Oncaspar (Pegaspargase)

ONCASPAR®

Rhône-Poulenc Rorer

Pegaspargase

Antineoplasic

Caution: Allergic reactions may occur during therapy with pegaspargase, especially in patients with known hypersensitivity to the other forms of L-asparaginase.

In view of the unpredictability of adverse reactions, pegaspargase should be given under the supervision of a physician who is qualified by training and experience to administer cancer chemotherapeutic agents.

Pegaspargase has an adverse effect on liver function in some patients. Therapy with pegaspargase may increase pre-existing liver impairment caused by prior therapy or underlying disease. Because of this, there is a possibility that pegaspargase may increase the toxicity of other concomitant medication.

Action And Clinical Pharmacology: In a significant number of patients with acute leukemia, particularly lymphoblastic, the malignant cells are dependent on an exogenous source of L-asparagine for survival. Normal cells, however, are able to synthesize L-asparagine and thus are less affected by its rapid depletion produced by treatment with the enzyme L-asparaginase which hydrolyzes extracellar L-asparagine into L-aspartic acid and ammonia.

Pegaspargase, a pegylated form of the enzyme L-asparaginase derived from E. coli is an oncolytic agent used in combination with chemotherapy for the treatment of patients with acute lymphoblastic leukemia who are hypersensitive to native forms of L-asparaginase.

The disappearance of pegaspargase from plasma is monophasic. The mean half-life, volume of distribution and rate of total clearance were 14.9 days, 2.04 L/mand 0.13 L/mday, respectively, according to a pharmacokinetic study in 25 adult patients with various leukemic disorders who were given 1-hour infusions of pegaspargase 500 to 8 000 IU/m Plasma enzymatic concentrations were proportional to the dose of pegaspargase. The active enzyme was not detectable in urine. Compared with L-asparaginase, pegaspargase has a longer half-life (6 to 14 days for pegaspargase vs 0.6 to 1.2 days for L-asparaginase) and a slower total clearance but a similar volume of distribution.

Indications And Clinical Uses: In the treatment of acute lymphoblastic leukemia (ALL) of childhood (£ 21 years of age at the time of diagnosis), specifically for the patients with known hypersensitivity to other forms of L-asparaginase. Pegaspargase should not be used as the sole induction, consolidation or maintenance agent unless combination therapy is deemed inappropriate.

Contra-Indications: Patients with pancreatitis or a history of pancreatitis. Acute hemorrhagic pancreatitis has been reported following L-asparaginase administration. Pegaspargase is also contraindicated in patients who have had previous anaphylactic reactions to it and bleeding following L-asparaginase treatment.

Manufacturers’ Warnings In Clinical States: Allergic reactions may occur during therapy with pegaspargase, especially in patients with known hypersensitivity to the other forms of L-asparaginase.

In view of the unpredictability of adverse reactions, pegaspargase should be given under the supervision of a physician who is qualified by training and experience to administer cancer chemotherapeutic agents.

Pegaspargase has an adverse effect on liver function in some patients. Therapy with pegaspargase may increase pre-existing liver impairment caused by prior therapy or underlying disease. Because of this, there is a possibility that pegaspargase may increase the toxicity of other concomitant medication.

Pegaspargase may cause clinical pancreatitis in some patients.

L-asparaginase has been shown in animals to possess embryotoxic and teratogenic activity. Therefore, it should not be used in pregnant patients unless the clinician considers that the benefits to the patient outweigh the possible risks to the patient.

Precautions: General: Pegaspargase is a contact irritant and the solution must be handled and administered with care (see Dosage). Inhalation of vapors and contact with skin or mucous membranes, especially those of the eyes, must be avoided. In case of contact, wash with copious amounts of water for at least 15 minutes.

Patients administered pegaspargase should be observed for 1 hour after administration and all medication for management of anaphylactic reaction should be available on premises. Anaphylactic reactions require the immediate use of epinephrine, oxygen and i.v. steroids.

Patients should be informed of the possibility of allergic reactions to pegaspargase.

Patients administered pegaspargase are prone to infections and bleeding (see Adverse Effects).

Pegaspargase has been reported to have immunosuppressive activity in animal experiments. Accordingly, the possibility that use of the drug in man may predispose to infection should be considered.

Laboratory Tests: The fall in circulating lymphoblasts is often quite marked; normal or below normal leukocyte counts are noted frequently within the first several days after initiating therapy. This may be accompanied by a marked rise in serum uric acid. The development of uric acid nephropathy is possible. Appropriate preventive measures should be taken, e.g., allopurinol, increased fluid intake and alkalization of urine. As a guide to the effects of therapy, the patient’s peripheral blood count and bone marrow should be monitored frequently.

Frequent serum amylase determinations should be obtained to detect early evidence of pancreatitis. If pancreatitis occurs, therapy should be stopped and not reinstituted. Blood sugar should be monitored during therapy with pegaspargase because hyperglycemia may occur.

Drug Interactions: Native L-asparaginase has been shown to diminish or abolish the effect of arabinosyl cytosine and methotrexate on malignant cells. This effect lasts as long as L-asparagine levels are suppressed. Since pegaspargase depletes L-asparagine levels for several weeks, clinical use of arabinosyl cytosine or methotrexate may not be optimally effective for a period of time after administration of pegaspargase. Depletion of protein synthesis due to effect of pegaspargase may lead to increased toxicity of protein bound drugs, decreased enzymatic detoxification of other drugs by the liver and prolonged bleeding due to imbalances in coagulation factors. Therefore anticoagulant therapy should be used with caution.

Pregnancy: Animal reproduction studies have not been conducted with pegaspargase. It is also not known whether pegaspargase can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Pegaspargase should be given to a pregnant woman only if clearly needed. L-asparaginase has been shown in animals to possess embryotoxic and teratogenic activity. Therefore it should not be used in pregnant patients unless the clinician considers that the benefits to the patient outweigh the possible risks to the patient (see Warnings).

Lactation: It is not known whether pegaspargase is excreted in human milk.

Because many drugs are excreted in human milk, caution should be exercised when pegaspargase is administered to a nursing woman.

Adverse Reactions: Like asparaginase, pegaspargase can cause allergic reactions, including anaphylaxis. The incidence of hypersensitivity reactions to pegaspargase in patients who have had reaction to asparaginase is about 30%. Also like asparaginase, pegaspargase can cause pancreatitis, hypoproteinemia, hyperglycemia, bleeding, coagulopathy and hepatic dysfunction. Whether the longer half-life of pegaspargase might aggravate the drug’s toxicity is unclear. The i.v. route may be associated with increased toxicity.

Higher proportion of previously hypersensitive patients converted to a high antibody level during therapy than the non-hypersensitive patients. Not all of hypersensitive patients who developed high antibody levels experienced hypersensitivity reactions. Asparaginase specific IgG antibodies appear to correlate better with allergic reactions than do corresponding IgE antibodies and the clinical hypersensitivity reactions appear to be mediated by the complement pathway. While there may be some correlation between clinical hypersensitivity and high anti-asparaginase antibody levels, a causal relationship is not clear. Both of these phenomena may be related to the extent of previous asparaginase exposure. Hypersensitivity due to anti-asparaginase antibody formation may result in less than optimal asparagine depletion and diminished efficacy of asparaginase therapy.

Overall, 8% of patients treated with pegaspargase experienced hypersensitivity reactions that resulted in termination from the study. Another 8% experienced nonallergic reactions that resulted in termination from study.

Acute clinical pancreatitis may include symptoms of nausea, vomiting and abdominal pain. Elevation of lipase and amylase concentrations may be present. However, due to the inhibition of protein synthesis, these concentrations may also appear normal. These symptoms usually subside with withdrawal of the drug, but fulminant pancreatitis has resulted in death.

Inhibition of insulin production may lead to clinical hyperglycemia, which requires treatment with insulin, in 2 to 3% of patients treated with pegaspargase. Therefore, patients should be monitored for hyperglycemia as well as alerted to the signs and symptoms of hyperglycemia.

Hemorrhagic events can result from the inhibition of vitamin K-dependent clotting factor synthesis and the prolongation of prothrombin time and partial thromboplastin time. Thromboses can also occur due to inhibition of the synthesis of anticoagulant proteins such as antithrombin III.

Elevations in liver enzymes such as aspartate aminotransferase, alanine aminotransferase, total bilirubin, and alkaline phosphatase are usually seen within the first 2 weeks of treatment and tend to be transient and a function of protein synthesis inhibition.

Gastrointestinal adverse effects may occur with pegaspargase use. Mild to moderate nausea and vomiting may occur in some patients but it can be easily controlled with standard antiemetic therapy. Prophylactic antiemetic therapy is recommended. Other gastrointestinal adverse effects include anorexia and constipation.

CNS changes can occur with the use of pegaspargase. Somnolence, lethargy and generalized weakness have been observed in 33% of patients treated with pegaspargase. More severe CNS changes are rare (2%) but have been observed (e.g., confusion, stupor, coma).

Due to enzyme action of pegaspargase, ammonia may accumulate as an end product in the serum, resulting in the clinical symptomatology. The symptoms tend to disappear when ammonia concentrations return to normal limits and the level of L-asparaginase is depleted in the body.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Pegaspargase is safe and well tolerated in single doses ranging from 500 to 8 000 IU/m No consistent, dose-related, dose-limiting toxicity has been observed over this dosage range. Depletion of serum proteins by pegaspargase may increase the toxicity of other drugs that are protein bound. tag_DosageDosage

Dosage And Administration: As a component of selected multiple agent regimens, pegaspargase can be administered by either the i.v. or i.m. route. The preferred route of administration, however, is the i.m. route because of a reported lower incidence of toxicity and hypersensitivity reactions (including anaphylaxis) associated with this route of administration. The usual dosage is 2 500 IU/m(see Recommended Induction Regimens).

