SYNRIBO

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

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 [36o F to 46o F])

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.

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