Gamifant Drug Information

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. adult and pediatric patients with HLH/macrophage activation syndrome (MAS) in known or suspected Still’s disease, including systemic Juvenile Idiopathic Arthritis (sJIA), with an inadequate response or intolerance to glucocorticoids, or with recurrent MAS.

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. 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.

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. Table 1.

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.

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 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.

Dose Modification Based on Response for Primary Hemophagocytic Lymphohistiocytosis The GAMIFANT dose may be titrated up if disease response is unsatisfactory (see Table 2). After the patient's clinical condition is stabilized, decrease the dose to the previous level to maintain clinical response. Table 2: Dose Titration Criteria

Dose Modification Based on Response for Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome Table 3: Dosage Adjustment Criteria

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.

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.

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.

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Primary HLH The safety data described in this section reflect exposure to GAMIFANT in which 34 patients with untreated primary HLH and previously treated patients with primary HLH ( NCT01818492 ) received GAMIFANT at a starting dose of 1 mg/kg every 3 days with dose increases up to 10 mg/kg. Serious adverse reactions were reported in 53% of patients.

The most common serious adverse reactions (≥3%) included infections, gastrointestinal hemorrhage, and multiple organ dysfunction. Fatal adverse reactions occurred in two (6%) of patients and included septic shock and gastrointestinal hemorrhage. Disseminated histoplasmosis led to drug discontinuation in one patient.

The most commonly reported adverse reactions (≥20%) were infections, hypertension, infusion-related reactions, and pyrexia. Adverse reactions reported in ≥10% of patients during treatment with GAMIFANT are presented in Table 4. Table 4: a Includes viral, bacterial, fungal, and infections in which no pathogen was identified b Includes secondary hypertension c Includes events of drug eruption, pyrexia, rash, erythema, and hyperhidrosis Additional selected adverse reactions (all grades) that were reported in less than 10% of patients treated with GAMIFANT included: vomiting, acute kidney injury, asthenia, bradycardia, dyspnea, gastro-intestinal hemorrhage, epistaxis, and peripheral edema.

HLH/MAS The safety of GAMIFANT was evaluated in two open-label clinical studies in patients with HLH/MAS in Stills disease, including sJIA. Serious adverse reactions were reported in 12 patients (31%), with the most common serious adverse reaction being pneumonia (5%). Fatal adverse reactions occurred in two patients (5%) and included multiple organ dysfunction and circulatory shock.

Pneumonia led to drug discontinuation in one patient (3%). The most common adverse reactions (≥20%) were viral infections, including cytomegalovirus infection or reactivation, and rash. Table 5: Adverse Reactions Reported in ≥10% of Patients with HLH/MAS in Still's disease, Adenovirus test positive, Cytomegalovirus test positive, BK polyomavirus test positive, Respirovirus test positive, Parainfluenzae virus infection, COVID-19, Rhinovirus infection, gastroenteritis Rotavirus, Adenovirus infection, Human herpesvirus 6 infection reactivation, Adenovirus reactivation b Includes: rash maculo-papular, rash erythematous, rash pruritic, urticaria c Includes: anemia macrocytic, and hypochromic anemia d Includes: granulocytopenia, neutropenia e Infusion-related reactions were defined as any event reported to have occurred within 24 hours after the start of infusion and assessed as related to study treatment

Effect of GAMIFANT on Cytochrome P450 Substrates

The formation of CYP450 enzymes may be suppressed by increased levels of cytokines (such as IFNγ) during chronic inflammation. By neutralizing IFNγ, use of GAMIFANT may normalize CYP450 activities which may reduce the efficacy of drugs that are CYP450 substrates due to increased metabolism. Upon initiation or discontinuation of concomitant GAMIFANT, monitor for reduced efficacy and adjust dosage of CYP450 substrate drugs as appropriate.

Pregnancy Risk Summary There are no available data on GAMIFANT use in pregnant women to inform a drug-associated risk of adverse developmental outcomes. In an animal reproduction study, a murine surrogate anti-mouse IFNγ antibody administered to pregnant mice throughout gestation crossed the placental barrier, and no fetal harm was observed (see Data ). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively. Data Animal Data In a mouse embryo-fetal development study, a murine surrogate anti-mouse IFNγ antibody was administered every 3-4 days throughout organogenesis and late gestation at doses of mg/kg/occasion.

The surrogate antibody was detected in the plasma of all treated pregnant mice and their corresponding fetuses. No maternal toxicity occurred and there was no evidence of teratogenicity or effects on embryo-fetal survival or growth.

Pediatric Use Safety and effectiveness of GAMIFANT have been established in pediatric patients with primary HLH that is reactivated or refractory to conventional therapies and with HLH/MAS in Still’s Disease (including sJIA) with an inadequate response to glucocorticoids.

Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.