Elspar (asparaginase) contains the enzyme L-asparagine amidohydro-lase, type EC-2, derived from Escherichia coli. Elspar activity is expressed in terms of International Units according to the recommendation of the International Union of Biochemistry. One International Unit of asparaginase is defined as that amount of enzyme required to generate 1 μmol of ammonia per minute at pH 7.3 and 37°C. The specific activity of Elspar is at least 225 International Units per milligram of protein. Elspar is provided as a sterile, white lyophilized plug or powder. Each vial contains 10, 000 International Units of asparaginase and 80 mg of mannitol.

Last updated on RxList: 10/10/2008

Elspar is indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of patients with acute lymphoblastic leukemia (ALL ).

Recommended Dose

The recommended dose of Elspar is 6, 000 International Units/m² intramuscularly (IM) or intravenously (IV) three times a week.

Instructions for Administration

When Elspar is administered IM, the volume at a single injection site should be limited to 2 mL. If a volume greater than 2 ml is to be administered, two injection sites should be used.

When administered IV, give Elspar over a period of not less than thirty minutes through the side arm of an infusion of Sodium Chloride Injection or Dextrose Injection 5% (D₅W).

Preparation and Handling Precautions

For IM administration, reconstitute Elspar by adding 2 ml Sodium Chloride Injection to the 10, 000 unit vial. Withdraw volume of reconstituted Elspar containing calculated dose into sterile syringe. For IV administration, reconstitute Elspar by adding 5 ml Sterile Water for Injection or Sodium Chloride Injection to the 10, 000 unit vial. Withdraw volume of reconstituted Elspar containing calculated dose into sterile syringe.

Use reconstituted Elspar within eight hours.

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 solution. However, occasionally, a very small number of gelatinous fiber-like particles may develop on standing. Filtration through a 5.0 micron filter during administration will remove the particles with no resultant loss in potency.

Dosage Forms And Strengths

10, 000 International Units as lyophilized powder in single-use vial.

Storage And Handling

Dosage Form

NDC 67386-411-51

10, 000 International Units as lyophilized powder in single dose vial individually packaged in a carton.

Storage and Handling

Keep vials refrigerated at 2-8°C (36-46°F).

Elspar does not contain a preservative. Store unused, reconstituted solution at 2-8°C (36-46°F) and discard after eight hours, or sooner if it becomes cloudy.

Ovation Pharmaceuticals, Inc., Deerfield, IL 60015, U.S.A. Revised: 3/2007. FDA revision date: 3/30/2007

Last updated on RxList: 10/10/2008

The following serious adverse reactions occur with Elspar treatment [See WARNINGS AND PRECAUTIONS]:

• Anaphylaxis and serious allergic reactions
• Serious thrombosis
• Pancreatitis
• Glucose intolerance
• Coagulopathy

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

Clinical Trials and Post-Marketing Experience

The adverse reactions included in this section were identified in single-arm clinical trials in which Elspar was administered as part of a multi-agent regimen or from spontaneous post-marketing reports or published literature.

Because these adverse events were identified in clinical trials that were not designed to isolate the adverse effects of Elspar or were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Serious Adverse Reactions

Anaphylaxis and serious allergic reactions. Allergic reactions have occurred with the first dose and with subsequent doses of Elspar. The risk of serious allergic reactions appears to be higher in patients with prior exposure to Elspar or other Escherichia coli-derived L-asparaginases.

Serious thrombosis, including sagittal sinus thrombosis Pancreatitis, in some cases fulminant or fatal Glucose intolerance, in some cases irreversible

Coagulopathy, including increased prothrombin time, increased partial thromboplastin time, and decreased fibrinogen, protein C, protein S and antithrombin III. CNS hemorrhages have been reported.

Central Nervous System effects including coma, seizures, and hallucinations.

Common Adverse Reactions

Azotemia, liver function abnormalities, including hyperbilirubinemia, and elevated transaminases.

