Generic Name
Melphalan
Brand Names
Hepzato, IVRA, Evomela
FDA approval date: January 10, 2013
Classification: Alkylating Drug
Form: Injection, Kit
What is Hepzato (Melphalan)?
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.
Approved To Treat
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Brand Information
Hepzato Kit (melphalan hydrochloride injection, powder, lyophilized, for solution)
WARNING: PERI-PROCEDURAL COMPLICATIONS, MYELOSUPPRESSION
- Severe peri-procedural complications including hemorrhage, hepatocellular injury, and thromboembolic events may occur via hepatic intra-arterial administration of HEPZATO. Assess patients for these adverse reactions during and for at least 72 hours following administration of HEPZATO[see Warnings and Precautions (
- HEPZATO is available only through a restricted program under a Risk Evaluation and Mitigation Strategy called the HEPZATO KIT REMS[see Warnings and Precautions (
- Myelosuppression with resulting severe infection, bleeding, or symptomatic anemia may occur with HEPZATO. Monitor hematologic laboratory parameters and delay additional cycles of HEPZATO therapy until blood counts have improved.[see Warnings and Precautions (
1INDICATIONS AND USAGE
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.
2DOSAGE FORMS AND STRENGTHS
HEPZATO (melphalan) is supplied in the HEPZATO KIT that contains the following:
- Melphalan for injection: 5 single dose, clear glass vials for injection, containing 50 mg white to pale yellow lyophilized powder, intended for reconstitution with the supplied diluents
3CONTRAINDICATIONS
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
4ADVERSE 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 (
- Myelosuppression [see Warnings and Precautions (
- Hypersensitivity Reactions [see Warnings and Precautions (
- Gastrointestinal Adverse Reactions [see Warnings and Precautions (
- Secondary Malignancies [see Warnings and Precautions (
4.1Clinical 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%).
5OVERDOSE
No information on melphalan overdosage is available following administration of HEPZATO. Overdoses resulting in death have been reported following treatment with high intravenous (IV) doses of melphalan.
Overdoses via the IV route, including doses up to 290 mg/m
The principal toxic effect is bone marrow suppression. Hematologic parameters should be closely followed for three (3) to six (6) weeks. General supportive measures together with appropriate blood transfusions and antibiotics should be instituted as deemed necessary by the physician. General supportive measures, together with appropriate blood and platelet transfusions, should be instituted if necessary and consideration given to hospitalization, antibiotic cover, and the use of hematological growth factors.
This drug is not removed from systemic plasma to any significant degree by hemodialysis or hemoperfusion.
6DESCRIPTION
Melphalan, is a bifunctional alkylating drug that is active against selected human neoplastic diseases. Melphalan is available as melphalan hydrochloride salt. The chemical name of melphalan hydrochloride is 4-[bis(2-chloroethyl)amino]-L-phenylalanine hydrochloride. The molecular formula is C
Melphalan is practically insoluble in water and has a pKa1 of ~2.5.
HEPZATO, for injection, is supplied as a sterile, nonpyrogenic, freeze-dried white to pale yellow freeze-dried cake/ powder. Each single dose vial contains melphalan 50 mg, equivalent to 56 mg of melphalan hydrochloride and 20 mg povidone.
HEPZATO (melphalan) is reconstituted using the sterile diluent provided. Each vial of sterile diluent contains sodium citrate 0.2 g, propylene glycol 6.0 mL, ethanol (96%) 0.52 mL, and water for injection to a total of 10 mL.
HEPZATO (melphalan) for use with the hepatic delivery system is administered intra-arterially.
7REFERENCES
1OSHA Hazardous Drugs. OSHA. http://www.osha.gov/hazardous-drugs
8Patient Counseling Information
Advise patients or their caregivers of the following risks of the HEPZATO KIT: