USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed. (8.2)Renal insufficiency (BUN >=30 mg/dL): Consider dosage reduction (2.2, 8.6). 8.1 Pregnancy Risk SummaryBased on its mechanism of action and findings from animal studies, IVRA can cause fetal harm when administered to pregnant woman. There are no available data on IVRA use in pregnant women to evaluate for 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 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies.DataAnimal DataAdequate animal studies have not been conducted with intravenous melphalan. Melphalan was embryolethal and teratogenic in rats following oral administration of to 18 mg/m2/day for 10 days (0.06 to 0.18 times the highest recommended clinical dose of 100 mg/m2/day) and intraperitoneal administration of 18 mg/m2 (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).. 8.2 Lactation. Risk SummaryThere 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 breastfed child, advise women not to breastfeed during treatment with IVRA and for week following the last dose.. 8.3 Females and Males of Reproductive Potential. IVRA can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)].ContraceptionFemalesAdvise females of reproductive potential to use effective contraception during treatment with IVRA and for months after the last dose.MalesMelphalan 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 months after the last dose [see Nonclinical Toxicology (13.1)].InfertilityFemalesMelphalan causes suppression of ovarian function in premenopausal women, resulting in amenorrhea in significant number of patients.MalesReversible and irreversible testicular suppression has been reported in male patients after administration of melphalan.. 8.4 Pediatric Use. The safety and effectiveness of IVRA in pediatric patients have not been established.. 8.5 Geriatric Use. 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.. 8.6 Renal Impairment. Consider dosage reduction in patients with renal insufficiency receiving intravenous IVRA [see Dosage and Administration (2.2)]. In one trial, increased bone marrow suppression was observed in patients with elevated BUN [see Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Gastrointestinal toxicity: Nausea, vomiting, diarrhea, or oral mucositis may occur; provide supportive care using antiemetic and antidiarrheal medications as needed. (5.2) Embryo-fetal toxicity: Can cause fetal harm. Advise females of reproductive potential and males with female partners of reproductive potential of potential risk to fetus and to use effective contraception. (5.6, 8.1) Infertility: Melphalan may cause ovarian function suppression or testicular suppression. (5.7) Gastrointestinal toxicity: Nausea, vomiting, diarrhea, or oral mucositis may occur; provide supportive care using antiemetic and antidiarrheal medications as needed. (5.2) Embryo-fetal toxicity: Can cause fetal harm. Advise females of reproductive potential and males with female partners of reproductive potential of potential risk to fetus and to use effective contraception. (5.6, 8.1) Infertility: Melphalan may cause ovarian function suppression or testicular suppression. (5.7) 5.1 Bone Marrow Suppression. IVRA causes bone marrow suppression in most patients.Obtain complete blood counts with differential at the start of therapy and prior to each subsequent dose of IVRA. Withhold treatment for grade thrombocytopenia and/ or leukopenia until blood counts have returned to grade [see Dosage and Administration (2.2)]. Consider dose adjustment on the basis of blood counts at the nadir and day of treatment.. 5.2 Gastrointestinal Toxicity. Gastrointestinal disturbances such as nausea and vomiting, diarrhea, and oral ulceration can occur with melphalan treatment.Severe mucositis, stomatitis, colitis, diarrhea, and hemorrhage of the gastrointestinal tract occur at high doses (greater than 100 mg/m2 times the recommended approved dose).Use prophylactic antiemetics [see Dosage and Administration (2.1)]. Provide supportive care for nausea, vomiting, diarrhea, and mucositis.. 5.3 Hepatotoxicity. Hepatic disorders ranging from abnormal liver function tests to clinical manifestations such as hepatitis and jaundice have been reported during treatment with melphalan. Hepatic veno-occlusive disease has been reported. Monitor liver enzymes as clinically indicated.. 5.4 Hypersensitivity. Acute hypersensitivity reactions including anaphylaxis were reported in 2.4% of 425 patients receiving melphalan injection for myeloma. These reactions were characterized by urticaria, pruritus, edema, skin rashes, and in some patients, tachycardia, bronchospasm, dyspnea, and hypotension. These patients appeared to respond to antihistamine and corticosteroid therapy. If hypersensitivity reaction occurs, intravenous or oral melphalan should not be readministered since hypersensitivity reactions have also been reported with oral melphalan. Cardiac arrest has also been reported in association with such reports.Discontinue treatment with IVRA for serious hypersensitivity reactions.. 5.5 Secondary Malignancies. Melphalan has been shown to cause chromatid or chromosome damage in humans. Secondary malignancies, including acute nonlymphocytic leukemia, myeloproliferative syndrome, and carcinoma, have been reported in patients with cancer treated with alkylating agents (including melphalan). Some patients also received other chemotherapeutic agents or radiation therapy. The potential benefits from melphalan therapy must be weighed on an individual basis against the possible risk of the induction of second malignancy.. 5.6 Embryo-Fetal Toxicity. Based on its mechanism of action, IVRA can cause fetal harm when administered to pregnant woman. Melphalan is genotoxic, targets actively dividing cells, and was embryolethal and teratogenic in rats. While adequate animal studies have not been conducted with intravenous melphalan, oral (6 to 18 mg/m2/day for 10 days) and IP (18 mg/m2) administration in rats was embryolethal and teratogenic. Malformations resulting from melphalan included alterations of the brain (underdevelopment, deformation, meningocele, and encephalocele) and eye (anophthalmia and microphthalmos), reduction of the mandible and tail, as well as hepatocele (exomphaly).If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, advise pregnant woman of the of potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with IVRA and for months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with IVRA and for months after the last dose [see Use in Specific Populations (8.1, 8.3)].. 5.7 Infertility. Melphalan causes suppression of ovarian function in premenopausal women, resulting in amenorrhea in significant number of patients. Reversible and irreversible testicular suppression have also been reported [see Use in Specific Populations (8.3)].

