GAMIFANT

2 DOSAGE AND ADMINISTRATION For intravenous infusion only: Primary HLH recommended starting dosage: 1 mg/kg as an intravenous infusion over 1 hour twice per week. ( 2.1 ) HLH/MAS in Still’s disease recommended dosage schedule: 6 mg/kg, followed by 3 mg/kg every 3 days for 5 doses, then 3 mg/kg twice per week. Given as an intravenous infusion over 1 hour. ( 2.2 ) For both indications, the dose may be titrated up to a maximum of 10 mg/kg. ( 2.5 , 2.6 ) 2.1 Recommended Dosage for Primary Hemophagocytic Lymphohistiocytosis The recommended starting dose of GAMIFANT is 1 mg/kg given as a central or peripheral intravenous infusion over 1 hour twice per week (every three to four days). Doses subsequent to the initial dose may be increased based on clinical and laboratory criteria [see Dosage and Administration ( 2.5 )] . Administer GAMIFANT until hematopoietic stem cell transplantation (HSCT) is performed or unacceptable toxicity. Discontinue GAMIFANT when a patient no longer requires therapy for the treatment of HLH. 2.2 Recommended Dosage for Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome GAMIFANT is administered as a central or peripheral intravenous infusion over 1 hour according to the dosage schedule in Table 1. Doses may be increased based on clinical and laboratory criteria [see Dosage and Administration ( 2.6 )] . Discontinue GAMIFANT when a patient no longer requires therapy for the treatment of HLH/MAS. Table 1. GAMIFANT Dosage in Patients with HLH/MAS Treatment Day GAMIFANT Dosage Day 1 6 mg/kg Days 4 to 16 3 mg/kg every 3 days for 5 doses From Day 19 onward 3 mg/kg twice per week (i.e., every 3 to 4 days) 2.3 Monitoring to Assess Safety Before Initiating GAMIFANT Treatment Conduct testing for latent tuberculosis infections using the purified protein derivative (PPD) or IFNγ release assay and evaluate patients for tuberculosis risk factors prior to initiating GAMIFANT. Administer tuberculosis prophylaxis to patients at risk for tuberculosis, or known to have a positive PPD test result, or positive IFNγ release assay. During GAMIFANT Treatment Monitor for herpes zoster infection, adenovirus, EBV and CMV as clinically indicated. 2.4 Prophylaxis and Concomitant Medication Information Prophylaxis Consider prophylaxis for herpes zoster, Pneumocystis jirovecii , and for fungal infections prior to GAMIFANT administration. Concomitant Medications For primary HLH patients who are not receiving baseline dexamethasone treatment, begin dexamethasone at a daily dose of at least 5 mg/m 2 to 10 mg/m 2 the day before GAMIFANT treatment begins. For patients who were receiving baseline dexamethasone, they may continue their regular dose provided the dose is at least 5 mg/m2. Dexamethasone can be tapered according to the judgment of the treating physician [see Clinical Studies ( 14 )] . 2.5 Dose Modification Based on Response for Primary Hemophagocytic Lymphohistiocytosis The GAMIFANT dose may be titrated up if disease response is unsatisfactory (see Table 2) [see Clinical Pharmacology ( 12.3 )] . After the patient's clinical condition is stabilized, decrease the dose to the previous level to maintain clinical response. Table 2: Dose Titration Criteria Treatment Day GAMIFANT Dose Criteria for Dose Increase Day 1 Starting Dose of 1 mg/kg N/A From Day 4 onwards Increase to 3 mg/kg Unsatisfactory improvement in clinical condition, as assessed by a healthcare provider AND at least one of the following: Fever - persistence or recurrence Platelet count If baseline 50,000/mm 3 If baseline > 50,000/mm 3 and less than 30% improvement If baseline > 100,000/mm 3 and decrease to 500/mm 3 If baseline > 500/mm 3 to 1,000/mm 3 and decrease to 3,000 ng/mL Splenomegaly - any worsening Coagulopathy (both D-Dimer and Fibrinogen must apply) D-Dimer If abnormal at baseline and no improvement Fibrinogen (mg/dL) If baseline levels ≤100 mg/dL and no improvement If baseline levels > 100 mg/dL and any decrease to < 100 mg/dL From Day 7 onwards Increase to 6 mg/kg From Day 10 onwards Increase to 10 mg/kg Assessment by a healthcare provider that based on initial signs of response, a further increase in GAMIFANT dose can be of benefit 2.6 Dose Modification Based on Response for Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome Table 3: Dosage Adjustment Criteria Treatment Day GAMIFANT Dose Dose Adjustments Day 1 Initial dose of 6 mg/kg If unsatisfactory improvement in clinical condition, as assessed by a healthcare provider, the dose of GAMIFANT may be increased to: a maximum cumulative dose of 10 mg/kg over 3 days AND the frequency may be increased to: every 2 days or once daily After the patient’s clinical condition has improved, consider decreasing the dose to the previous level and assess whether clinical response is maintained. If the clinical condition is not stabilized while receiving the maximum dosage, consider discontinuing GAMIFANT. Days 4 to 16 3 mg/kg every 3 days for 5 doses From Day 19 onwards 3 mg/kg twice per week (i.e., every 3 to 4 days) 2.7 Instructions for Preparation and Administration Preparation GAMIFANT vials are for single dose only. Do not mix GAMIFANT 5 mg/mL and 25 mg/mL vials together. Prepare the solution for infusion as follows: Calculate the dose (mg/kg), total volume (mL) of GAMIFANT required and the number of GAMIFANT vials needed based on patient actual body weight [see Dosage and Administration ( 2.1 )] . Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. GAMIFANT is a clear to slightly opalescent, colorless to slightly yellow liquid. Do not administer if discolored or foreign particulate matter is present. Withdraw the necessary amount of GAMIFANT solution and dilute with 0.9% Sodium Chloride Injection, USP. For GAMIFANT 5 mg/mL vials: Dilute to a maximum concentration of 2.5 mg/mL. Do not dilute product to less than 0.25 mg/mL. The diluted solution can be placed in either a syringe or an infusion bag, depending on the volume needed. When using a syringe, use a gamma irradiated or ethylene oxide sterilized latex-free, polyvinyl chloride (PVC)-free syringe. When using an infusion bag, use a non-PVC polyolefin infusion bag. For GAMIFANT 25 mg/mL vials: Dilute to a maximum concentration of 12.5 mg/mL. Do not dilute product to less than 1.25 mg/mL. Use a non-PVC polyolefin infusion bag made from either polyethylene or ethylene/propylene copolymer. Discard any unused portion left in the vial(s). Administration Administer GAMIFANT diluted solution intravenously over 1 hour through a central or peripheral intravenous line containing a sterile, non-pyrogenic, low-protein binding 0.2 micron in-line filter. Do not infuse GAMIFANT concomitantly with other agents and do not add any other product to the infusion bag or syringe. Do not store any unused portion of the infusion solution for reuse. Any unused product or waste material should be disposed of in accordance with local requirements. Storage of Diluted Solution This product does not contain a preservative. If not administered immediately: Store the diluted solution of GAMIFANT under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 4 hours from the time of dilution. If refrigerated, allow the diluted solution to come to room temperature, typically 20°C to 25°C (68°F to 77°F), prior to administration. Do not freeze. Do not shake.

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1 INDICATIONS AND USAGE GAMIFANT is indicated for the treatment of: adult and pediatric patients with primary hemophagocytic lymphohistiocytosis (HLH) with refractory, recurrent or progressive disease or intolerance with conventional HLH therapy.