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DRUGS & SUPPLEMENTS
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Norubin
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Norubin uses
- Indications and usage
- Contraindications
- Warnings
- Precautions
- Adverse reactions
- Dosage and administration
- How supplied
- References
INDICATIONS AND USAGE
Norubin Hydrochloride for Injection USP in combination with other approved anticancer drugs is indicated for remission induction in acute nonlymphocytic leukemia (myelogenous, monocytic, erythroid) of adults and for remission induction in acute lymphocytic leukemia of children and adults.
CONTRAINDICATIONS
Norubin Hydrochloride for Injection USP is contraindicated in patients who have shown a hypersensitivity to it.
WARNINGS
Bone Marrow
Norubin Hydrochloride is a potent bone marrow suppressant. Suppression will occur in all patients given a therapeutic dose of this drug. Therapy with Norubin Hydrochloride should not be started in patients with pre-existing drug-induced bone marrow suppression unless the benefit from such treatment warrants the risk. Persistent, severe myelosuppression may result in superinfection or hemorrhage.
Cardiac Effects
Special attention must be given to the potential cardiac toxicity of Norubin Hydrochloride, particularly in infants and children. Pre-existing heart disease and previous therapy with doxorubicin are co-factors of increased risk of Norubin Hydrochloride-induced cardiac toxicity and the benefit-to-risk ratio of Norubin Hydrochloride therapy in such patients should be weighed before starting Norubin Hydrochloride. In adults, at total cumulative doses less than 550 mg/m2, acute congestive heart failure is seldom encountered. However, rare instances of pericarditis-myocarditis, not dose-related, have been reported.
In adults, at cumulative doses exceeding 550 mg/m2, there is an increased incidence of drug-induced congestive heart failure. Based on prior clinical experience with doxorubicin, this limit appears lower, namely 400 mg/m2, in patients who received radiation therapy that encompassed the heart.
In infants and children, there appears to be a greater susceptibility to anthracycline-induced cardiotoxicity compared to that in adults, which is more clearly dose-related. Anthracycline therapy in pediatric patients has been reported to produce impaired left ventricular systolic performance, reduced contractility, congestive heart failure or death. These conditions may occur months to years following cessation of chemotherapy. This appears to be dose-dependent and aggravated by thoracic irradiation. Long-term periodic evaluation of cardiac function in such patients should, thus, be performed. In both children and adults, the total dose of Norubin Hydrochloride administered should also take into account any previous or concomitant therapy with other potentially cardiotoxic agents or related compounds such as doxorubicin.
There is no absolutely reliable method of predicting the patients in whom acute congestive heart failure will develop as a result of the cardiac toxic effect of Norubin Hydrochloride. However, certain changes in the electrocardiogram and a decrease in the systolic ejection fraction from pre-treatment baseline may help to recognize those patients at greatest risk to develop congestive heart failure. On the basis of the electrocardiogram, a decrease equal to or greater than 30% in limb lead QRS voltage has been associated with a significant risk of drug-induced cardiomyopathy. Therefore, an electrocardiogram and/or determination of systolic ejection fraction should be performed before each course of Norubin Hydrochloride. In the event that one or the other of these predictive parameters should occur, the benefit of continued therapy must be weighed against the risk of producing cardiac damage.
Early clinical diagnosis of drug-induced congestive heart failure appears to be essential for successful treatment.
Evaluation of Hepatic and Renal Function
Significant hepatic or renal impairment can enhance the toxicity of the recommended doses of Norubin Hydrochloride; therefore, prior to administration, evaluation of hepatic function and renal function using conventional clinical laboratory tests is recommended.
Pregnancy
Norubin Hydrochloride may cause fetal harm when administered to a pregnant woman. An increased incidence of fetal abnormalities and abortions was reported in rabbits at doses of 0.05 mg/kg/day or approximately 1/100th of the highest recommended human dose on a body surface area basis. Rats showed an increased incidence of esophageal, cardiovascular and urogenital abnormalities as well as rib fusions at doses of 4 mg/kg/day or approximately 1/2 the human dose on a body surface area basis. Decreases in fetal birth weight and post-delivery growth rate were observed in mice. There are no adequate and well-controlled studies in 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 the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.
Secondary Leukemias
There have been reports of secondary leukemias in patients exposed to topoisomerase II inhibitors when used in combination with other antineoplastic agents or radiation therapy.
Extravasation at Injection Site
Extravasation of Norubin Hydrochloride at the site of intravenous administration can cause severe local tissue necrosis.
