Hepzato Drug Information

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.

Important Pre-Treatment and Administration Information HEPZATO is a component of the HEPZATO KIT Hepatic Delivery System. Refer to the HEPZATO KIT Hepatic Delivery System Instructions for Use (IFU) for additional instructions including pre-infusion evaluation, hydration, premedication, anticoagulation, and supportive care. Caution: The double balloon catheter component of the HDS contains natural rubber latex which may cause allergic reactions.

Healthcare providers must complete the required HEPZATO KIT REMS training prior to administration of the HEPZATO KIT. Discontinue oral anticoagulation and drugs affecting platelet function prior to the procedure. Discontinue ACE-inhibitors, calcium channel blockers, or alpha-1-adrenergic blockers prior to the procedure.

Conduct baseline hematologic testing. Administer intra-hepatic HEPZATO with the HEPZATO KIT only to patients with the following. Hemoglobin ≥ 10 g/dL Platelets ≥ 100,000/microliter Neutrophils > 2000/microliter

Recommended Dosage Administer

HEPZATO via the HEPZATO KIT Hepatic Delivery System only to patients weighing 35 kg or greater due to potential size limitations with respect to percutaneous catheterization. HEPZATO, a component of the HEPZATO KIT, is administered by infusion into the hepatic artery (see IFU) every 6 to 8 weeks for up to 6 total infusions. The recommended HEPZATO dose is 3 mg/kg based on ideal body weight (IBW), as calculated per Table 1 below, with a maximum of 220 mg during a single treatment.

Table 1: Calculation of IBW for HEPZATO Dosing

Dosage Modifications for Adverse Reactions

A dosage reduction to 2 mg/kg is recommended for subsequent treatments for the following reasons: Grade 4 neutropenia of > 5 days duration despite growth factor support or associated with neutropenic fever; Grade 4 thrombocytopenia of > 5 days duration or associated with a hemorrhage that required a transfusion; HEPZATO administered with the HEPZATO KIT should be discontinued if patients have life threatening or HEPZATO-related persistent toxicity that has not resolved to Grade 2 or less by 8 weeks following treatment.

Preparation and Administration Refer to the HEPZATO KIT Hepatic Delivery System IFU for further details and instructions. Reconstitute and dilute melphalan immediately prior to beginning intra-arterial infusion. Reconstituted and diluted solutions of HEPZATO are unstable.

No more than 60 minutes should elapse from reconstitution and completion of the intra-hepatic infusion of the diluted HEPZATO solution. A citrate derivative of melphalan has been detected in reconstituted HEPZATO in 30 minutes, and nearly 1% of labeled strength of melphalan hydrolyzes every 10 minutes when reconstituted HEPZATO is further diluted in 0.9% Sodium Chloride. A precipitate forms if the reconstituted solution is stored at 5°C.

Do not refrigerate HEPZATO once reconstituted. HEPZATO is a hazardous drug 1. Follow applicable special handling and disposal procedures.

Reconstitution and Dilution Instructions: Rapidly (in 5 seconds or less) inject 10 mL of the supplied sterile diluent into the HEPZATO 50 mg vial using a sterile needle (20-gauge or larger) and syringe. The resulting solution will contain melphalan 5 mg/mL Immediately shake the vial vigorously until a clear solution is obtained. No more than five seconds should elapse between the discharge of the syringe and the commencement of shaking.

If particulates and discolorations are noted, the product should not be used. Administer diluted HEPZATO intra-arterially as described in the IFU. Complete the infusion within 30 minutes, followed by a 30-minute washout period.

Refer to the IFU for additional administration procedures.

Clinical 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. 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. Table 2 and Table 3 summarize adverse reactions and laboratory abnormalities, respectively, that occurred in FOCUS.

Pregnancy 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. Melphalan is a genotoxic drug and can cause chromatid or chromosome damage in humans. In animal studies, melphalan was embryolethal and teratogenic in rats at doses below the recommended clinical doses.

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. Data Animal Data Adequate animal studies have not been conducted with IV melphalan.

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).

Pediatric Use The safety and effectiveness in pediatric patients have not been established.

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