Immunogenicity

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

Elspar is a bacterial protein and can elicit antibodies in patients treated with the drug. In 2 prospectively designed clinical trials (N=59 and 24), approximately one quarter of the patients developed antibodies that bound to Elspar as measured by enzyme-linked immunosorbent assays (ELISA).^{1, 2} Clinical hypersensitivity reactions to Elspar in studies were common ranging from 32.5%³ to 75%.¹ In these studies, con-comitant medications and dosing schedules varied. Patients with hypersensitivity reactions were more likely to have antibodies than those without hypersensitivity reactions.¹ Hypersensitivity reactions have been associated with increased clearance of Elspar.⁴ Incidence of antibody formation was lower upon first administration of Elspar than second administration.^{1, 2} The frequency of antibody formation in adults relative to children is unknown. There is insufficient information to comment on neutralizing antibodies; however, higher levels of antibody correlated with a decrease in asparaginase activity.² 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 Elspar with the incidence of antibodies to other products may be misleading.

No formal drug interaction studies between Elspar and other drugs have been performed.

REFERENCES

1.Wang, B.; Relling, M.V.; Storm, M.C.; Woo, M.H.; Ribeiro, R.; Pui, C.H.; Hak, L.J.: Evaluation of immunologic crossreaction of anti-asparaginase antibodies in acute lymphoblastic leukemia (ALL) and lymphoma patients, Leukemia 17: 1583-1588, 2003.

2. Avramis, V.I.; Sencer, S.; Periclou, A.P.; Sather, H.; Bostrom, B.C.; Cohen, L.J.; Ettinger, A.G.; Ettinger, L.J.; Franklin, J.; Gaynon, P.S.; Hilden, J.M.; Lange, B.; Majlessipour, F.; Mathew, P.; Needle, M.; Neglia, J.; Reaman, G.; Holcenberg, J.S.: A randomized comparison of native Escherichia coli asparaginase and polyethylene glycol conjugated asparaginase for treatment of children with newly diagnosed standard-risk acute lymphoblastic leukemia: a Children's Cancer Group study, Blood 99:1986-1994, 2002.

3. Woo, M.H.; Hak, L.J.; Storm, M.C.; Sandlund, J.T.; Ribeiro, R.C.; Rivera, G.K.; Rubnitz, J.E.; Harrison, P.L.; Wang, B.; Evans, W.E.; Pui, C.H.; Relling, MV:Hypersensitivity or development of antibodies to asparaginase does not impact treatment outcome of childhood acute lymphoblastic leukemia, J.Clin.Oncol. 18(7): 1525-1532, Apr.2000.

4. Asselin, B.L.: The three asparaginases: Comparative pharmacology and optimal use in childhood leukemia, Adv. Exp. Med. Biol. 457: 621-629, 1999.

Last updated on RxList: 10/10/2008

Included as part of the PRECAUTIONS section.

Anaphylaxis and Serious Allergic Reactions

Serious allergic reactions can occur in patients receiving Elspar. The risk of serious allergic reactions is higher in patients with prior exposure to Elspar or other Escherichia coli-derived L-asparaginases. Observe patients for one hour after administration of Elspar in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (for example, epinephrine, oxygen, intravenous steroids, antihistamines).Discontinue Elspar in patients with serious allergic reactions.

Thrombosis

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

Pancreatitis

Pancreatitis, in some cases fulminant or fatal, can occur in patients receiving Elspar. Evaluate patients with abdominal pain for evidence of pancreatitis. Discontinue Elspar in patients with pancreatitis.

Intolerence

Glucose intolerance can occur in patients receiving Elspar. In some cases, glucose intolerance is irreversible. Monitor serum glucose.

Coagulopathy

Increased prothrombin time, increased partial thromboplastin time, and hypofibrinogenemia can occur in patients receiving Elspar. CNS hemorrhages have been observed. 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.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, and Impairment of Fertility

No long-term carcinogenicity studies in animals have been performed with Elspar.

No relevant studies addressing mutagenic potential have been conducted. Elspar 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. In mice and rats Elspar has been shown to retard the weight gain of mothers and fetuses when given in doses of more than 1000 International Units/kg (approximately equivalent to the recommended human dose, when adjusted for total body surface area). Resorptions, gross abnormalities and skeletal abnormalities were observed. The intravenous administration of 50 or 100 International Units/kg (approximately equivalent to 10 to 20% of the recommended human dose, when adjusted for total body surface area) to pregnant rabbits on Day 8 and 9 of gestation resulted in dose dependent embryotoxicity and gross abnormalities. There are no adequate and well-controlled studies in pregnant women. Elspar should be given to a pregnant woman only if clearly needed.

Nursing Mothers

It is not known whether Elspar 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 ELSPAR, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

[See Clinical Studies]

Geriatric Use

Clinical studies of Elspar did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects.

Last updated on RxList: 10/10/2008

No information provided.

• Serious allergic reactions to Elspar or other Escherichia coli-derived L-asparaginases
• Serious thrombosis with prior L-asparaginase therapy
• Pancreatitis with prior L-asparaginase therapy
• Serious hemorrhagic events with prior L-asparaginase therapy

Last updated on RxList: 10/10/2008

Mechanism of Action

The mechanism of action of Elspar is thought to be based on selective killing of leukemic cells due to depletion of plasma asparagine. Some leukemic cells are unable to synthesize asparagine due to a lack of asparagine synthetase and are dependent on an exogenous source of asparagine for survival. Depletion of asparagine, which results from treatment with the enzyme L-asparaginase, kills the leukemic cells. Normal cells, however, are less affected by the depletion due to their ability to synthesize asparagine.

Pharmacodynamics

The relationship between asparaginase activity and asparagine levels has been studied in clinical trials. In previously untreated, standard-risk ALL patients treated with native asparaginase in whom plasma enzyme activity was greater than 0.1 International Units/ml, plasma asparagine levels decreased from a pretreatment average level of 41 μM to less than 3 μM. In this study, cerebrospinal fluid asparagine levels in patients treated with asparaginase decreased from 2.8 μM (pretreatment) to 1.0 μM and 0.3 μM at day 7 and day 28 of induction, respectively.²

Pharmacokinetics

In a study ⁵ in patients with metastatic cancer and leukemia, daily intravenous administration of L-asparaginase resulted in a cumulative increase in plasma levels. Plasma half-life varied from 8 to 30 hours. Apparent volume of distribution was slightly greater than the plasma volume. Asparaginase levels in cerebrospinal fluid were less than 1% of concurrent plasma levels.

In a study ⁶ in which patients with leukemia and metastatic cancer received intramuscular L-asparaginase, peak plasma levels of asparaginase were reached 14 to 24 hours after dosing. Plasma half-life was 34 to 49 hours.

Animal Toxicology

Edema and necrosis of pancreatic islets were observed in rabbits following a single, intravenous injection of 12, 500 to 50, 000 International Units Elspar/kg (approximately equivalent to 25 to 100-fold the recommended human dose, when adjusted for total body surface area). These changes were not reflective of pancreatitis, and were not observed in rabbits following a single intravenous injection of 1000 International Units/kg (approximately equivalent to two times the recommended human dose, when adjusted for total body surface area).

Clinical Studies

Elspar was evaluated in an open-label, multi-center, single-arm study in which 823 patients less than 16 years of age with previously untreated acute lymphoblastic or acute undifferentiated leukemia received Elspar as a component of multi-agent chemotherapy for induction of first remission. Elspar was administered at a dose of 6, 000 International Units/m²intramuscularly 3 times a week for a total of 9 doses.⁷ Of 815 evaluable patients, 758 (93%) achieved a complete remission. In a previous study, in a similar patient popula-tion, which utilized an initial induction chemotherapy regimen containing the same agents without Elspar, 429 of 499 (86%) patients achieved a complete remission.

REFERENCES

2. Avramis, VI; Sencer, S.; Periclou, AP; Sather, H.; Bostrom, BC; Cohen, L.J.; Ettinger, A.G.; Ettinger, L.J.; Franklin, J.; Gaynon, PS; Hilden, J.M.; Lange, B.; Majlessipour, F.; Mathew, P.; Needle, M.; Neglia, J.; Reaman, G.; Holcenberg, J.S.: A randomized comparison of native Escherichia coli asparaginase and polyethylene glycol conjugated asparaginase for treatment of children with newly diagnosed standard-risk acute lymphoblastic leukemia: a Children's Cancer Group study, Blood 99:1986-1994, 2002.

