SYNRIBO Powder for solution for injection Ref.[10354] Active ingredients: Omacetaxine mepesuccinate

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

Based on findings from animal reproduction studies and the drug’s mechanism of action, SYNRIBO can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use an effective method of contraception during treatment with SYNRIBO and for 6 months after the final dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)].

Advise males with female partners of reproductive potential to use effective contraception during treatment with SYNRIBO and for 3 months after the final dose [see Use in Specific Populations (8.3)].

The following clinically significant 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)]

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.

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):

^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):

^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 ¾ 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 ¾ Laboratory Abnormalities in Clinical Studies in Patients with Chronic Phase and Accelerated Phase CML:

Risk Summary

Based on its mechanism of action and findings from animal studies, SYNRIBO can cause fetal harm when administered to pregnant women. In animal reproduction studies, subcutaneous administration of omacetaxine mepesuccinate to pregnant mice during organogenesis at doses approximately 0.25-0.5 times the maximum recommended human doses (MRHD) resulted in embryo-fetal mortality, structural abnormalities, and alterations to growth (see Data). There are no available data on SYNRIBO use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Advise pregnant women of the potential risk to a fetus [see Warnings and Precautions (5.4)].

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Animal Data

In an embryo-fetal development study, pregnant mice were administered omacetaxine mepesuccinate subcutaneously during the period of organogenesis at doses of 0.63 or 1.23 mg/m²/day (approximately 0.25-0.5 times the MRHD on a body surface area basis). 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 1.23 mg/m²/day, which is approximately half the recommended daily human dose.

Risk Summary

There are no data on the presence of omacetaxine mepesuccinate in either human or animal milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in the breastfed child, advise patients that breastfeeding is not recommended during treatment with SYNRIBO, and for 2 weeks after the final dose.

Pregnancy Testing

Pregnancy testing is recommended for females of reproductive potential prior to initiating SYNRIBO.

Contraception

Females

SYNRIBO can cause embryo-fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)]. Advise female patients of reproductive potential to use effective contraception during treatment with SYNRIBO and for 6 months after the final dose.

Males

Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with SYNRIBO and for 3 months after the final dose [see Nonclinical Toxicology (13.1)].

Infertility

Males

Based on findings from animal studies, SYNRIBO may impair male fertility. Studies in mice demonstrated adverse effects on male reproductive organs where bilateral degeneration of the seminiferous tubular epithelium in testes and hypospermia/aspermia were observed [see Nonclinical Toxicology (13.1)]. The long-term effects of SYNRIBO on male fertility, including the reversibility of adverse effects, have not been studied.

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

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.