HEPZATO for injection, as a component of the HEPZATO KIT, is indicated as a liver-directed treatment for adult patients with uveal melanoma with unresectable hepatic metastases affecting less than 50% of the liver and no extrahepatic disease or extrahepatic disease limited to the bone, lymph nodes, subcutaneous tissues, or lung that is amenable to resection or radiation. HEPZATO is an alkylating drug indicated as a liver-directed treatment for adult patients with uveal melanoma with unresectable hepatic metastases affecting less than 50% of the liver and no extrahepatic disease, or extrahepatic disease limited to the bone, lymph nodes, subcutaneous tissues, or lung that is amenable to resection or radiation.( 1 )
Contraindications
HEPZATO and the HEPZATO KIT are contraindicated in patients with: Active intracranial metastases or brain lesions with a propensity to bleed Liver failure, portal hypertension, or known varices at risk for bleeding Surgery or medical treatment of the liver in the previous 4 weeks Uncorrectable coagulopathy Inability to safely undergo general anesthesia, including active cardiac conditions including, but not limited to, unstable coronary syndromes (unstable or severe angina or myocardial infarction), worsening or new-onset congestive heart failure, significant arrhythmias, or severe valvular disease History of allergies or known hypersensitivity to melphalan History of allergies or known hypersensitivity to a component or material utilized within the HEPZATO KIT including History of allergy to natural rubber latex History of allergy or hypersensitivity to heparin or presence of heparin-induced thrombocytopenia (HIT) History of severe allergic reaction to iodinated contrast not controlled by premedication with antihistamines and steroids Active intracranial metastases or brain lesions with a propensity to bleed Liver failure, portal hypertension, or known varices at risk for bleeding Surgery or medical treatment of the liver in the previous 4 weeks Active cardiac conditions including, but not limited to, unstable coronary syndromes (unstable or severe angina or myocardial infarction), worsening or new-onset congestive heart failure, significant arrhythmias, or severe valvular disease History of allergies or known hypersensitivity to melphalan or a component or material utilized within the HEPZATO KIT including natural rubber latex, heparin, and severe hypersensitivity to iodinated contrast not controlled by antihistamines and steroids ( 4 )
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Hypersensitivity reactions, including anaphylaxis, have occurred in patients who received an intravenous (IV) formulation of melphalan. Immediately terminate hepatic arterial melphalan infusion for hypersensitivity reactions and administer supportive care. ( 5.4 ) Gastrointestinal disturbances such as nausea and vomiting, abdominal pain and diarrhea are common. ( 5.5 ) Carcinogenic/Mutagenic effects: Secondary malignancies, including acute nonlymphocytic leukemia, myeloproliferative syndrome, and carcinoma, have been reported in patients with cancer treated with alkylating drugs (including melphalan).
Melphalan has been shown to cause chromatid or chromosome damage in humans. ( 5.6 ) Embryo-fetal toxicity: Can cause fetal harm. Advise females of reproductive potential and males with female partners of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.7 , 8.1 , 8.3 ) Infertility: Melphalan-based chemotherapy regimens have been reported to cause suppression of ovarian function in premenopausal women and testicular suppression in men.
( 5.8 )
5.1Peri-Procedural Complications
Hemorrhage, hepatocellular injury, and thromboembolic events have been observed when HEPZATO has been administered via hepatic intra-arterial administration. Administration of HEPZATO requires general anesthesia and extracorporeal bypass of circulation which may cause life threatening or fatal adverse effects. Ensure the patient is euvolemic but do not overhydrate the patient. Monitor for these peri-procedural complications during the procedure and for at least 72 hours following the procedure.
To mitigate the risk of thromboembolic events, administer anticoagulation as described in the IFU during the procedure. Due to the risk of bleeding, do not use in patients with uncorrectable coagulopathies and delay treatment with the HEPZATO KIT for at least 4 weeks after surgery or other medical procedure involving the liver. Platelets and clotting factors may be removed during the HEPZATO KIT procedure. Monitor platelets and coagulation parameters as described in the IFU.
If life-threatening bleeding occurs during the procedure, reverse anticoagulation as described in the IFU and correct coagulopathy as appropriate. Discontinue anticoagulation with warfarin or other oral anticoagulants prior to the procedure; resume when hemostasis has been restored after the procedure, provided no bleeding complications have been observed. Refer to the Prescribing Information of the anticoagulant agent for bridging recommendations for anti-coagulation prior to surgical procedures.
Discontinue drugs affecting platelet function such as aspirin, non-steroidal anti-inflammatory drugs, or other anti-platelet drugs one week before the procedure. Patients with abnormal hepatic vascular (especially arterial supply) or biliary (especially re-implantation of bile duct) anatomy or gastric acid hypersecretion syndromes may be at increased risk of peri-procedural complications or other severe adverse reactions.
Screen patients for a history of prior surgeries involving the bile duct to assess whether the patient is an appropriate candidate for HEPZATO KIT and monitor patients for adverse reactions following HEPZATO KIT administration. Procedure-related reductions in blood pressure including severe hypotension can occur during the HEPZATO KIT procedure. Closely monitor blood pressure during the procedure. Patients may require fluid support and vasopressors.
