Gao Rui Te

Gao Rui Te 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).

Induction Schedule

The recommended starting schedule for induction is 1.25 mg/m²administered subcutaneously twice daily 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/m²administered subcutaneously twice daily for 7 consecutive days every 28 days, over a 28-day cycle. Treatment should continue as long as patients are clinically benefiting from therapy.

Dose Adjustments And Modifications

Hematologic Toxicity

Gao Rui Te treatment cycles may be delayed and/or the number of days of dosing during the cycle reduced for hematologic toxicities (e.g. neutropenia, thrombocytopenia).

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 Gao Rui Te until toxicity is resolved.

Preparation And Administration Precautions

Gao Rui Te should be prepared in a healthcare facility and administered by a healthcare professional. Omacetaxine mepesuccinate is an antineoplastic product. Follow special handling and disposal procedures.

Reconstitute Gao Rui Te 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 will contain 3.5 mg/mL Gao Rui Te.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Avoid contact with the skin. If Gao Rui Te comes into contact with skin, immediately and thoroughly wash affected area with soap and water.

Use Gao Rui Te within 12 hours of reconstitution when stored at room temperature and within 24 hours of reconstitution if stored at 2°C to 8°C (36°F to 46°F). Protect reconstituted solution from light. After administration, any unused solution should be discarded properly¹.

None.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Myelosuppression

In uncontrolled trials with Gao Rui Te, 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 Gao Rui Te.

Bleeding

Gao Rui Te 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 Gao Rui Te 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. 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

Gao Rui Te 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 Gao Rui Te in the safety population. Monitor blood glucose levels frequently, especially in patients with diabetes or risk factors for diabetes. Avoid Gao Rui Te in patients with poorly controlled diabetes mellitus until good glycemic control has been established.

Embryo-Fetal Toxicity

Gao Rui Te 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 Gao Rui Te. There are no adequate and well-controlled studies of Gao Rui Te 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.

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. Gao Rui Te 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.

Use In Specific Populations

Pregnancy

Pregnancy Category D

Based on its mechanism of action and findings from animal studies, Gao Rui Te 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. 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 Gao Rui Te 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.

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

• Myelosuppression
• Bleeding
• Hyperglycemia

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 Gao Rui Te 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/m²administered 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 reactions (Table 1).

Table 1: Adverse Reactions Occurring^a in at Least 10% of Patients (Chronic Myeloid Leukemia – Chronic Phase)

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 2).

Table 2: Adverse Reactions Occurring^a in at Least 10% of Patients (Chronic Myeloid Leukemia – Accelerated Phase)

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 3. Myelosuppression occurred in all patients treated with Gao Rui Te. Five patients with chronic phase CML and 4 patients with accelerated phase CML permanently discontinued Gao Rui Te 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 Gao Rui Te due to elevated transaminases.

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

Additional Data From Safety Population

The following adverse reactions were reported in patients in the Gao Rui Te 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.

A patient in the clinical program received an overdose of 2.5 mg/m²twice daily for 5 days. The patient presented with gastrointestinal disorders, gingival hemorrhage, alopecia, and Grade 4 thrombocytopenia and neutropenia. When Gao Rui Te 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 Gao Rui Te was restarted.

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/m²twice 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.