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2.1        Recommendations Prior to ELFABRIO Treatment

Pretreatment

• In enzyme replacement therapy (ERT)-experienced patients, if pretreatment with antihistamines, antipyretics, and/or corticosteroids was used prior to ERT administration, consider similar pretreatment with these medications before the first several ELFABRIO infusions. After 4 to 6 ELFABRIO infusions, a stepwise decrease in the pretreatment medication dose(s) and/or discontinuation of the pretreatment medication(s) may be considered if treatment with ELFABRIO was tolerated.
  
• In ERT-naïve patients, prior to ELFABRIO administration, pre-treating with antihistamines, antipyretics, and/or corticosteroids may be considered [see Warnings and Precautions ( 5.1, 5.2)].

Medical Support

Appropriate medical support measures including cardiopulmonary resuscitation equipment should be readily available during ELFABRIO administration.

2.2        Recommended Dosage and Administration

The recommended dosage of ELFABRIO, based on actual body weight, is 1 mg/kg administered by intravenous infusion every 2 weeks.

The initial recommended ELFABRIO infusion rates for ERT-experienced or ERT-naïve patients are based on actual body weight [see Tables 1 and 2].

If one or more doses are missed, restart ELFABRIO treatment as soon as possible, maintaining the 2 week interval between infusions thereafter. Do not double a dose to compensate for a missed dose.

2.3        Administration Modifications Due to Hypersensitivity Reactions and/or Infusion-Associated Reactions

In the event of a severe hypersensitivity reaction (e.g., anaphylaxis) or severe infusion-associated reaction (IAR), immediately discontinue ELFABRIO administration and initiate appropriate medical treatment. For additional recommendations in the event of a severe hypersensitivity reaction or IAR, see Warnings and Precautions ( 5.1, 5.2).

In the event of a mild to moderate hypersensitivity reaction or a mild to moderate IAR, consider temporarily holding the infusion for 15 to 30 minutes or slowing the infusion rate by 25% to 50% [see Dosage and Administration ( 2.6)], and initiating appropriate medical treatment [see Warnings and Precautions ( 5.1, 5.2)]. 

• If symptoms persist despite holding or slowing the infusion, stop the infusion and monitor the patient. Consider re-initiating the infusion within 7 to 14 days at 25% to 50% of the rate at which the reaction occurred with appropriate pretreatment.
  
• If symptoms subside after holding the infusion, resume infusion at a 25% to 50% reduced rate as tolerated. Alternatively, if symptoms subside after slowing the infusion, complete infusion at the reduced rate as tolerated.
  
• Starting with the next infusion, increase the infusion rate by increments of 25% every third infusion as tolerated until the infusion rate at which the reaction occurred is reached. Closely monitor the patient.

2.4        Preparation Instructions

Use aseptic technique during preparation. Dilute ELFABRIO in the following manner:

• Determine the number of ELFABRIO vials to be diluted based on actual body weight in kg and the recommended dose [see Dosage and Administration ( 2.2) and Dosage Forms and Strengths ( 3)]. Round the number of vials up to the next whole number.
  
• Remove the appropriate number of ELFABRIO vials from the refrigerator and allow the vials to sit for 15-30 minutes at room temperature 20°C to 25°C (68°F to 77°F) before use. Do not use an external heat source to heat the product because heat may damage the product.
  
• Visually inspect the solution in the vials for particulate matter and discoloration. The solution should be clear and colorless. Discard if the solution is discolored or if visible particulate matter is present.
  
• Dilute the supplied ELFABRIO solution required for a dose in 0.9% Sodium Chloride Injection to a total volume based on actual body weight specified in Tables 1 and 2 below.
  
• Prior to adding the volume of ELFABRIO required for the dose, remove the equal volume of 0.9% Sodium Chloride Injection from the infusion bag.
  
• Withdraw the volume of ELFABRIO required for the dose from the vials (discard any unused solution remaining in the vial).
  
• Inject the ELFABRIO solution directly into the 0.9% Sodium Chloride Injection solution through the port of the infusion bag. Do not inject in the airspace within the infusion bag.
  
• Gently invert infusion bag to mix the solution. Avoid vigorous shaking or agitation.

2.5        Storage of the Diluted Solution

• If the diluted ELFABRIO solution is not used immediately:
  ○ Refrigerate the diluted solution at 2°C to 8°C (36°F to 46°F) for up to 24 hours. The solution must be infused within 8 hours after removal from the refrigerator, inclusive of the total infusion time, or discarded.
  ○ Store the diluted solution at room temperature at 20°C to 25°C (68°F to 77°F) for up to 8 hours. The solution must be used within 8 hours, inclusive of infusion time, or discarded.
  
• Do not freeze or shake.

2.6        Administration Instructions

Administer ELFABRIO as follows:

• Use an in-line low protein-binding, 0.2 micron, in-line filter during administration.
  
• For the initial 4-6 infusions, infuse ELFABRIO using the infusion rates described in Table 1 for ERT-experienced patients and Table 2 for ERT-naïve patients.
  
• If a patient tolerates the initial 4-6 ELFABRIO infusions, the duration of every third infusion may be decreased in decrements of 30 minutes as tolerated. The minimum recommended infusion duration is 1.5 hours.
  
• At the end of the infusion, flush the line with 0.9% Sodium Chloride Injection using the same infusion rate as the one used for the last part of the ELFABRIO infusion.
  
