IVRA - melphalan hcl_injection, solution

Melphalan is an alkylating agent of the bischloroethylamine type. As a result, its cytotoxicity appears to be related to the extent of its interstrand cross-linking with DNA, probably by binding at the N 7 Due to lack of information, melphalan exposure-response relationships and the time course of pharmacodynamic response are unknown. The mean +/-SD melphalan peak plasma concentration is 1. 4 following an intravenous dosage of 10 mg/m 2 2 Distribution The melphalan steady-state volume of distribution is 0. Melphalan penetration into cerebrospinal fluid (CSF) is low. The mean melphalan plasma protein binding ranges from 53% to 92% with approximately 30% irreversible (covalent). Serum albumin accounts for approximately 40% to 60% and alpha 1 Elimination The melphalan elimination half-life is approximately 75 minutes. Mean total body melphalan clearance varied among studies, but typical values of approximately 7 to 9 mL/min/kg (250 to 325 mL/min/m 2 Metabolism Melphalan primarily metabolized by hydrolysis to monohydroxymelphalan and dihydroxymelphalan, which are inactive. Excretion Following a radiolabeled dose of intravenous melphalan in 9 patients with cancer, the mean (+/- SD) excretion of melphalan over 24 hours was 13% +/- 5. 4% of the total dose. Specific Populations Patients with renal Impairment Although melphalan renal clearance appears to be low, one study reported an increase in the occurrence of severe leukopenia in patients with BUN levels >=30 mg/dL after 10 weeks of therapy. A 50% reduction in the IV melphalan dosage decreased the incidence of severe bone marrow suppression in the latter portion of this study. Drug Interaction Studies Cyclosporine Patients treated with a single dose of intravenous melphalan followed by standard oral doses of cyclosporine were reported to develop severe renal failure. Immunoglobulins Interactions between melphalan and immunoglobulins are negligible.

Multiple Myeloma-Palliative Treatment IVRA is indicated for the palliative treatment of patients with multiple myeloma for whom oral therapy is not appropriate. IVRA is an alkylating drug indicated for palliative treatment of patients with multiple myeloma for whom oral therapy is not appropriate.

Recommended dosage is 16 mg/m 2 2. 2 See full prescribing information for preparation and administration instructions. 3 The recommended dosage is 16 mg/m 2 Administer prophylactic antiemetics [see Warnings and Precautions ( 5. 2 See Table 1 for dosage modifications for adverse reactions related to bone marrow suppression [see Warnings and Precautions ( 5. Dosage Modifications for Adverse Reaction: Bone Marrow Suppression Parameter Dosing Recommendations White Blood Cell Count (WBC/mm 3 Platelet Count (Per mcL) Greater than or equal to 4,000 Greater than or equal to 100,000 Continue full IVRA dose Greater than or equal to 3,000 Greater than or equal to 75,000 Reduce IVRA to 75% of full dose Greater than or equal to 2,000 Greater than or equal to 50,000 Reduce IVRA to 50% of full dose Less than 2,000 Less than 50,000 Withold IVRA Consider a dosage reduction of up to 50% in patients with renal insufficiency (BUN >=30 mg/dL) [see Use in Specific Populations ( 8. 6 Preparation IVRA is a hazardous drug. Follow applicable special handling and disposal procedures 1 Parenteral drug products should be visually inspected for particulate matter and discoloration prior to administration whenever solution and container permit. If either occurs, do not use this product. IVRA is light sensitive. After first use, store the partially used vial refrigerated at 2°C to 8°C [36°F to 46°F] in the original carton for use within 28 days and then discard the remaining contents. Retain vial in original carton until contents are used. Do not mix IVRA with other melphalan hydrochloride drug products. Dilution Calculate the required volume of IVRA needed for a patient’s dose and withdraw that volume from the vial(s). Add the required volume of IVRA to the appropriate volume of 0. 9% Sodium Chloride Injection to obtain a solution with a concentration not greater than 0. Immediately mix the contents of infusion vigorously by manual rotation. The diluted product is stable for 1 hour at room temperature. Administration Infuse over 15 to 20 minutes via an injection port or central venous catheter. Complete administration within 60 minutes of dilution. IVRA may cause local tissue damage should extravasation occur. Administer IVRA only by injecting slowly into a fast-running intravenous infusion via an injection port or, central venous access line.

The following clinically significant adverse reactions are described elsewhere in the labeling: Bone Marrow Suppression [see Warnings and Precautions 5. 1 Gastrointestinal Toxicity [see Warnings and Precautions 5. 2 Hepatotoxicity [see Warnings and Precautions 5. 3 Hypersensitivity [see Warnings and Precautions 5. 4 Secondary Malignancies [see Warnings and Precautions 5. 5 Most common adverse reactions (>=50%) are neutrophil count decreased, white blood cell count decreased, lymphocyte count decreased, platelet count decreased, diarrhea, nausea, fatigue, hypokalemia, anemia, and vomiting. 1 To report SUSPECTED ADVERSE REACTIONS, contact Apotex Corp. at 1-800-706-5575 or FDA at 1-800-FDA-1088 or www. gov/medwatch ­ Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of melphalan may not reflect the rates observed in practice. The most common adverse reactions observed in at least 50% of patients with multiple myeloma treated with melphalan were neutrophil count decreased, white blood cell count decreased, lymphocyte count decreased, platelet count decreased, diarrhea, nausea, fatigue, hypokalemia, anemia, and vomiting. Palliative Treatment of Patients with Multiple Myeloma The safety of melphalan was evaluated in 295 patients with multiple myeloma in the randomized clinical trial [see Clinical Studies ( 14 2 q 2 weeks x 4 (over 6 weeks) followed by the same dose every 4 weeks. One hundred patients were administered oral melphalan at a dosage of 0. 15 mg/kg/day x 7 followed by 0. 05 mg/kg/day when WBC counts began to rise. Severe myelotoxicity (WBC <=1,000 and/or platelets <=25,000) was more common in the intravenous melphalan arm (28%) than in the oral melphalan arm (11%).