When administered i.v., this enzyme should be given over a period of not less than 2 hours through the side arm of an already running infusion of Sodium Chloride Injection or Dextrose Injection 5%. Pegaspargase has little tendency to cause phlebitis when given i.v. Anaphylactic reactions require the immediate use of epinephrine, oxygen and i.v. steroids. The i.v. route may be associated with increased toxicity.

When administering pegaspargase i.m., the volume at a single injection site should be limited to 2 mL. If a volume greater than 2 mL is to be administered, multiple injection sites should be used.

Pegaspargase significantly inhibits cellular protein synthesis, resulting in a number of drug-drug interactions. Methotrexate and cytarabine exhibit schedule-dependent interactions with L-asparaginase and these interactions are expected to occur with pegaspargase as well. Pegaspargase may interfere with the enzymatic detoxification of other drugs, particularly in the liver. It is recommended, therefore, that pegaspargase be used in combination regimens only by physicians familiar with the benefits and risks of a given regimen.

Recommended Induction Regimens: When using chemotherapeutic agents in combination for the induction of remission in patients with acute lymphoblastic leukemia, regimens are sought which provide a maximum chance of success while avoiding excessive cumulative toxicity or drug interactions.

One of the following combination regimens incorporating pegaspargase is recommended for acute lymphoblastic leukemia in patients with known hypersensitivity to other forms of L-asparaginase.

In the regimens below, day 1 is considered to be the first day of induction therapy.

Regimen/I: Administer prednisone, 40 mg/mday, orally, in 3 divided doses for 28 days (the total daily dose should be to the nearest 2.5 mg). This dosage of prednisone should be tapered gradually over a 7-day period.

Administer vincristine sulfate, 1.5 mg/mweek, i.v., on days 1, 8, 15 and 22 of the treatment period. The maximum single dose should not exceed 2 mg.

Administer pegaspargase, 2 500 IU/mi.m. on days 1 and 15 of the treatment period.

Administer Daunorubicin, 25 mg/mi.v. on days 1, 8, 15 and 22 of treatment.

Regimen/II: Administer prednisone, 40 mg/mday, orally, in 3 divided doses for 28 days (the total daily dose should be to the nearest 2.5 mg). This dosage of prednisone should be tapered gradually over a 7-day period.

Administer vincristine sulfate, 1.5 mg/mweek, i.v., for 4 doses, on days 1, 8, 15, and 22 of the treatment period. The maximum single dose should not exceed 2 mg.

Administer pegaspargase, 2 500 IU/mi.m. on days 1 and 15 of the treatment period.

When a remission is obtained with either of these regimens, appropriate maintenance therapy must be instituted. Pegaspargase may be used as part of a maintenance regimen. The above regimens do not preclude a need for special therapy directed toward the prevention of CNS leukemia.

It should be noted that pegaspargase has been used in combination regimens other than those recommended above. It is important to keep in mind that pegaspargase administered i.v., concurrently with or immediately before a course of vincristine and prednisone, may be associated with increased toxicity. Use of pegaspargase as the sole induction agent should be undertaken only in an unusual situation when a combined regimen is inappropriate because of toxicity or other specific patient-related factors, or in patients refractory to other therapy. When pegaspargase is to be used as the sole induction agent, the recommended dosage regimen is 2 500 IU/mevery 2 weeks. Physicians using a given regimen should be thoroughly familiar with its benefits and risks.

Patients undergoing induction therapy must be carefully monitored and the therapeutic regimen adjusted according to response and toxicity. Such adjustments should always involve decreasing dosages of one or more agents or discontinuation, depending on the degree of toxicity.

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

Availability And Storage: Each mL of isotonic, sterile, clear, colorless, phosphate buffered, saline solution contains: pegaspargase 750 IU. Nonmedicinal ingredients: dibasic sodium phosphate, monobasic sodium phosphate, sodium chloride and water for injection. pH 7.3. Single use vials of 5 mL, packages of 1. Store at 2 to 8°C. Avoid excessive agitation. Do not use if cloudy or if precipitate is present. Do not use if stored at room temperature for more than 48 hours. Do not freeze. Do not use past the expiration date. Single use vials, discard any unused portion.

ONCASPAR® Rhône-Poulenc Rorer Pegaspargase Antineoplasic Caution: Allergic reactions may occur during therapy with pegaspargase, especially in patients with known hypersensitivity to the other forms of L-asparaginase. In view of the unpredictability of adverse reactions, pegaspargase should be given under the supervision of a physician who is qualified by training and experience to administer cancer chemotherapeutic agents. Pegaspargase has an adverse effect on liver function in some patients. Therapy with pegaspargase may increase pre-existing liver impairment caused by prior therapy or underlying disease. Because of this, there is a possibility that pegaspargase may increase the toxicity of other concomitant medication.

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