SYNRIBO- omacetaxine mepesuccinate injection, powder, lyophilized, for solution 
Cephalon, Inc.

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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.

SYNRIBO ® (omacetaxine mepesuccinate) for injection, for subcutaneous use Initial U.S. Approval: 2012

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) (1).

DOSAGE AND ADMINISTRATION

  • Induction Dose: 1.25 mg/m2 administered by subcutaneous injection twice daily for 14 consecutive days of a 28-day cycle (2.1).
  • Maintenance Dose: 1.25 mg/m2 administered by subcutaneous injection twice daily for 7 consecutive days of a 28-day cycle (2.2).
  • Dose modifications are needed for toxicity (2.3).

DOSAGE FORMS AND STRENGTHS

Single-dose vial containing 3.5 mg of omacetaxine mepesuccinate as a lyophilized powder (3).

CONTRAINDICATIONS

None. (4)

WARNINGS AND PRECAUTIONS

  • Myelosuppression: severe and fatal thrombocytopenia, neutropenia and anemia. Monitor hematologic parameters frequently (2.3, 5.1).
  • Bleeding: severe thrombocytopenia and increased risk of hemorrhage. Fatal cerebral hemorrhage and severe, non-fatal gastrointestinal hemorrhage (5.1, 5.2).
  • Hyperglycemia: glucose intolerance and hyperglycemia including hyperosmolar non-ketotic hyperglycemia (5.3).
  • Embryo-fetal toxicity: can cause fetal harm. Advise females of reproductive potential to avoid pregnancy (5.4, 8.1).

ADVERSE REACTIONS

Most common adverse reactions (frequency ≥ 20%): thrombocytopenia, anemia, neutropenia, diarrhea, nausea, fatigue, asthenia, injection site reaction, pyrexia, infection, and lymphopenia (6.1).

To report SUSPECTED ADVERSE REACTIONS, contact Teva Pharmaceuticals USA, Inc. at 1-888-483-8279 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 1/2019

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Induction Schedule

2.2 Maintenance Dosing

2.3 Dose Adjustments and Modifications

2.4 Reconstitution Instructions and Handling Precautions

2.5 Storage Conditions and Storage Time after Preparation of Syringes

2.6 Considerations for Home Administration

2.7 Disposal and Accidental Spillage Procedures

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Myelosuppression

5.2 Bleeding

5.3 Hyperglycemia

5.4 Embryo-Fetal Toxicity

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Additional Data from Safety Population

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Effect of Gender

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

15 REFERENCES

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

16.2 Storage and Handling

17 PATIENT COUNSELING INFORMATION

*
Sections or subsections omitted from the full prescribing information are not listed.

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

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).

2 DOSAGE AND ADMINISTRATION

2.1 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.

2.2 Maintenance Dosing

The recommended maintenance schedule is 1.25 mg/m2 administered subcutaneously twice daily at 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.

2.3 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)].

Perform complete blood counts (CBCs) 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.

2.4 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.

2.5 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

2.6 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.

2.7 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.

3 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-dose vial.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 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)].

5.2 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.

5.3 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.

5.4 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)].

6 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.

6.1 Clinical Trials Experience

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). 

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 Occurringa in at Least 10% of Patients (Chronic Myeloid Leukemia – Chronic Phase)
  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 reactionsb

38 (35)

0

Infections and Infestationsc

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

a   Occurred in the period between the first dose and 30 days after the last dose. 

b  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.

c   Infection includes bacterial, viral, fungal, and non-specified.

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 Occurringa in at Least 10% of Patients (Chronic Myeloid Leukemia – Accelerated Phase)
  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 reactionsb

12 (22)

0

Infections and Infestationsc

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)

a   Occurred in the period between the first dose and 30 days after the last dose.

b    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.

c    Infection includes bacterial, viral, fungal, and non-specified.

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 Accelerate Phase
  % %
Hematology Parameters    

Hemoglobin Decreased

62

80

Leukocytes Decreased

72

61

Neutrophils Decreased

81

71

Platelets Decreased

85

88

Biochemistry Parameters

   

Alanine aminotransferase (ALT) Increased

6

2

Bilirubin Increased

Creatinine Increased

9

6

9

16

Glucose Increased

10

15

Uric Acid Increased

56

57

Glucose Decreased

8

6

6.2 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.