• Do not infuse ELFABRIO in the same intravenous line with other products.

Table 1 presents the recommended infusion rates for the initial 4-6 ELFABRIO infusions based on actual body weight for ERT-experienced patients.

1 Infusion rate may be increased if the patient tolerates the initial 4-6 infusions (see above). Infusion rate may be slowed in case of a hypersensitivity reaction or an IAR [see Dosage and Administration ( 2.3)].

Table 2 presents the recommended infusion rates for the initial 4-6 ELFABRIO infusions based on actual body weight for ERT-naïve patients.

1 Infusion rate may be increased if the patient tolerates the initial 4-6 infusions (see above). Infusion rate may be slowed in case of a hypersensitivity reaction or an IAR [see Dosage and Administration ( 2.3)].

Administration of ELFABRIO to Patients Previously Treated with ERT with an Infusion Duration Over 3 Hours

In patients previously treated with an ERT with an infusion duration over 3 hours:

• Use the same infusion rate for the ELFABRIO infusion.
  
• May decrease the duration of every third infusion after the initial 4-6 ELFABRIO infusions in decrements of 30 minutes as tolerated. The recommended minimum infusion duration of the maintenance infusion is 1.5 hours.

Home Infusion

Home administration under the supervision of a healthcare provider may be considered for patients who have reached an infusion duration that is tolerated well [see Dosage and Administration ( 2.1, 2.3)]. The decision to have a patient move to home infusion should be made after evaluation and recommendation by a healthcare provider.

The infusion duration should remain constant for home administration and the duration should only be decreased in a healthcare facility. In case of a missed dose or delayed infusion, a healthcare provider should be contacted.

8.1        Pregnancy

Risk Summary

There are no available data on ELFABRIO use in pregnant females to evaluate a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes; however, as an enzyme replacement, ELFABRIO is not expected to cause adverse outcomes. Animal reproduction studies have been conducted with pegunigalsidase alfa-iwxj in pregnant rats and rabbits. No adverse effects on embryofetal development were observed in pregnant rats intravenously administered pegunigalsidase alfa-iwxj twice per week at exposures up to 3.6 times that of the maximum recommended human dose (MRHD) (based on area under the concentration-time curve (AUC)). Maternal toxicity was observed in pregnant rabbits intravenously administered pegunigalsidase alfa-iwxj twice per week at doses that were ≥ 3.2 times the MRHD (based on human equivalent dose) [see Data].

The estimated background risk of major birth defects and miscarriage in 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 2% to 4% and 15% to 20%, respectively.

There is a pregnancy safety study for ELFABRIO. If a patient becomes pregnant while receiving ELFABRIO, healthcare providers should report ELFABRIO exposure by calling 1-888-661-9260 or visiting https://chiesirarediseases.com/contact-us/medical-information-form.

Data

Animal Data

In an embryofetal development study in the rat, pegunigalsidase alfa-iwxj was administered during the period of organogenesis on gestation day 6, 9, 12, and 15. No maternal or fetal adverse effects were noted at exposures that were up to 3.6-fold greater than the recommended dose of 1 mg/kg every two weeks.

In an embryofetal development study in the rabbit, administration of pegunigalsidase alfa-iwxj during the period of organogenesis on gestation day 6, 9, 12, 15, and 18, resulted in maternal toxicity, including maternal mortality, decreased body weight, and decreased feed consumption. These effects were observed at exposures that were ≥ 3.2-fold greater than the recommended dose of 1 mg/kg every two weeks. Adverse embryofetal effects included abortion, increased late resorptions, number of does with resorptions, and increased post-implantation loss at exposures that were 6.5 fold greater than the recommended dose of 1 mg/kg every two weeks. Decreased fetal body weight was observed at exposures that were ≥ 3.2 times greater than the recommended dose of 1 mg/kg every two weeks. There was no increase in fetal external, skeletal, or visceral malformations.

8.2        Lactation

Risk Summary

There are no data on the presence of pegunigalsidase alfa-iwxj in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ELFABRIO and any potential adverse effects on the breastfed infant from pegunigalsidase alfa-iwxj or from the underlying maternal condition.

8.4        Pediatric Use

The safety and effectiveness of ELFABRIO have not been established in pediatric patients.

8.5        Geriatric Use

Clinical trials of ELFABRIO did not include patients 65 years of age and older to determine if they respond differently from younger adult patients.

8.6        Patients with Prior Enzyme Replacement Therapy

Patients that received prior ERT are more likely to have pre-existing anti-drug antibodies (ADA) to pegunigalsidase alfa-iwxj which could be due to the ADA cross-reactivity to pegunigalsidase alfa-iwxj by prior ERT. When switching from other ERT to ELFABRIO:

• Pre-existing ADA may reduce the plasma pegunigalsidase alfa-iwxj concentrations, which may reduce ELFABRIO efficacy [see Clinical Pharmacology ( 12.2,  12.6)].
  
• The risk of ELFABRIO-related hypersensitivity and infusion-associated reactions may be increased in certain patients with pre-existing ADA from prior ERT [see Warnings and Precautions ( 5.1, 5.2) and Adverse Reactions ( 6.1)].

Consider monitoring clinical or pharmacodynamic responses (e.g., plasma lyso-Gb3 levels) when switching from agalsidase beta to ELFABRIO, in patients with pre-existing ADA.