IVRA is contraindicated in patients with a history of severe hypersensitivity to melphalan. Reactions have included anaphylaxis [see Warnings and Precautions ( 5. 4 History of severe hypersensitivity to melphalan.

Lactation: Advise not to breastfeed. 2 Renal insufficiency (BUN >=30 mg/dL): Consider dosage reduction ( 2. 6 Risk Summary Based on its mechanism of action and findings from animal studies, IVRA can cause fetal harm when administered to a pregnant woman. There are no available data on IVRA use in pregnant women to evaluate for a drug-associated risk. In rats, melphalan was embryolethal and teratogenic at doses lower than the highest recommended clinical dose (see Data). 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 risk to the fetus. The background risk in the U. general population of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies. Data Animal Data Adequate animal studies have not been conducted with intravenous melphalan. Melphalan was embryolethal and teratogenic in rats following oral administration of 6 to 18 mg/m 2 2 2 Risk Summary There are no data on the presence of melphalan in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with IVRA and for 1 week following the last dose. IVRA can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8. 1 Contraception Females Advise females of reproductive potential to use effective contraception during treatment with IVRA and for 6 months after the last dose. Males Melphalan may damage spermatozoa and testicular tissue, resulting in possible genetic fetal abnormalities. Advise males with female partners of reproductive potential to use effective contraception during treatment with IVRA and for 3 months after the last dose [see Nonclinical Toxicology ( 13. 1 Infertility Females Melphalan causes suppression of ovarian function in premenopausal women, resulting in amenorrhea in a significant number of patients. Males Reversible and irreversible testicular suppression has been reported in male patients after administration of melphalan. The safety and effectiveness of IVRA in pediatric patients have not been established. Clinical studies of melphalan did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Consider a dosage reduction in patients with renal insufficiency receiving intravenous IVRA [see Dosage and Administration ( 2. 2 [see Clinical Pharmacology ( 12.

Cisplatin Concomitant use with cisplatin may alter melphalan clearance by inducing renal dysfunction. Consider intravenous IVRA dosage reduction in patients with renal insufficiency following concomitant use with cisplatin [see Dosage and Administration ( 2. 2 BCNU Concomitant use with BCNU may reduce the threshold for lung toxicity. Monitor for increased lung toxicity. Concomitant use with cyclosporine may increase the risk of developing severe renal failure [see Clinical Pharmacology ( 12. 3 [see Dosage and Administration ( 2.

OVERDOSAGE
Overdoses resulting in death have been reported. Overdoses, including doses up to 290 mg/m 2 2 The principal toxic effect is bone marrow suppression. In the event of an overdosage, monitor hematologic parameters for 3 to 6 weeks. General supportive measures together with appropriate blood transfusions and antibiotics should be instituted as deemed necessary by the physician. This drug is not removed from plasma to any significant degree by hemodialysis or hemoperfusion.
NONCLINICAL TOXICOLOGY
Adequate and well-controlled carcinogenicity studies with melphalan have not been conducted in animals. However, intraperitoneal (IP) administration of melphalan in rats (5.4 to 10.8 mg/m 2 2 Intramuscular administration of melphalan at 6 and 60 mg/m 2
CLINICAL STUDIES
Palliative Treatment of Patients with Multiple Myeloma A randomized trial compared prednisone plus intravenous melphalan to prednisone plus oral melphalan in the treatment of myeloma. Both arms received oral prednisone starting at 0.8 mg/kg/day with doses tapered over 6 weeks. Melphalan doses in each arm were: Arm 1: Oral melphalan 0.15 mg/kg/day x 7 followed by 0.05 mg/kg/day when WBC began to rise. Arm 2: Intravenous melphalan 16 mg/m 2 One hundred seven patients were randomized to the oral melphalan arm and 203 patients to the intravenous melphalan arm. More patients had a poor-risk classification (58% versus 44%) and high tumor load (51% versus 34%) on the oral compared to the intravenous arm (P<0.04). Response rates at week 22 are shown in the following table: Table 2. Response Rates at Week 22 In Patients with Multiple Myeloma Who Received Oral or Intravenous Melphalan with Prednisone Initial Arm Evaluable Patients Responders n (%) P Oral melphalan 100 44 (44%) P>0.2 Intravenous melphalan 195 74 (38%) Because of changes in protocol design after week 22, other efficacy parameters such as response duration and survival cannot be compared.
REFERENCES
1. OSHA Hazardous Drugs https://www.osha.gov/hazardous-drugs

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IVRA - melphalan hcl_injection, solution Product manual source documgent