Asparlas
(calaspargase pegol-mknl)Dosage & Administration
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Asparlas Prescribing Information
Acute Lymphoblastic Leukemia
ASPARLAS is indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of acute lymphoblastic leukemia in pediatric and young adult patients age 1 month to 21 years.
Recommended Dosage
The recommended dose of ASPARLAS is 2,500 units/m2 given intravenously no more frequently than every 21 days.
Recommended Premedication
Premedicate patients with acetaminophen, an H-1 receptor blocker (such as diphenhydramine), and an H-2 receptor blocker (such as famotidine) 30-60 minutes prior to administration of ASPARLAS to decrease the risk and severity of both infusion and hypersensitivity reactions [see Warnings and Precautions (5.1)].
Recommended Monitoring and Dosage Modifications for Adverse Reactions
Monitor patients at least weekly with bilirubin, transaminases, glucose, and clinical examinations until recovery from the cycle of therapy. If an adverse reaction should occur, modify treatment according to Table 1.
| Adverse Reaction | Severity * | Action |
|---|---|---|
| ||
| Infusion Reaction/ Hypersensitivity Reaction [see Warnings and Precautions (5.1)] | Grade 1 |
|
| Grade 2 |
| |
| Grade 3 to 4 |
| |
| Pancreatitis [see Warnings and Precautions (5.2)] | Grades 3 to 4 |
|
| Thrombosis [see Warnings and Precautions (5.3)] | Uncomplicated deep vein thrombosis |
|
| Severe or life-threatening thrombosis |
| |
| Hemorrhage [see Warnings and Precautions (5.4)] | Grade 3 to 4 |
|
| Hepatotoxicity [see Warnings and Precautions (5.5)] | Total bilirubin more than 3 times to no more than 10 times the ULN |
|
| Total bilirubin more than 10 times the ULN |
| |
Preparation and Administration
ASPARLAS is a clear and colorless solution. Visually inspect parenteral drug products for particulate matter, cloudiness, or discoloration prior to administration. If any of these are present, discard the vial. Do not administer if ASPARLAS has been shaken or vigorously agitated, frozen, or stored at room temperature for more than 48 hours.
- Dilute ASPARLAS in 100 mL of 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP using sterile/aseptic technique. Discard any unused portion left in a vial.
- After dilution, administer immediately into a running infusion of either 0.9% sodium chloride or 5% dextrose, respectively.
- Administer the dose over a period of 1 hour.
- Do not infuse other drugs through the same intravenous line during administration of ASPARLAS.
- The diluted solution may be stored for up to 4 hours at room temperature (15°C to 25°C [59°F to 77°F]) or refrigerated at 2°C to 8°C (36°F to 46°F) for up to 24 hours.
- Protect from light. Do not shake or freeze.
Injection: 3,750 units/5 mL (750 units/mL) clear, colorless solution in a single-dose vial.
Pregnancy
Risk Summary
Based on published literature studies with L-asparaginase in pregnant animals, ASPARLAS can cause fetal harm when administered to a pregnant woman. There are no available data on ASPARLAS use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, intravenous administration of calaspargase pegol-mknl to pregnant rats during organogenesis at doses 0.2 to 1 times the maximum recommended human doses did not result in adverse developmental outcomes. Published literature studies in pregnant rabbits, however, suggest asparagine depletion may cause harm to the animal offspring (see Data). Advise pregnant women of the potential risk to a fetus.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies are 2 to 4% and 15 to 20%, respectively.
Data
Animal Data
In an embryo-fetal development study, calaspargase pegol-mknl was administered intravenously at doses of 75, 150, and 300 U/kg (0.2, 0.6 and 1 times the maximum recommended human dose, respectively, based on AUC) to pregnant rats during the period of organogenesis. Maternal toxicity of decreased body weight and food consumption was seen at all dose levels resulting in reductions in gravid uterine and placental weights, and slight reductions in fetal body weights. No evidence of structural abnormalities or embryo-fetal mortality were observed in this study at any of the doses tested. Published literature studies in which pregnant rabbits were administered L-asparaginase suggested harm to the animal offspring.
Lactation
Risk Summary
There are no data on the presence of calaspargase pegol-mknl in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for adverse reactions in the breastfed child, advise women not to breastfeed during treatment with ASPARLAS and for 3 months after the last dose.
Females and Males of Reproductive Potential
ASPARLAS can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].
Pregnancy Testing
Pregnancy testing is recommended in females of reproductive potential prior to initiating ASPARLAS.
Contraception
Advise females of reproductive potential to use effective non-hormonal contraceptive methods during treatment with ASPARLAS and for at least 3 months after the last dose.
