2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosing

The recommended starting dose of GAMIFANT is 1 mg/kg given as an 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 ( 2.4)] .

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 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 tuberculosis, adenovirus, EBV and CMV every 2 weeks and as clinically indicated.

2.3 Pre-Medications and Concomitant Medication Information

Pre-Medications

Administer prophylaxis for Herpes Zoster, Pneumocystis jirovecii, and for fungal infections prior to GAMIFANT administration.

Concomitant Medications

For patients who are not receiving baseline dexamethasone treatment, begin dexamethasone at a daily dose of at least 5 to 10 mg/m 2the 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/m 2. Dexamethasone can be tapered according to the judgment of the treating physician [see Clinical Studies ( 14)] .

2.4 Dose Modification Based on Response

The GAMIFANT dose may be titrated up if disease response is unsatisfactory (see Table 1) [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 1: Dose Titration Criteria
Treatment Day	GAMIFANT Dose	Criteria for Dose Increase
Day 1	Starting Dose of 1 mg/kg	N/A
On Day 3	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 and no improvement to > 50,000/mm 3 If baseline > 50,000/mm 3 and less than 30% improvement If baseline > 100,000/mm 3 and decrease to < 100,000/mm 3 Neutrophil count If baseline < 500/mm 3 and no improvement to > 500/mm 3 If baseline > 500-1000/mm 3 and decrease to < 500/mm 3 If baseline 1000-1500/mm 3 and decrease to < 1000/mm 3 Ferritin (ng/mL) If baseline ≥ 3000 ng/mL and < 20% decrease If baseline < 3000 ng/mL and any increase to > 3000 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 6 onwards	Increase to 6 mg/kg
From Day 9 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

2.5 Instructions for Preparation and Administration

Preparation

GAMIFANT vials are for single-use 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 an 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 prior to administration.
Do not freeze. Do not shake.