.
Do not change your dose or the timing of when you inject Synribo, unless your healthcare provider tells you to.
Synribo is given as an injection under the skin (subcutaneous injection) of your thigh or stomach-area (abdomen). The injection can be given in the back of the arm if a caregiver is giving the injection.
If your healthcare provider decides that you or a caregiver can inject Synribo, your healthcare provider will show you or your caregiver how to prepare for an injection and how to inject Synribo before you use it for the first time.
Synribo is injected 2 times each day, about every 12 hours.
Your healthcare provider may tell you to stop using Synribo for a period of time, or tell you to use Synribo less often depending on the side effects that you get.
Your healthcare provider will arrange for you to receive syringes filled with Synribo that are ready to inject, along with the other supplies that you will need to inject Synribo. Each syringe contains 1 dose of Synribo as prescribed by your healthcare provider.
Follow your healthcare provider’s instructions for how to carry (transport) Synribo using ice packs or a cooler.
Do not eat or drink while handling Synribo.
You or your caregiver should wear gloves and protective eyewear, for example protective eyeglasses (not regular eyeglasses) or face shield when handling Synribo and while giving your injection.
If you or your caregiver get Synribo on your skin, wash the area with soap and water.
If you or your caregiver get Synribo in your eyes, flush your eyes with water and call your healthcare provider right away.
If you miss a dose of Synribo, just skip the missed dose. Give your next injection of Synribo at your next scheduled time. Do not give 2 doses of Synribo at the same time to make up for a missed dose.
If you inject too much Synribo, call your healthcare provider or go to the nearest emergency room right away. Follow your healthcare provider’s instructions for when you should inject your next dose of Synribo.
If another person accidentally injects themself with Synribo, or if anyone accidentally swallows Synribo, call your doctor or get emergency help right away.

What should I avoid while using Synribo?

Synribo may cause tiredness. Avoid driving, or operating dangerous tools or machinery if you develop tiredness when using Synribo.

What are the possible side effects of Synribo?

Synribo may cause serious side effects, including:

See “What is the most important information I should know about Synribo?
High blood sugar levels (hyperglycemia). Synribo can cause high blood sugar levels. If you have diabetes or are at risk for diabetes, your healthcare provider will check your blood glucose levels often during treatment with Synribo. If you have diabetes or if your blood sugar is not well controlled, your healthcare provider may decide not to start treatment with Synribo until your diabetes is under control first.

The most common side effects of Synribo are:

Infections. See the information about low blood cell counts in the section “What is the most important information I should know about Synribo?”
diarrhea
nausea
tiredness
weakness
redness, swelling, or pain at injection site

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all of the side effects of Synribo. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Synribo?

Carry (transport) Synribo as instructed by your healthcare provider. It is important to use ice packs or a cooler.
When stored in a refrigerator 36°F to 46°F (2°C to 8°C), use Synribowithin 6 days from when it was mixed.
When stored at room temperature, 68°F to 77°F (20°C to 25°C), use Synribo within 12 hours from when it was mixed.
When stored in a refrigerator, keep Synribo from coming into contact with food or drink

Keep Synribo and all medicines out of the reach of children.

General information about the safe and effective use of Synribo.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Synribo for a condition for which it was not prescribed. Do not give Synribo to other people even if they have the same symptoms you have. It may harm them.

If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Synribo that is written for health professionals.

For more information, go to www.Synribo.com or call Teva at 1-800-896-5855.

What are the ingredients in Synribo?

Active ingredient: omacetaxine mepesuccinate

Inactive ingredients: mannitol

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Distributed by:

Teva Pharmaceuticals USA, Inc.

North Wales, PA 19454

SYNMG-001

Issued: April 2014

Instructions for Use

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 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.

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.
Gather the rest of your supplies and place them on your work surface.

Step 2. Choose an injection site.

You may inject Synribo into your thigh or stomach-area (abdomen). See Figure A. The injection can be given in the back of your arm if a caregiver is giving the injection. See Figure B.
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 A Figure B

Step 3. Prepare the injection site.

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

Figure C

Step 4. Inject Synribo.

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

Figure D

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

Figure E

With your other hand, hold the syringeat 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 F and G. The needle should go through the skin but not into your muscle.

Figure F Figure G

Slowly push down on the plunger with your thumb until syringe is empty. See Figure H.

Figure H

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 I.

Figure I

Follow the instructions below for how to dispose of the syringe, needle, and other supplies used to give your injection.
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 recap or clip the used needle.
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-001

Issued: April 2014

Package/Label Display Panel, Part 1 of 2

Package/Label Display Panel, Part 2 of 2

SynriboTM (Omacetaxine Mepesuccinate) for Injection 3.5 mg/vial, Single-Use Vial Carton Text

NDC 63459-177-14 Rx only

Single-Use Vial.
Discard unused portion.

SynriboTM
(omacetaxine mepesuccinate)
for Injection

3.5 mg/vial

For Subcutaneous Use Only
Must be Reconstituted Before Use

Distributed by:
Teva Pharmaceuticals USA, Inc.
North Wales, PA 19454

TEVA

Synribo 
omacetaxine mepesuccinate injection, powder, lyophilized, for solution
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:63459-177
Route of Administration SUBCUTANEOUS DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
OMACETAXINE MEPESUCCINATE (OMACETAXINE) OMACETAXINE MEPESUCCINATE 3.5 mg  in 1 mL
Inactive Ingredients
Ingredient Name Strength
MANNITOL  
Packaging
# Item Code Package Description
1 NDC:63459-177-14 1 VIAL, SINGLE-USE in 1 CARTON
1 1 mL in 1 VIAL, SINGLE-USE
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA203585 11/19/2012
Labeler - Cephalon, Inc. (183236314)
Revised: 05/2014
 
Cephalon, Inc.
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