Pediatric Use
The safety and effectiveness of ASPARLAS in the treatment of ALL have been established in pediatric patients 1 month to <17 years (no data for the age group <1 month old). Use of ASPARLAS in these age groups is supported by evidence from an adequate and well-controlled trial with additional safety from a second trial. The trials included 208 children with ALL or lymphoblastic lymphoma treated with ASPARLAS; there were 19 infants (1 month to <2 years old), 128 children (2 years to <12 years old), and 61 adolescents (12 years to <17 years old). There were no clinically meaningful differences in safety or nadir serum asparaginase activity across age groups [see Adverse Reactions (6.1), Clinical Studies (14)].
ASPARLAS is contraindicated in patients with:
- History of serious hypersensitivity reactions, including anaphylaxis, to pegylated L-asparaginase therapy [see Warnings and Precautions (5.1)]
- History of serious pancreatitis during previous L-asparaginase therapy [see Warnings and Precautions (5.2)]
- History of serious thrombosis during previous L-asparaginase therapy [see Warnings and Precautions (5.3)]
- History of serious hemorrhagic events during previous L-asparaginase therapy [see Warnings and Precautions (5.4)]
- Severe hepatic impairment [see Warnings and Precautions (5.5)]
Hypersensitivity
Grade 3 and 4 hypersensitivity reactions, including anaphylaxis, have been reported in clinical trials with ASPARLAS with an incidence between 7 and 21% [see Contraindications (4), Adverse Reactions (6.1)]. Hypersensitivity reactions observed with other asparaginases include angioedema, lip swelling, eye swelling, erythema, blood pressure decreased, bronchospasm, dyspnea, pruritus, and rash [see Adverse Reactions (6.1)].
Premedicate patients 30-60 minutes prior to administration of ASPARLAS [see Dosage and Administration (2.2)]. Because of the risk of serious allergic reactions (e.g., life-threatening anaphylaxis), administer ASPARLAS in a clinical setting with resuscitation equipment and other agents necessary to treat anaphylaxis (e.g., epinephrine, oxygen, intravenous steroids, antihistamines) [see Dosage and Administration (2.4)] and observe patients for 1 hour after administration. Discontinue ASPARLAS in patients with serious hypersensitivity reactions.
Pancreatitis
Cases of pancreatitis have been reported in clinical trials with ASPARLAS with an incidence between 12 and 16% [see Adverse Reactions (6.1)]. Hemorrhagic or necrotizing pancreatitis have been reported with other asparaginases.
Inform patients of the signs and symptoms of pancreatitis, which, if left untreated, could be fatal. Assess serum amylase and/or lipase levels to identify early signs of pancreatic inflammation. Discontinue ASPARLAS if pancreatitis is suspected; if pancreatitis is confirmed, do not resume ASPARLAS [see Dosage and Administration (2.3)].
Thrombosis
Serious thrombotic events, including sagittal sinus thrombosis, have been reported in clinical trials with ASPARLAS with an incidence of 9 to 12%. Discontinue ASPARLAS in patients experiencing serious thrombotic events [see Dosage and Administration (2.3), Adverse Reactions (6.1)].
Hemorrhage
Hemorrhage associated with increased prothrombin time (PT), increased partial thromboplastin time (PTT), and hypofibrinogenemia have been reported in patients receiving ASPARLAS [see Adverse Reactions (6.1)]. Evaluate patients with signs and symptoms of hemorrhage with coagulation parameters including PT, PTT, fibrinogen. Consider appropriate replacement therapy in patients with severe or symptomatic coagulopathy [see Dosage and Administration (2.3)].
Hepatotoxicity, Including Hepatic Veno-Occlusive Disease
Hepatotoxicity, including severe, life-threatening, and potentially fatal cases of hepatic veno-occlusive disease (VOD), have been observed in patients treated with ASPARLAS in combination with standard chemotherapy, including during the induction phase of multiphase chemotherapy [see Adverse Reactions (6)]. Do not administer ASPARLAS to patients with severe hepatic impairment [see Contraindications (4)].
Evaluate bilirubin and transaminases prior to each dose of ASPARLAS and at least weekly, during cycles of treatment that include ASPARLAS, through 6 weeks after the last dose of ASPARLAS. Monitor frequently for signs and symptoms of hepatic VOD, which may include rapid weight gain, fluid retention with ascites, hepatomegaly (which may be painful), and rapid increase of bilirubin. For patients who develop abnormal liver tests after ASPARLAS, more frequent monitoring for liver test abnormalities and clinical signs and symptoms of VOD is recommended. In the event of serious liver toxicity, including VOD, discontinue treatment with ASPARLAS and provide supportive care [see Dosage and Administration (2.3)].