ADVERSE REACTIONS SECTION.

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)]. 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 MyelomaThe 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 dosage of 16 mg/m2 2 weeks 4 (over weeks) followed by the same dose every weeks. One hundred patients were administered oral melphalan at dosage of 0.15 mg/kg/day 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%).

BOXED WARNING SECTION.

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)].. 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 LEUKEMOGENICITYSee 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).. 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).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Melphalan is an alkylating agent of the bischloroethylamine type. As result, its cytotoxicity appears to be related to the extent of its interstrand cross-linking with DNA, probably by binding at the N7 position of guanine. Like other bifunctional alkylating agents, it is active against both resting and rapidly dividing tumor cells.. 12.2 Pharmacodynamics. Due to lack of information, melphalan exposure-response relationships and the time course of pharmacodynamic response are unknown.. 12.3 Pharmacokinetics. The mean +-SD melphalan peak plasma concentration is 1.2 +- 0.4 following an intravenous dosage of 10 mg/m2 (0.62 times the approved recommended dosage) and 2.8 +- 1.9 mcg/mL following an intravenous dosage of 20 mg/m2 (1.25 times the approved recommended dosage) in myeloma patients.DistributionThe melphalan steady-state volume of distribution is 0.5 L/kg. 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 1-acid glycoprotein approximately 20% of the plasma protein binding.EliminationThe melphalan elimination half-life is approximately 75 minutes. Mean total body melphalan clearance varied among studies, but typical values of approximately to mL/min/kg (250 to 325 mL/min/m2) were observed. MetabolismMelphalan primarily metabolized by hydrolysis to monohydroxymelphalan and dihydroxymelphalan, which are inactive.Excretion Following radiolabeled dose of intravenous melphalan in patients with cancer, the mean (+- SD) excretion of melphalan over 24 hours was 13% +- 5.4% of the total dose. Specific PopulationsPatients with renal ImpairmentAlthough 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. 50% reduction in the IV melphalan dosage decreased the incidence of severe bone marrow suppression in the latter portion of this study.Drug Interaction StudiesCyclosporinePatients treated with single dose of intravenous melphalan followed by standard oral doses of cyclosporine were reported to develop severe renal failure.ImmunoglobulinsInteractions between melphalan and immunoglobulins are negligible.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Palliative Treatment of Patients with Multiple MyelomaA 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 weeks. Melphalan doses in each arm were: Arm 1: Oral melphalan 0.15 mg/kg/day 7 followed by 0.05 mg/kg/day when WBC began to rise. Arm 2: Intravenous melphalan 16 mg/m2 2 weeks 4 (over weeks) followed by the same dose every weeks.One hundred seven patients were randomized to the oral melphalan arm and 203 patients to the intravenous melphalan arm. More patients had 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 PrednisoneInitial ArmEvaluable PatientsResponders (%)POral melphalan10044 (44%)P>0.2Intravenous melphalan19574 (38%)Because of changes in protocol design after week 22, other efficacy parameters such as response duration and survival cannot be compared.

