Ai Yang

First Line Acute Lymphoblastic Leukemia (ALL)

Ai Yang® is indicated as a component of a multi-agent chemotherapeutic regimen for the first line treatment of patients with ALL.

Acute Lymphoblastic Leukemia And Hypersensitivity To Asparaginase

Ai Yang® is indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of patients with ALL and hypersensitivity to native forms of L-asparaginase.

Recommended Dose

The recommended dose of Ai Yang® is 2,500 International Units/m² intramuscularly or intravenously. Ai Yang® should be administered no more frequently than every 14 days.

Instructions For Administration

When Ai Yang® is administered intramuscularly, the volume at a single injection site should be limited to 2 mL. If the volume to be administered is greater than 2 mL, multiple injection sites should be used. Ai Yang® does not contain a preservative. Use only one dose per vial; discard unused product.

When administered intravenously, Ai Yang® should be given over a period of 1 to 2 hours in 100 mL of sodium chloride or dextrose injection 5%, through an infusion that is already running. After the solution is diluted for intravenous use, the solution should be used immediately. If immediate use is not possible, the diluted solution should be stored refrigerated at 2°C to 8°C (36°F to 46°F). Storage after dilution should not exceed 48 hours from the time of preparation to completion of administration. Protect infusion bags from direct sunlight.

Preparation And Handling Precautions

Do not administer Ai Yang® if drug has been:

• frozen
• stored at room temperature 15° to 25°C (59° to 77°F) for more than 48 hours
• shaken or vigorously agitated

Parenteral drug products should be inspected visually for particulate matter, cloudiness, or discoloration prior to administration, whenever solution and container permit. If any of these are present, discard the vial.

• History of serious allergic reactions to Ai Yang®.
• History of serious thrombosis with prior L-asparaginase therapy.
• History of pancreatitis with prior L-asparaginase therapy.
• History of serious hemorrhagic events with prior L-asparaginase therapy.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Anaphylaxis And Serious Allergic Reactions

Anaphylaxis and serious allergic reactions can occur in patients receiving Ai Yang®. The risk of serious allergic reactions is higher in patients with known hypersensitivity to other forms of L-asparaginase. Observe patients for 1 hour after administration of Ai Yang® in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (for example, epinephrine, oxygen, intravenous steroids, antihistamines). Discontinue Ai Yang® in patients with serious allergic reactions.

Thrombosis

Serious thrombotic events, including sagittal sinus thrombosis can occur in patients receiving Ai Yang®. Discontinue Ai Yang® in patients with serious thrombotic events.

Pancreatitis

Pancreatitis can occur in patients receiving Ai Yang®. Evaluate patients with abdominal pain for evidence of pancreatitis. Discontinue Ai Yang® in patients with pancreatitis.

Glucose Intolerance

Glucose intolerance can occur in patients receiving Ai Yang®. In some cases, glucose intolerance is irreversible.

Coagulopathy

Increased prothrombin time, increased partial thromboplastin time, and hypofibrinogenemia can occur in patients receiving Ai Yang®. Monitor coagulation parameters at baseline and periodically during and after treatment. Initiate treatment with fresh-frozen plasma to replace coagulation factors in patients with severe or symptomatic coagulopathy.

Hepatotoxicity And Abnormal Liver Function

Hepatotoxicity and abnormal liver function, including elevations of AST (SGOT), ALT (SGPT), alkaline phosphatase, bilirubin (direct and indirect), and depression of serum albumin, and plasma fibrinogen can occur. Perform appropriate monitoring.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

• No long-term carcinogenicity studies in animals have been performed with Ai Yang®.
• No relevant studies addressing mutagenic potential have been conducted. Ai Yang® did not exhibit a mutagenic effect when tested against Salmonella typhimurium strains in the Ames assay.
• No studies have been performed on impairment of fertility.