8 USE IN SPECIFIC POPULATIONS

8.1 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.

8.3 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.

8.4 Pediatric Use

The safety and effectiveness of SYNRIBO in pediatric patients have not been established.

8.5 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.

8.6 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.

10 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.

11 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:

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.

12 CLINICAL PHARMACOLOGY

12.1 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.

12.2 Pharmacodynamics

Cardiac Electrophysiology

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.

12.3 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%.

Elimination

The terminal elimination half-life of omacetaxine mepesuccinate in plasma is 14.6 hours.

Metabolism

Omacetaxine mepesuccinate is primarily hydrolyzed to 4′-DMHHT via plasma esterases with little hepatic microsomal oxidative and/or esterase-mediated metabolism in vitro.

Excretion

Following a single subcutaneous dose of radiolabeled omacetaxine mepesuccinate, the mean total recovery of radioactivity in excreta was approximately 81% of the radioactive dose. Approximately 37% of the radioactivity was recovered in urine and approximately 44% in feces.

Drug Interaction Studies

Cytochrome P450 (CYP) Enzymes: Omacetaxine mepesuccinate and 4′-DMHHT do not inhibit major CYP enzymes in vitro at concentrations that can be expected clinically. The potential for omacetaxine mepesuccinate or 4′-DMHHT to induce CYP 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.

13 NONCLINICAL TOXICOLOGY

13.1 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.

14 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

   

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).

15 REFERENCES

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

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

SYNRIBO (omacetaxine mepesuccinate) for Injection is supplied in 8 mL clear glass single-dose vial in individual cartons. Each vial contains 3.5 mg of SYNRIBO (omacetaxine mepesuccinate) for Injection (NDC 63459-177-14).

16.2 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.

17 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)]:

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 [see Warnings and Precautions (5.1)].

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 [see Warnings and Precautions (5.2)].

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 [see Warnings and Precautions (5.3)].

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 [see Warnings and Precautions (5.4)]. Advise females to avoid nursing while receiving SYNRIBO [see Use in Specific Populations (8.3)].

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-005

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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):

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:

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?

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:

The most common side effects of SYNRIBO are:

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?

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.

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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:

Important:

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

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.

Figure A

Figure A

Step 2. Choose an injection site.

Figure B     

 Figure B

Figure C

Figure C

 

 

Step 3. Prepare the injection site.

Figure D

Figure D

Step 4. Inject SYNRIBO.

Figure E

Figure E

Figure F

Figure F

Figure G

Figure G

Figure H

Figure H

Figure I

Figure I

Figure J

Figure J

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

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

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

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SYNIFU-003

Issued:07/2018

Package/Label Display Panel

carton image

NDC 63459-177-14 Rx only

Single-Use Vial.

Discard unused portion.

Synribo® (omacetaxine mepesuccinate) for Injection

3.5 mg/vial

For Subcutaneous Use Only

Must be Reconstituted Before Use

Medication Guide Required: Each time SYNRIBO is dispensed, give the patient a Medication Guide.

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TEVA

SYNRIBO 
omacetaxine mepesuccinate injection, powder, lyophilized, for solution
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:63459-177
Route of Administration SUBCUTANEOUS
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
OMACETAXINE MEPESUCCINATE (UNII: 6FG8041S5B) (OMACETAXINE - UNII:84MI6OYN4Z) OMACETAXINE MEPESUCCINATE 3.5 mg  in 1 mL
Inactive Ingredients
Ingredient Name Strength
MANNITOL (UNII: 3OWL53L36A)  
Packaging
# Item Code Package Description Marketing Start Date Marketing End Date
1 NDC:63459-177-14 1 in 1 CARTON 11/19/2012
1 1 mL in 1 VIAL, SINGLE-USE; Type 0: Not a Combination Product
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: 1/2019
Document Id: cbbbb180-0cb1-4290-842a-828242b6d322
Set id: 83a504ef-cf92-467d-9ecf-d251194a3484
Version: 12
Effective Time: 20190115
 
Cephalon, Inc.