DESCRIPTION SECTION.

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 C13H18Cl2N2O2 HCl and the molecular weight is 341.67. The structural formula is:Melphalan hydrochloride is white to off-white powder, with melting range of 199C to 201C. It is practically insoluble in water, but freely soluble in 1N HCl and methanol.IVRA is supplied as sterile, clear colorless to yellow solution in multiple-dose vial for intravenous use. Each mL contains 90 mg melphalan free base equivalent to 100.75 mg melphalan hydrochloride, 170 mg propylene glycol, mg monothioglycerol, 0.5 mg (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid dihydrate), and 0.025 mL water for injection in polyethylene glycol 400. May contain hydrochloric acid and/or sodium hydroxide for pH adjustment. The pH of the drug product solution after dilution with 0.9% sodium chloride ranges from 2.4 3.5. Each mL contains 90 mg melphalan free base equivalent to 100.75 mg melphalan hydrochloride.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Recommended dosage is 16 mg/m2 administered intravenously over 15 to 20 minutes at 2-week intervals for 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/m2 intravenously over 15 to 20 minutes at 2-week intervals for 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 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 SuppressionParameterDosing RecommendationsWhite Blood Cell Count (WBC/mm3)Platelet Count (Per mcL)Greater than or equal to 4,000Greater than or equal to 100,000Continue full IVRA doseGreater than or equal to 3,000Greater than or equal to 75,000Reduce IVRA to 75% of full doseGreater than or equal to 2,000Greater than or equal to 50,000Reduce IVRA to 50% of full doseLess than 2,000Less than 50,000Withold IVRA. 2.3 Dosage Modifications for Renal Impairment. Consider 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. PreparationIVRA is hazardous drug. Follow applicable special handling and disposal procedures1.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 2C to 8C [36F to 46F] 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.DilutionCalculate the required volume of IVRA needed for patients 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 solution with concentration not greater than 0.45 mg/mL. Immediately mix the contents of infusion vigorously by manual rotation. The diluted product is stable for hour at room temperature.AdministrationInfuse 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 fast-running intravenous infusion via an injection port or, central venous access line.. IVRA is hazardous drug. Follow applicable special handling and disposal procedures1.. 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 2C to 8C [36F to 46F] 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.. Calculate the required volume of IVRA needed for patients 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 solution with concentration not greater than 0.45 mg/mL. Immediately mix the contents of infusion vigorously by manual rotation. The diluted product is stable for hour at room temperature.. 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 fast-running intravenous infusion via an injection port or, central venous access line.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Low Blood Cell CountsAdvise patients to report any signs or symptoms of thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia. Inform patients of the need for routine blood counts [see Warnings and Precautions (5.1)]. MucositisInform patients of the signs and symptoms of mucositis. Instruct patients on ways to reduce the risk of its development, and on ways to maintain nutrition and control discomfort if it occurs [see Warnings and Precautions (5.2)]. Allergic ReactionsAdvise patients to immediately report symptoms of hypersensitivity reactions including changes involving the skin, breathing or heart rate, so that antihistamine or corticosteroid therapy can be administered [see Warnings and Precautions (5.4)]. Secondary MalignanciesAdvise patients of the potential long-term risks related to secondary malignancy [see Warnings and Precautions (5.5)]. Embryo Fetal ToxicityAdvise pregnant women of the potential risk to fetus [see Warnings and Precautions (5.6) and Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during and for months after treatment with IVRA. Advise males with female partners of reproductive potential to use effective contraception during treatment with IVRA and for months after the last dose. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking IVRA [see Warnings and Precautions (5.6) and Use in Specific Populations (8.1)]. Inform females of reproductive potential about the risk for infertility. Advise males that reversible and irreversible testicular suppression have been reported [see Warnings and Precautions (5.7)]. Advise women not to breastfeed during treatment with IVRA and for week following the last dose [see Use in Specific Populations (8.2)]. Manufactured by: AqVida GmbH 23942 Dassow Germany Manufactured for: Apotex Corp. Weston, Florida, USA 33326Rev 1. Advise pregnant women of the potential risk to fetus [see Warnings and Precautions (5.6) and Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during and for months after treatment with IVRA. Advise males with female partners of reproductive potential to use effective contraception during treatment with IVRA and for months after the last dose. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking IVRA [see Warnings and Precautions (5.6) and Use in Specific Populations (8.1)]. Inform females of reproductive potential about the risk for infertility. Advise males that reversible and irreversible testicular suppression have been reported [see Warnings and Precautions (5.7)]. Advise women not to breastfeed during treatment with IVRA and for week following the last dose [see Use in Specific Populations (8.2)].