PRECAUTIONS
General
Therapy with Norubin Hydrochloride requires close patient observation and frequent complete blood-count determinations. Cardiac, renal, and hepatic function should be evaluated prior to each course of treatment.
Appropriate measures must be taken to control any systemic infection before beginning therapy with Norubin Hydrochloride.
Norubin Hydrochloride may transiently impart a red coloration to the urine after administration, and patients should be advised to expect this.
Laboratory Tests
Norubin Hydrochloride may induce hyperuricemia secondary to rapid lysis of leukemic renal cells. As a precaution, allopurinol administration is usually begun prior to initiating antileukemic therapy. Blood uric acid levels should be monitored and appropriate therapy initiated in the event that hyperuricemia develops.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Norubin Hydrochloride, when injected subcutaneously into mice, causes fibrosarcomas to develop at the injection site. When administered to mice thrice weekly intraperitoneally, no carcinogenic effect was noted after 18 months of observation. In male rats administered Norubin Hydrochloride thrice weekly for 6 months, at 1/70th the recommended human dose on a body surface area basis, peritoneal sarcomas were found at 18 months. A single IV dose of Norubin Hydrochloride administered to rats at 1.6 fold the recommended human dose on a body surface area basis caused mammary adenocarcinomas to appear at 1 year. Norubin Hydrochloride was mutagenic in vitro, and clastogenic in vitro (CCRFCEM human lymphoblasts) and in vivo (SCE assay in mouse bone marrow) tests.
In male dogs at a daily dose of 0.25 mg/kg administered intravenously, testicular atrophy was noted at autopsy. Histologic examination revealed total aplasia of the spermatocyte series in the seminiferous tubules with complete aspermatogenesis.
Pregnancy Category D
Nursing Mothers
It is not known whether this drug 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 Norubin Hydrochloride, mothers should be advised to discontinue nursing during Norubin Hydrochloride therapy.
Elderly
Pediatric Use
Drug Interactions
Use of Norubin Hydrochloride in a patient who has previously received doxorubicin increases the risk of cardiotoxicity. Norubin Hydrochloride should not be used in patients who have previously received the recommended maximum cumulative doses of doxorubicin or Norubin Hydrochloride. Cyclophosphamide used concurrently with Norubin Hydrochloride may also result in increased cardiotoxicity.
Dosage reduction of Norubin Hydrochloride may be required when used concurrently with other myelosuppressive agents.
Hepatotoxic medications, such as high-dose methotrexate, may impair liver function and increase the risk of toxicity.
ADVERSE REACTIONS
Dose-limiting toxicity includes myelosuppression and cardiotoxicity. Other reactions include:
Cutaneous
Reversible alopecia occurs in most patients. Rash, contact dermatitis and urticaria have occurred rarely.
Gastrointestinal
Acute nausea and vomiting occur but are usually mild. Antiemetic therapy may be of some help. Mucositis may occur 3 to 7 days after administration. Diarrhea and abdominal pain have occasionally been reported.
Local
If extravasation occurs during administration, severe local tissue necrosis, severe cellulitis, thrombophlebitis, or painful induration can result.
Acute Reactions
Rarely, anaphylactoid reaction, fever, and chills can occur. Hyperuricemia may occur, especially in patients with leukemia, and serum uric acid levels should be monitored.
DOSAGE AND ADMINISTRATION
Parenteral drug products should be inspected visually for particulate matter prior to administration, whenever solution and container permit.
Principles
In order to eradicate the leukemic cells and induce a complete remission, a profound suppression of the bone marrow is usually required. Evaluation of both the peripheral blood and bone marrow is mandatory in the formulation of appropriate treatment plans.
It is recommended that the dosage of Norubin Hydrochloride for Injection USP be reduced in instances of hepatic or renal impairment. For example, using serum bilirubin and serum creatinine as indicators of liver and kidney function, the following dose modifications are recommended:
| Serum Bilirubin | Serum Creatinine | Dose Reduction |
| 1.2 to 3.0 mg% | - | 25% |
| >3 mg% | - | 50% |
| - | >3 mg% | 50% |
Representative Dose Schedules and Combination for the Approved Indication of Remission Induction in Adult Acute Nonlymphocytic Leukemia
In Combination
For patients under age 60, Norubin Hydrochloride for Injection USP 45 mg/m2/day IV on days 1, 2, and 3 of the first course and on days 1, 2 of subsequent courses AND cytosine arabinoside 100 mg/m2/day IV infusion daily for 7 days for the first course and for 5 days for subsequent courses.
For patients 60 years of age and above, Norubin Hydrochloride for Injection USP 30 mg/m2/day IV on days 1, 2, and 3 of the first course and on days 1, 2 of subsequent courses AND cytosine arabinoside 100 mg/m2/day IV infusion daily for 7 days for the first course and for 5 days for subsequent courses. This Norubin Hydrochloride for Injection USP dose-reduction is based on a single study and may not be appropriate if optimal supportive care is available.
The attainment of a normal-appearing bone marrow may require up to three courses of induction therapy. Evaluation of the bone marrow following recovery from the previous course of induction therapy determines whether a further course of induction treatment is required.
Representative Dose Schedule and Combination for the Approved Indication of Remission Induction in Pediatric Acute Lymphocytic Leukemia
In Combination
Norubin Hydrochloride for Injection USP 25 mg/m2 IV on day 1 every week, vincristine 1.5 mg/m2 IV on day 1 every week, prednisone 40 mg/m2 PO daily. Generally, a complete remission will be obtained within four such courses of therapy; however, if after four courses the patient is in partial remission, an additional one or, if necessary, two courses may be given in an effort to obtain a complete remission.
In children less than 2 years of age or below 0.5 m2 body surface area, it has been recommended that the Norubin Hydrochloride for Injection USP dosage calculation should be based on weight instead of body surface area.
Representative Dose Schedules and Combination for the Approved Indication of Remission Induction in Adult Acute Lymphocytic Leukemia
In Combination
Norubin Hydrochloride for Injection USP 45 mg/m2/day IV on days 1, 2, and 3 AND vincristine 2 mg IV on days 1, 8, and 15; prednisone 40 mg/m2/day PO on days 1 through 22, then tapered between days 22 to 29; L-asparaginase 500 IU/kg/day x 10 days IV on days 22 through 32.
The contents of a vial should be reconstituted with 4 mL of Sterile Water for Injection and agitated gently until the material has completely dissolved. The sterile vial contents provide 20 mg of Norubin, with 5 mg of Norubin per mL. The desired dose is withdrawn into a syringe containing 10 mL to 15 mL of 0.9% Sodium Chloride Injection, USP and then injected into the tubing or sidearm in a rapidly flowing IV infusion of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP. Norubin Hydrochloride for Injection USP should not be administered mixed with other drugs or heparin.
Storage and Handling
Store unreconstituted powder between 20° to 25°C (68° to 77°F); ; Excursions permitted to 15° to 30°C (59° to 86°F). The reconstituted solution is stable for 24 hours at controlled room temperature and 48 hours under refrigeration. It should be protected from exposure to sunlight. Protect from light. Retain in carton until time of use.
If Norubin Hydrochloride for Injection USP contacts the skin or mucosae, the area should be washed thoroughly with soap and water. Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-7 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
HOW SUPPLIED
Norubin Hydrochloride for Injection, is available in butyl-rubber-stoppered vials, each containing 21.4 mg Norubin hydrochloride (equivalent to 20 mg of Norubin) and 100 mg of mannitol, as a sterile reddish lyophilized powder. When reconstituted with 4 mL of Sterile Water for Injection, USP, each mL contains 5 mg Norubin activity.
NDC 42658-007-01 20 mg, single dose vials, single dose vials; one vial in one inner carton and ten inner cartons in one outer carton.
REFERENCES
- Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs. NIH Publication No. 83-2621. For sale by the Superintendent of Documents, U.S. Government Printing Office, Washington, D.C. 20402.
- AMA Council Report. Guidelines for Handling Parenteral Antineoplastics. JAMA, March 15,1985.
- National Study Commission on Cytotoxic Exposure Recommendations for Handling Cytotoxic Agents. Available from Louis R Jeffrey, Sc. D., Chairman, National Study Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied HealthSciences, 179 Longwood Avenue, Boston, Massachusetts 02115.
- Clinical Oncological Society of Australia: Guidelines and recommendations for safe handling of antineoplastic agents. Med J Australia 1:426-428, 1983.
- Jones RB, et al: Safe handling of chemotherapeutic agents: A report from the Mount Sinai Medical Center, Ca A Cancer Joumal for Clinicians Sept/Oct, 258-263, 1983.
- American Society of Hospital Pharmacists technical assistance bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm 47:1033-1049, 1990.
- Controlling Occupational Exposure to Hazardous Drugs. (OSHA Work-Practice Guidelines),Am J Health-Syst Pharm, 15:1669-1685, 1996.
Distributed by:
Halison Pharmaceuticals USA, Inc.
Princeton, NJ 08540 USA
Manufactured in China
Issued: 07/2014
Vial Label 20 mg BASE
Norubin pharmaceutical active ingredients containing related brand and generic drugs:
Norubin available forms, composition, doses:
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.