To reduce the risk of severe hypotension, assess hypothalamic-pituitary-adrenal axis function, and temporarily discontinue ACE-inhibitors, calcium channel blockers, or alpha-1-adrenergic blockers for at least 5 half-lives prior to treatment with the HEPZATO-KIT. If necessary, use other short-acting antihypertensive drugs to manage blood pressure during the peri-procedure period.
5.2HEPZATO KIT REMS PROGRAM The
HEPZATO KIT is only available through a restricted program under a REMS, because of the risk of severe peri-procedural complications including hemorrhage, hepatocellular injury, and thromboembolic events defined in the REMS. The HEPZATO KIT should only be used by trained healthcare providers [see Warnings and Precautions ( 5.1 )]. Important requirements of the HEPZATO KIT REMS include: Healthcare settings that dispense and administer HEPZATO KIT must be enrolled, certified, and comply with the REMS requirements.
Certified healthcare facilities must ensure that healthcare providers who perform the Percutaneous Hepatic Perfusion (PHP) procedure are trained on the use of HEPZATO KIT and must only dispense HEPZATO when authorized to do so by the REMS. Certified healthcare facilities must ensure that patients are assessed for severe peri-procedural complications during the procedure and for at least 72 hours following the procedure.
Further information is available at www.HEPZATOKITREMS.com or contact Delcath Systems at 1-833-632-0457.
5.3Myelosuppression
Hematologic adverse reactions, including thrombocytopenia, anemia, and neutropenia have been reported in patients treated with HEPZATO. The risk of hematologic adverse reactions may be increased in patients who have received prior chemotherapy, bone irradiation, or who have compromised bone marrow function. In the 95 patients who received HEPZATO in the FOCUS trial, 68% had Grade 3 or 4 myelosuppression. A total of 55%, 33%, and 30% experienced Grade 3 or 4 thrombocytopenia, anemia, and neutropenia, respectively.
Median time to thrombocyte nadir was 13 days (range: 3-33) after treatment with median recovery in 20 days (range: 4-29) after treatment. Median time to hemoglobin nadir was 10 days (range: 3-21) after treatment with median recovery in 13 days (range: 4-28) after treatment. Median time to neutrophil nadir was 11 days (range: 3-36) after treatment with median recovery in 17 days (range: 9-36) after treatment. Monitor patients for severe infections, bleeding, and symptomatic anemia.
Only administer HEPZATO in patients with platelets >100,000/microliter, hemoglobin ≥10.0 gm/dL and neutrophils >2,000/microliter. Administer transfusions or growth factors as appropriate [see Dosage and Administration ( 2.1 )].
5.4Hypersensitivity Reactions
Hypersensitivity reactions, including anaphylaxis, have occurred in approximately 2% of patients who received an intravenous (IV) formulation of melphalan. These reactions with melphalan are characterized by urticaria, pruritus, edema, skin rashes, and in some patients, tachycardia, bronchospasm, dyspnea, and hypotension. Hypersensitivity can occur in patients with or without prior exposure to IV or oral melphalan. When a hypersensitivity reaction is observed, immediately terminate the hepatic arterial HEPZATO infusion and administer necessary supportive care [see Contraindications ( 4 )] .
Patients with a history of allergic reactions to iodinated contrast may experience hypersensitivity reactions, including anaphylaxis, during treatment with the HEPZATO KIT. Premedicate patients with a history of allergic reaction to iodinated contrast prior to treatment with HEPZATO KIT. Do not administer HEPZATO KIT in patients with a history of severe allergic reactions or anaphylaxis to iodinated contrast [see IFU, see Contraindications ( 4 )].
5.5Gastrointestinal Adverse Reactions
Gastrointestinal adverse reactions including nausea and vomiting, abdominal pain, and diarrhea are common, and occurred in 84% of patients treated with HEPZATO in the FOCUS trial. Administer a proton pump inhibitor the day prior to and the morning of the procedure. If anti-emetic treatment is required, pre-medicate with anti-emetic therapy in subsequent cycles.
5.6Secondary 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 intrav
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Pregnancy and breastfeeding
8.1Pregnancy Risk Summary Based
on animal studies and its mechanism of action, melphalan can cause fetal harm when administered to a pregnant woman, including teratogenicity and/or embryo-fetal lethality [see Clinical Pharmacology ( 12.1 ) ]. Melphalan is a genotoxic drug and can cause chromatid or chromosome damage in humans [see Nonclinical Toxicology ( 13.1 ) ]. In animal studies, melphalan was embryolethal and teratogenic in rats at doses below the recommended clinical doses [see Data ].
Advise a pregnant woman of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated populations are unknown. However, the background risk in the United States 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 IV melphalan. Melphalan was embryolethal and teratogenic in rats following oral administration of 6 to 18 mg/m 2 /day for ten (10) days (0.05 to 0.16 times the recommended clinical dose of 3 mg/kg or 111 mg/m 2 /day) and intraperitoneal administration of 18 mg/m 2 (0.16 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).
