Melphalan Hcl
FDA Drug Information • Also known as: Ivra
- Brand Names
- Ivra
- Dosage Form
- POWDER
- Product Type
- BULK INGREDIENT
⚠ Boxed Warning (Black Box)
WARNING: SEVERE BONE MARROW SUPPRESSION, HYPERSENSITIVITY and LEUKEMOGENICITY Severe bone marrow suppression with resulting infection or bleeding may occur. Controlled trials comparing intravenous melphalan to oral melphalan have shown more myelosuppression with the intravenous formulation. Monitor hematologic laboratory parameters [see Warnings and Precautions ( 5.1 )] . Hypersensitivity reactions, including anaphylaxis, have occurred in approximately 2% of patients who received the intravenous formulation of melphalan. Discontinue treatment with IVRA for serious hypersensitivity reactions [see Warnings and Precautions ( 5.4 )] . Melphalan produces chromosomal aberrations in vitro and in vivo . IVRA should be considered potentially leukemogenic in humans [see Warnings and Precautions ( 5.5 )]. WARNING: SEVERE BONE MARROW SUPPRESSION, HYPERSENSITIVITY and LEUKEMOGENICITY See full prescribing information for complete boxed warning. Severe bone marrow suppression with resulting infection or bleeding may occur. Controlled trials comparing intravenous melphalan to oral melphalan have shown more myelosuppression with the intravenous formulation. Monitor hematologic laboratory parameters ( 5.1 ). Hypersensitivity reactions, including anaphylaxis, have occurred in approximately 2% of patients who received the intravenous formulation of melphalan. Discontinue treatment with IVRA for serious hypersensitivity reactions ( 5.4 ). Melphalan produces chromosomal aberrations in vitro and in vivo. IVRA should be considered potentially leukemogenic in humans ( 5.5 ).
Description
11 DESCRIPTION IVRA contains melphalan which is an alkylating drug. The chemical name of melphalan hydrochloride is 4-[bis(2-chloroethyl)amino]-L-phenylalanine hydrochloride. The molecular formula is C 13 H 18 Cl 2 N 2 O 2
What Is Melphalan Hcl Used For?
1 INDICATIONS AND USAGE 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. ( 1 )
Dosage and Administration
2 DOSAGE AND ADMINISTRATION Recommended dosage is 16 mg/m 2 administered intravenously over 15 to 20 minutes at 2-week intervals for 4 doses, then, after adequate recovery from toxicity, at 4-week intervals. ( 2.2 ) See full prescribing information for preparation and administration instructions. ( 2.3 ) 2.1 Recommended Dosage The recommended dosage is 16 mg/m 2 intravenously over 15 to 20 minutes at 2-week intervals for 4 doses, then at 4-week intervals until unacceptable toxicity. Administer prophylactic antiemetics [see Warnings and Precautions ( 5.2 )]. 2.2 Dosage Modifications for Adverse Reactions See Table 1 for dosage modifications for adverse reactions related to bone marrow suppression [see Warnings and Precautions ( 5.1 )]. Table 1. 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 2.3 Dosage Modifications for Renal Impairment Consider a dosage reduction of up to 50% in patients with renal insufficiency (BUN ≥30 mg/dL) [see Use in Specific Populations ( 8.6 )] . 2.4 Preparation and Administration 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 0.45 mg/mL. 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.
Side Effects (Adverse Reactions)
6 ADVERSE REACTIONS 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. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Apotex Corp. at 1-800-706-5575 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience 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 )]. One hundred and ninety-five patients were administered intravenous melphalan at a dosage of 16 mg/m 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%).
Drug Interactions
7 DRUG INTERACTIONS 7.1 Effect of Other Drugs on IVRA 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 )] . 7.2 Effect of IVRA on Other Drugs BCNU Concomitant use with BCNU may reduce the threshold for lung toxicity. Monitor for increased lung toxicity. 7.3 Cyclosporine Concomitant use with cyclosporine may increase the risk of developing severe renal failure [see Clinical Pharmacology ( 12.3 ) ]. Consider intravenous IVRA dosage reduction in patients with renal insufficiency following concomitant use with cyclosporine [see Dosage and Administration ( 2.2 )] .
Contraindications
4 CONTRAINDICATIONS 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. ( 4 )
Pregnancy and Breastfeeding
8.1 Pregnancy 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.S. 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 /day for 10 days (0.06 to 0.18 times the highest recommended clinical dose of 100 mg/m 2 /day) and intraperitoneal administration of 18 mg/m 2 (0.18 times the highest recommended clinical dose). Malformations resulting from melphalan administration included alterations of the brain (underdevelopment, deformation, meningocele, and encephalocele) and eye (anophthalmia and microphthalmos), reduction of the mandible and tail, and hepatocele (exomphaly).
Overdosage
10 OVERDOSAGE Overdoses resulting in death have been reported. Overdoses, including doses up to 290 mg/m 2 (18 times the recommended dose), have produced the following symptoms: severe nausea and vomiting, decreased consciousness, convulsions, muscular paralysis, and cholinomimetic effects. Severe mucositis, stomatitis, colitis, diarrhea, and hemorrhage of the gastrointestinal tract occur at high doses (greater than 100 mg/m 2 6 times the recommended dose). Elevations in liver enzymes and veno-occlusive disease have occurred. Significant hyponatremia caused by an associated inappropriate secretion of ADH syndrome has been observed. Nephrotoxicity and adult respiratory distress syndrome have been reported. 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.
How Supplied
16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied IVRA (melphalan) injection is a clear colorless to yellow solution supplied in a carton containing one 90 mg/mL amber glass multiple-dose vial for dilution. (NDC 60505-6414-1). Storage and Handling Store IVRA refrigerated at 2°C to 8°C (36°F to 46°F). IVRA is light sensitive. Retain in original carton when not in use. IVRA is a hazardous drug 1 . Follow special handling and disposal procedures 1 .
About This Information
This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.
What are side effects?
Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.
What are drug interactions?
Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.