5. Ho, D.H.W.; Thetford, B.S.; Carter, C.J.K.; Frei, E., III:Clinical pharmacologic studies of L-asparaginase, Clin.Pharmacol. Ther. 11:408-417, May-June 1970.

6. Ho, D.H.W.; Yap, H.Y.; Brown, N.; Benjamin, R.S.; Friereich, E.J.; Blumenschein, G.R.; Bodey, G.P.:Clinical pharmacology of intramuscularly administered L-asparaginase, J.Clin.Pharmacol. 21: 72-78, Feb.-Mar. 1981.

7. Ortega, J.A.; Nesbit, M.E.; Donaldson, M.H.; Hittle, R.E.; Weiner, J.; Karon, M.; Hammond, D.: L-asparaginase, vincristine and prednisone for induction of first remission in acute lymphocytic leukemia, Cancer Research 37: 535-540, Feb. 1977.

Last updated on RxList: 10/10/2008

Serious Allergic Reactions

Patients should be informed of the possibility of serious allergic reac-tions, including anaphylaxis, and advised to immediately report any swellings or difficulty breathing.

Thrombosis

Patients should be advised to immediately report any severe headache. Arm or leg swelling, acute shortness of breath, and chest pain also should be reported immediately.

Pancreatitis

Patients should be advised to immediately report any severe abdominal pain.

Glucose Intolerance

Patients should be advised to report excessive thirst or any increase in the volume or frequency of urination.

Last updated on RxList: 10/10/2008

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

ASPARAGINASE - INJECTION

(as-PAR-adge-ih-naze)

COMMON BRAND NAME(S): Elspar

WARNING: Severe allergic reactions (sometimes fatal) have occurred despite testing for the reaction (test dosing) and the use of preventative medications; therefore, asparaginase must be given in the hospital. Seek immediate medical attention if you develop signs of an allergic reaction, such as rash, hives, itching, swelling, or breathing problems.

USES: Asparaginase is used with or without other anticancer (chemotherapy) drugs to treat acute lymphocytic leukemia (ALL). It works by starving tumor cells of needed nutrients and slowing tumor cell growth.

OTHER USES: This section contains uses of this drug that are not listed in the approved professional labeling for the drug but that may be prescribed by your health care professional. Use this drug for a condition that is listed in this section only if it has been so prescribed by your health care professional.

Asparaginase may also be used for other cancers such as lymphomas.

HOW TO USE: This medication is given by vein (intravenously-IV), into the muscle (intramuscularly-IM), or under the skin (subcutaneously-SubQ). The dosage is based on your medical condition and response to therapy.

Your doctor may give you a skin test before your first treatment and if a long time has passed since your last dose of asparaginase. Though skin testing does not always correctly show that you will not have an allergic reaction to this drug, your doctor may still use it to help predict such a reaction. If you have a reaction to the test dose, your doctor may decide not to treat you with asparaginase or to give you small, slowly increasing doses while monitoring you for allergic reactions until you reach the full treatment dose.

Your doctor will give you pre-medication to help prevent allergic reactions.

Unless your doctor instructs you otherwise, drink plenty of fluids while using this medication.

Follow all instructions for proper mixing. When mixed in the vial, this medication should be clear. Before using, check this product visually for particles or discoloration. If either is present, do not use the liquid. When receiving asparaginase by vein, follow all instructions for dilution with the correct IV fluid.

This medication may contain small particles after it is added to the solution in the IV infusion bag. It is important to use an IV filter ("in-line" filter) while giving this solution by vein. Consult your pharmacist about the proper size (5 micron filter) and use of this filter.