Use In Specific Populations

Pregnancy

Pregnancy Category C

Animal reproduction studies have not been conducted with Ai Yang®. It is also not known whether Ai Yang® can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Ai Yang® should be given to a pregnant woman only if clearly needed.

Nursing Mothers

It is not known whether Ai Yang® is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Ai Yang®, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Geriatric Use

Clinical studies of Ai Yang® did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently than younger subjects.

The following serious adverse reactions are described in greater detail in other sections of the label:

• Anaphylaxis and serious allergic reactions
• Serious thrombosis
• Pancreatitis
• Glucose intolerance
• Coagulopathy
• Hepatotoxicity and abnormal liver function

The most common adverse reactions with Ai Yang® are allergic reactions (including anaphylaxis), hyperglycemia, pancreatitis, central nervous system (CNS) thrombosis, coagulopathy, hyperbilirubinemia, hepatotoxicity and elevated transaminases.

Hyperlipidemia (hypercholesterolemia and hypertriglyceridemia) has been reported in patients exposed to Ai Yang.

Clinical Trials Experience

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

First-Line ALL

The data presented below are derived from 2 studies in patients with standard-risk ALL who received Ai Yang® as a component of first-line multi-agent chemotherapy. Study 1 was a randomized (1:1), active-controlled study that enrolled 118 patients, with a median age of 4.7 years (1.1-9.9 years), of whom 54% were males and 65% White, 14% Hispanic, 8% Black, 8% Asian, and 6% other. Of the 59 patients in Study 1 who were randomized to Ai Yang® , 48 patients (81%) received all 3 planned doses of Ai Yang®, 6 (10%) received 2 doses, 4 (7%) received 1 dose, and 1 patient (2%) did not receive the assigned treatment. Study 2 is an ongoing, multi-factorial design study in which all patients received Ai Yang® as a component of various multi-agent chemotherapy regimens; interim safety data are available for 2,770 patients. Study participants had a median age of 4 years (1-10 years), and were 55% male, 68% White, 18% Hispanic, 4% Black, 3% Asian, and 7% other. Per protocol, the schedule of Ai Yang® varied by treatment arm, with intermittent doses of Ai Yang® for up to 10 months.

In Study 1, detailed safety information was collected for pre-specified adverse reactions identified as asparaginase-induced adverse reactions and for grade 3 and 4 non-hematologic adverse reactions according to the Children's Cancer Group (CCG) Toxicity and Complication Criteria. The per-patient incidence, by treatment arm, for these selected adverse reactions occurring at a severity of grade 3 or 4 are presented in Table 1 below:

TABLE 1 : STUDY 1: PER-PATIENT INCIDENCE OF SELECTED GRADE 3 AND 4 ADVERSE REACTIONS

Safety data were collected in Study 2 only for National Cancer Institute Common Toxicity Criteria (NCI CTC) version 2.0, grade 3 and 4 non-hematologic toxicities. In this study, the per-patient incidence for the following adverse reactions occurring during treatment courses in which patients received Ai Yang® were: elevated transaminases, 11%; coagulopathy, 7%; hyperglycemia, 5%; CNS thrombosis/hemorrhage, 2%; pancreatitis, 2%; clinical allergic reaction, 1%; and hyperbilirubinemia, 1%. There were 3 deaths due to pancreatitis.

Previously Treated ALL

Adverse reaction information was obtained from 5 clinical trials that enrolled a total of 174 patients with relapsed ALL who received Ai Yang® as a single agent or in combination with multi-agent chemotherapy. The toxicity profile of Ai Yang® in patients with previously treated relapsed ALL is similar to that reported above with the exception of clinical allergic reactions (see Table 2). The most common adverse reactions of Ai Yang® were clinical allergic reactions, elevated transaminases, hyperbilirubinemia, and coagulopathies. The most common serious adverse events due to Ai Yang® treatment were thrombosis (4%), hyperglycemia requiring insulin therapy (3%), and pancreatitis (1%).

