Pombiliti + Opfolda

 Pregnancy Evaluation Prior to Initiating Treatment

Verify the pregnancy status of females of reproductive potential prior to initiating POMBILITI in combination with Opfolda [see Use in Specific Populations (8.1, 8.3)].

 Recommended Dosage and Administration

POMBILITI must be administered in combination with Opfolda (see Figure 1 for the dosing timeline). If the Opfolda dose is missed, POMBILITI should not be administered. Refer to the Opfolda Prescribing Information for Opfolda dosage and administration recommendations.

Prior to POMBILITI administration, consider pretreating with antihistamines, antipyretics, and/or corticosteroids [see Warnings and Precautions (5.1, 5.2)]. If premedication was used with previous enzyme replacement therapy (ERT), prior to POMBILITI administration, pretreat with antihistamines, antipyretics, and/or corticosteroids.

The recommended dosage of POMBILITI is 20 mg/kg (of actual body weight) administered every other week as an intravenous infusion over approximately 4 hours (see Table 1 for the recommended total infusion volume based on the patient’s weight).

Start POMBILITI in combination with Opfolda 2 weeks after the last ERT dose.

Initiate the POMBILITI infusion approximately 1 hour after oral administration of Opfolda. If the POMBILITI infusion cannot be started within 3 hours of oral administration of Opfolda, reschedule POMBILITI in combination with Opfolda at least 24 hours after Opfolda was last taken. If POMBILITI in combination with Opfolda are both missed, re-start treatment as soon as possible.

Figure 1. Dosing Timeline

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

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

In the event of a mild to moderate hypersensitivity reaction or moderate IAR, consider temporarily holding or slowing the infusion rate and initiating appropriate medical treatment [see Warnings and Precautions (5.1, 5.2)]. If symptoms:

• Persist despite temporarily holding or slowing the infusion, stop the infusion for 30 to 60 minutes, monitor the patient, and consider resuming the infusion at a reduced rate if symptoms have improved. If symptoms continue to persist, discontinue the infusion, and consider re-initiating the infusion within 7 to 14 days with appropriate premedication.
• Subside following holding or slowing the infusion, increase the infusion rate to the rate at which the reaction occurred and consider continuing to increase the rate (every 30 minutes) in a stepwise manner up to the target infusion rate. Closely monitor the patient.

 Reconstitution and Dilution Instructions

Use aseptic technique during preparation. Reconstitute and dilute POMBILITI in the following manner:

Reconstitute the Lyophilized Powder

• Determine the number of POMBILITI vials to be reconstituted based on the calculated dose (based on patient’s actual body weight in kg) [see ].
• Remove vials from the refrigerator and set aside for approximately 30 minutes to allow vials to come to room temperature.
• Reconstitute each vial by slowly injecting 7.2 mL of Sterile Water for Injection, down the inside wall of each vial to avoid foaming. Avoid forceful impact of Sterile Water for Injection on the lyophilized powder and avoid foaming.
• Roll and tilt each vial to allow the lyophilized powder to dissolve completely which typically takes 2 minutes. Each vial will yield a concentration of 15 mg/mL. Do not invert, swirl, or shake.
• Visually inspect the reconstituted solution for particulate matter and discoloration. The reconstituted solution appears as a clear to opalescent, colorless to yellowish solution essentially particle free. Discard if foreign matter is observed or the solution is discolored.

Dilute the Reconstituted Solution

• Remove airspace within a bag of 0.9% Sodium Chloride Injection. Remove an equal volume of 0.9% Sodium Chloride Injection from the bag that will be replaced by the total volume (mL) of reconstituted POMBILITI (see Table 1 for the recommended total infusion volume based on the patient’s weight).
• Slowly withdraw 7 mL of reconstituted solution from each of the vials until the patient’s dose is obtained. Discard any remaining reconstituted solution in the last vial.
• Add the reconstituted solution slowly and directly into the infusion bag.
• To prevent foaming, gently invert infusion bag to mix the solution and avoid vigorous shaking or agitation. After dilution, the solution will have a final concentration of 0.5 to 4 mg/mL of cipaglucosidase alfa-atga. Do not use a pneumatic tube to transport the infusion bag.
• Administer the diluted solution at room temperature without delay [see ].

 Storage Instructions for the Reconstituted and Diluted Product

Storage of the Reconstituted Solution
If the reconstituted POMBILITI vials are not used immediately, store refrigerated at 2°C to 8°C (36°F to 46°F) for up to 24 hours. Do not freeze.

Storage of the Diluted Solution
If the diluted solution is not administered immediately, store refrigerated at 2°C to 8°C (36°F to 46°F) for up to 16 hours. Storage at room temperature is not recommended. Do not freeze.

 After removal of the diluted solution from the refrigerator:

• Completely infuse within 6 hours.
• Do not restore in the refrigerator.

 Discard the diluted solution if refrigerated more than 16 hours or if the diluted solution is not able to be completely infused within 6 hours after removal from the refrigerator.

 Administration Instructions

Prior to administration, inspect the infusion bag for foaming. If foaming is present, let foam dissipate before administering POMBILITI. If the diluted solution has been refrigerated, allow solution to equilibrate to room temperature for 30 minutes prior to infusion.

Use an administration set with an inline low protein binding 0.2‑micron filter to administer POMBILITI. Change filter if the filter becomes blocked.

Initiate the POMBILITI infusion approximately 1 hour after oral administration of Opfolda. In the event of POMBILITI infusion delay, the starting infusion time should not exceed 3 hours from the oral administration of Opfolda [see ].