Adverse reactions
Below are adverse reactions associated with HEPZATO KIT. Additional adverse reactions related to the procedure and/or medical device are described in further detail in the HEPZATO KIT IFU. The following clinically significant adverse reactions are described elsewhere in the labeling: Peri-procedural complications [see Warnings and Precautions ( 5.1 )] Myelosuppression [see Warnings and Precautions ( 5.3 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.4 )] Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.5 )] Secondary Malignancies [see Warnings and Precautions ( 5.6 )] Most common (≥20%) adverse reactions or laboratory abnormalities are thrombocytopenia, fatigue, anemia, nausea, musculoskeletal pain, leukopenia, abdominal pain, neutropenia, vomiting, increased alanine aminotransferase, prolonged activated partial thromboplastin time, increased aspartate aminotransferase, increased alkaline phosphatase, and dyspnea.
To report SUSPECTED ADVERSE REACTIONS, contact Delcath at 1-833-632-0458 and www.Delcath.com or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch.
6.1Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug-device combination cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse drug reactions (ADRs) described in this section were identified from the FOCUS trial. FOCUS was a multicenter trial that evaluated HEPZATO (melphalan) administered via the HEPZATO KIT in patients with unresectable hepatic metastases from uveal melanoma.
In the FOCUS trial, a total of 95 patients were enrolled into the HEPZATO KIT arm, of which 91 patients received treatment with HEPZATO. Serious adverse reactions occurred in 45% of patients who received HEPZATO. Serious adverse reactions occurring in ≥ 2% of patients were thrombocytopenia (10%), neutropenia (8%), febrile neutropenia (7%), platelet count decreased (6%), leukopenia (4.2%), cardiac arrest (3.2%), neutrophil count decreased (2.1%), hypoxia (2.1%), pleural effusion (2.1%), pulmonary edema (2.1%), and deep vein thrombosis (2.1%).
Fatal adverse reactions occurred in 3 (3.2%) patients who were treated with HEPZATO; these included cardiac arrest, acute hepatic failure and bacterial peritonitis. HEPZATO was permanently discontinued due to adverse reactions in 18% of patients with neutropenia being the most common adverse reaction (3.2%) requiring permanent discontinuation. Dose reductions due to an adverse reaction occurred in 14% of patients who received HEPZATO.
Adverse reactions which required dose reductions occurring in ≥ 2% of patients were platelet count decreased (6%), neutropenia (4.2%), anemia (2.1%), and thrombocytopenia (2.1%). Adverse reactions that required dosage interruption in ≥ 2% of patients who received HEPZATO were platelet count decreased (6%), neutropenia (5%), thrombocytopenia (3.2%), anemia (3.2%) and febrile neutropenia (2.1%). The most common (≥20%) adverse reactions or laboratory abnormalities reported in patients treated with HEPZATO were thrombocytopenia (65%), fatigue (65%), anemia (63%), nausea (57%), musculoskeletal pain (46%), leukopenia (46%), abdominal pain (39%), neutropenia (35%), vomiting (35%), increased alanine aminotransferase (32%), prolonged activated partial thromboplastin time (28%), increased aspartate aminotransferase (28%), increased blood alkaline phosphatase (27%), and dyspnea (23%).
Table 2 and Table 3 summarize adverse reactions and laboratory abnormalities, respectively, that occurred in FOCUS. Table 2 All Adverse Reactions Observed at a Frequency of >10% in Patients Treated with HEPZATO 1 Represents a composite of multiple, related preferred terms All Adverse Reactions N=95 All Grades (%) Grades 3 or 4 (%) Gastrointestinal disorders Nausea 57 0 Abdominal Pain 1 39 1 Vomiting 1 35 0 Diarrhea 1 17 1 General disorders Fatigue 1 65 0 Pyrexia 1 16 0 Musculoskeletal And Connective Tissue Disorders Musculoskeletal Pain 1 46 1 Groin Pain 11 0 Respiratory disorders Dyspnea 1 23 2 Cough 1 15 0 Nervous system disorders Headache 1 19 0 Lethargy 12 0 Dizziness 1 11 0 Injury and procedural complications Contusion 17 0 Metabolism and nutrition disorders Decreased appetite 16 0 Vascular disorders Hemorrhage 1 15 1 Hypotension 1 13 3 Table 3: Laboratory Abnormalities Observed at a Frequency of >10% in Patients Treated with HEPZATO a Represents a composite of multiple, related preferred terms Laboratory Abnormality All Laboratory Abnormalities N=95 All Grades (%) Grades 3 or 4 (%) Platelets decreased a 65 55 Hemoglobin decreased a 63 33 Leukocytes decreased a 46 34 Neutrophils decreased a 35 30 Alanine aminotransferase increased 32 3 International normalized ratio increased 31 8 Activated partial thromboplastin time prolonged 28 8 Aspartate aminotransferase increased 28 4 Blood alkaline phosphatase increased 27 2 Calcium decreased 13 3 Troponin I increased 13 2 Blood bilirubin increased 11 3
Composition
Active ingredients
MELPHALAN HYDROCHLORIDE EQ 50MG BASE/VIAL
Official product information
Drugs@FDA lists the approved labels, letters and reviews for application NDA201848.
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