SIDE EFFECTS: Pain or swelling at the injection site, nausea, vomiting, stomach cramps, loss of appetite, headache, loss of energy, and drowsiness may occur. Nausea and vomiting can be severe, and in some cases drug therapy may be needed. Not eating before your treatment may help relieve nausea and vomiting. Changes in diet such as eating several small meals or limiting activity may help lessen some of these effects. If these effects persist or worsen, notify your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: mental/mood changes, tremor, muscle stiffness, joint pain, swelling of hands/feet/lower legs, yellowing of the eyes or skin, unusual bleeding/bruising (e.g., nose bleeds, black or bloody stools).

Tell your doctor immediately if any of these rare but very serious side effects occur: unusual thirst, frequent urination, change in the amount of urine, abnormally high body temperature, severe stomach pain with nausea/vomiting.

Seek immediate medical attention if any of these rare but very serious side effects occur: vision changes, fainting, severe headache, severe dizziness, chest pain.

This medication can lower the body's ability to fight an infection. Notify your doctor promptly if you develop any signs of an infection such as fever, chills, sores in mouth or on lips, or persistent sore throat.

A very serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs (See also Warning section). Symptoms of a serious allergic reaction may include: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before receiving asparaginase, tell your doctor or pharmacist if you are allergic to it or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: pancreatitis.

Before using this medication, tell your doctor or pharmacist of your medical history, especially of: liver disease.

This drug may make you dizzy or drowsy; use caution engaging in activities requiring alertness such as driving or using machinery. Limit alcoholic beverages.

Also limit alcoholic beverages as drinking alcohol may increase your chance of bleeding in the stomach or intestines.

Do not have immunizations/vaccinations without the consent of your doctor and avoid contact with people who have recently received oral polio vaccine.

Wash hands well to prevent the spread of infections.

Use caution with sharp objects like razors or nail cutters and avoid activities such as contact sports to lower the chance of getting cut, bruised or injured.

This medication should be used only when clearly needed during pregnancy. Asparaginase may cause harm to an unborn baby. If you become pregnant or think you may be pregnant, inform your doctor immediately. Women of child-bearing age should use an effective form of birth control while using this medication. Discuss the risks, benefits and any other concerns with your doctor.

It is not known whether asparaginase passes into breast milk. Because of the potential risk to the infant, breast-feeding while using this drug is not recommended. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your healthcare professionals (e.g., doctor or pharmacist) may already be aware of any possible drug interactions and may be monitoring you for it. Do not start, stop or change the dosage of any medicine before checking with them first.

Asparaginase should not be used with the following medication because a very serious interaction may occur: live vaccines.

Asparaginase should not be used by vein with or immediately before vincristine or prednisone because very serious side effects such as blood problems (erythropoiesis) or numbness, tingling, burning, or pain in the hands or feet may occur. Talk to your doctor or pharmacist about the usefulness of receiving asparaginase after these drugs if they are part of your chemotherapy regimen.

Before using asparaginase, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: other drugs for cancer, drugs affected by liver enzymes (such as cyclophosphamide, methotrexate, vincristine, mercaptopurine, or prednisone).

Asparaginase can either decrease the beneficial effect of these drugs or increase their side effects when given before or at the same time as these drugs. If you are currently using any of these medications listed above, tell your doctor or pharmacist before taking asparaginase.

This product can affect the results of certain lab tests. Make sure laboratory personnel and your doctors know you use this drug.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly.

NOTES: Do not share this medication with others.

Laboratory tests (e.g., blood cell counts, liver function tests, amylase levels, lipids, and blood sugars) should be performed to monitor your progress or check for side effects. Consult your doctor for more details. Keep all scheduled medical appointments.

MISSED DOSE: It is important that you receive asparaginase as scheduled by your doctor. If you miss a dose, contact your doctor immediately to obtain a new dosing schedule.

STORAGE: Store the US product in the refrigerator between 36-46 degrees F (2-8 degrees C). Once mixed, asparaginase should be used within 8 hours.

Store the Canadian product in the refrigerator between 36-46 degrees F (2-8 degrees C). Once mixed, asparaginase must be used within 14 days.

Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For enrollment information call MedicAlert at 1-800-854-1166 (USA), or 1-800-668-1507 (Canada).

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.