Allergic Reactions

Allergic reactions include the following: bronchospasm, hypotension, laryngeal edema, local erythema or swelling, systemic rash, and urticaria.

First-Line ALL

Among 58 Ai Yang®-treated patients enrolled in Study 1, clinical allergic reactions were reported in 2 patients (3%). One patient experienced a grade 1 allergic reaction and the other grade 3 hives; both occurred during the first delayed intensification phase of the study (see Table 2).

Previously Treated ALL

Among 62 patients with relapsed ALL and prior hypersensitivity reactions to asparaginase, 35 patients (56%) had a history of clinical allergic reactions to native Escherichia (E.) coli L-asparaginase, and 27 patients (44%) had a history of clinical allergic reactions to both native E. coli and native Erwinia L-asparaginase. Twenty (32%) of these 62 patients experienced clinical allergic reactions to Ai Yang® (see Table 2).

Among 112 patients with relapsed ALL with no prior hypersensitivity reactions to asparaginase, 11 patients (10%) experienced clinical allergic reactions to Ai Yang® (see Table 2).

TABLE 2 : INCIDENCE OF CLINICAL ALLERGIC REACTIONS, OVERALL AND BY SEVERITY GRADE

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity, defined as development of binding and/or neutralizing antibodies to the product.

In Study 1, Ai Yang®-treated patients were assessed for evidence of binding antibodies using an enzyme-linked immunosorbent assay (ELISA) method. The incidence of protocol-specified “high-titer” antibody formation was 2% in Induction (n=48), 10% in Delayed Intensification 1 (n=50), and 11% in Delayed Intensification 2 (n=44). There is insufficient information to determine whether the development of antibodies is associated with an increased risk of clinical allergic reactions, altered pharmacokinetics, or loss of anti-leukemic efficacy.

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay, and the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, concomitant medications, and underlying disease. Therefore, comparison of the incidence of antibodies to Ai Yang® with the incidence of antibodies to other products may be misleading.

Three patients received 10,000 International Units/m² of Ai Yang® as an intravenous infusion. One patient experienced a slight increase in liver enzymes. A second patient developed a rash 10 minutes after the start of the infusion, which was controlled with the administration of an antihistamine and by slowing down the infusion rate. A third patient did not experience any adverse reactions.

In Study 1, pharmacodynamics were assessed in 57 newly diagnosed pediatric patients with standard-risk ALL who received three intramuscular doses of Ai Yang® (2,500 International Units/m²), one each during induction and two delayed intensification treatment phases. Pharmacodynamic activity was assessed through serial measurements of asparagine in sera (n=57) and cerebrospinal fluid (CSF) (n=50). The data for asparagine depletion are presented in CLINICAL STUDIES.

Pharmacokinetic assessments were based on an enzymatic assay measuring asparaginase activity. Serum pharmacokinetics were assessed in 34 newly diagnosed pediatric patients with standard-risk ALL in Study 1 following intramuscular administration of 2,500 International Units/m². The elimination half-life of Ai Yang® was approximately 5.8 days during the induction phase. Similar elimination half-lives were observed during Delayed Intensification 1 and Delayed Intensification 2. Concentrations greater than 0.1 International Units/mL were observed in over 90% of the samples from patients treated with Ai Yang® during induction, Delayed Intensification 1, and Delayed Intensification 2 for approximately 20 days.

In 3 pharmacokinetic studies, 37 patients with relapsed ALL received Ai Yang® at 2,500 International Units/m² intramuscularly every 2 weeks. The plasma half-life of Ai Yang® was 3.2 ± 1.8 days in 9 patients who were previously hypersensitive to native E. coli L-asparaginase and 5.7 ± 3.2 days in 28 non-hypersensitive patients. The area under the plasma concentration-time curve (AUC) was 9.5 ± 4.0 International Units/mL/day in the previously hypersensitive patients and 9.8 ± 6.0 International Units/mL/day in the non-hypersensitive patients.