OVERDOSAGE SECTION.

10 OVERDOSAGE. Overdoses resulting in death have been reported. Overdoses, including doses up to 290 mg/m2 (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/m2 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 to 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.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The mean +-SD melphalan peak plasma concentration is 1.2 +- 0.4 following an intravenous dosage of 10 mg/m2 (0.62 times the approved recommended dosage) and 2.8 +- 1.9 mcg/mL following an intravenous dosage of 20 mg/m2 (1.25 times the approved recommended dosage) in myeloma patients.DistributionThe melphalan steady-state volume of distribution is 0.5 L/kg. 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 1-acid glycoprotein approximately 20% of the plasma protein binding.EliminationThe melphalan elimination half-life is approximately 75 minutes. Mean total body melphalan clearance varied among studies, but typical values of approximately to mL/min/kg (250 to 325 mL/min/m2) were observed. MetabolismMelphalan primarily metabolized by hydrolysis to monohydroxymelphalan and dihydroxymelphalan, which are inactive.Excretion Following radiolabeled dose of intravenous melphalan in patients with cancer, the mean (+- SD) excretion of melphalan over 24 hours was 13% +- 5.4% of the total dose. Specific PopulationsPatients with renal ImpairmentAlthough 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. 50% reduction in the IV melphalan dosage decreased the incidence of severe bone marrow suppression in the latter portion of this study.Drug Interaction StudiesCyclosporinePatients treated with single dose of intravenous melphalan followed by standard oral doses of cyclosporine were reported to develop severe renal failure.ImmunoglobulinsInteractions between melphalan and immunoglobulins are negligible.

PREGNANCY SECTION.

8.1 Pregnancy Risk SummaryBased on its mechanism of action and findings from animal studies, IVRA can cause fetal harm when administered to pregnant woman. There are no available data on IVRA use in pregnant women to evaluate for 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 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies.DataAnimal DataAdequate animal studies have not been conducted with intravenous melphalan. Melphalan was embryolethal and teratogenic in rats following oral administration of to 18 mg/m2/day for 10 days (0.06 to 0.18 times the highest recommended clinical dose of 100 mg/m2/day) and intraperitoneal administration of 18 mg/m2 (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).