The initial recommended infusion rate is 1 mg/kg/hour (see Table 1). Gradually increase the infusion rate by 2 mg/kg/hour every 30 minutes if there are no signs of hypersensitivity or infusion-associated reactions (IARs) until a maximum rate of 7 mg/kg/hour is reached; then, maintain the infusion rate at 7 mg/kg/hour until the infusion is complete. The approximate total infusion duration is 4 hours.

See Table 1 for the rate of infusion at each step, expressed as mL/hour based on the recommended infusion volume by patient weight.

Do not infuse POMBILITI in the same intravenous line with other products.

Table 1. Recommended POMBILITI Infusion Volumes and Rates by Patient Weight

Pregnancy

Risk Summary

Based on findings from animal reproduction studies, POMBILITI in combination with Opfolda may cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy. In a rabbit embryo-fetal development study, great vessel and cardiac malformations were increased in offspring of pregnant rabbits treated with cipaglucosidase alfa-atga in combination with miglustat at 16-fold and 3-fold, respectively, the MRHD of POMBILITI and Opfolda based on plasma AUC exposure. A No Observed Adverse Effect Level (NOAEL) was not identified for the combination. In a pre- and post-natal development study in rats, increases in pup mortality were seen following maternal treatment with cipaglucosidase alfa-atga (400 mg/kg) in combination with miglustat, or with cipaglucosidase alfa-atga (400 mg/kg) alone. The NOAEL for cipaglucosidase alfa-atga alone is 150 mg/kg (5-fold the POMBILITI MRHD margin). A NOAEL for the combination was not identified. Margins at the lowest observed adverse effect level (LOAEL), relative to exposures at the MRHD of POMBILITI and Opfolda were 20-fold and 4-fold, respectively, based on plasma AUC exposure (see Data).

There are no available human data on POMBILITI in combination with Opfolda use in pregnant females to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes.

Data

Animal Data

Reproductive toxicity studies of cipaglucosidase alfa-atga in rats and rabbits included pretreatment with diphenhydramine (DPH) to prevent or minimize hypersensitivity reactions.

In a rabbit embryo-fetal development study, cipaglucosidase alfa-atga (30, 70, or 175 mg/kg) was administered intravenously every other day to pregnant females during organogenesis (Gestation Day [GD] 7 through GD 19). Additional experimental groups received 25 mg/kg oral miglustat alone, or in combination with intravenous cipaglucosidase alfa-atga 175 mg/kg, with the same dosing frequency during organogenesis. Clusters of great vessel and cardiac malformations were increased in offspring of pregnant rabbits treated with the combination of cipaglucosidase alfa-atga and miglustat at 16-fold and 3-fold the MRHD of POMBILITI and Opfolda, respectively, based on plasma AUC exposure. A NOAEL for the combination was not identified. One fetus treated with cipaglucosidase alfa-atga alone (175 mg/kg) and one fetus treated with miglustat alone (25 mg/kg), each showed a similar cluster of these great vessel and cardiac malformations.

In a rat embryo-fetal development study, cipaglucosidase alfa-atga (75, 150, or 400 mg/kg) was administered intravenously every other day to pregnant rats during organogenesis (GD 6 through GD 18). Additional experimental groups received 60 mg/kg oral miglustat alone, or in combination with intravenous cipaglucosidase alfa-atga 400 mg/kg, with the same dosing frequency during organogenesis. No evidence of adverse effects was noted in pregnant rats or their offspring in any experimental group. The margin at the NOAEL for cipaglucosidase alfa‑atga (400 mg/kg) was 20-fold the POMBILITI MRHD based on plasma AUC exposure. The margin at the NOAEL for miglustat (60 mg/kg) was 4-fold the Opfolda MRHD based on plasma AUC exposure.

In a pre-and post-natal development study in rats, cipaglucosidase alfa-atga (75, 150, or 400 mg/kg) was administered intravenously every other day to pregnant females from GD 6 through GD 18, and from Lactation Day (LD) 1 through LD 19. Additional experimental groups received 60 mg/kg oral miglustat alone, or in combination with intravenous cipaglucosidase alfa‑atga 400 mg/kg, with the same dosing frequency during pregnancy and lactation. Maternal and pup mortality were increased with the combination, and pup mortality was also increased with cipaglucosidase alfa-atga 400 mg/kg alone. The NOAEL for cipaglucosidase alfa-atga alone is 150 mg/kg (5-fold the POMBILITI MRHD margin). A NOAEL was not identified for the combination, for which LOAEL margins at the MRHD of POMBILITI and Opfolda were 20-fold and 4-fold, respectively, based on plasma AUC exposure.

Lactation

Risk Summary

There are no data on the presence of cipaglucosidase alfa-atga, alone or in combination with miglustat, in human milk, the effects on the breastfed infant, or the effects on milk production. Cipaglucosidase alfa‑atga is present in animal milk (see Data). When a drug is present in animal milk, it is likely that the drug will be present in human milk. Based on findings in animal studies, the use of POMBILITI in combination with Opfolda may lead to serious adverse reactions in breastfed infants. Advise females that breastfeeding is not recommended while on treatment with POMBILITI in combination with Opfolda.

Data

Evaluation of milk in rats from the pre- and post-natal development study of cipaglucosidase alfa atga in combination with miglustat (400 mg/kg and 60 mg/kg, respectively) showed excretion of cipaglucosidase alfa-atga and secretion of miglustat in rat milk. In this study, the ratio of cipaglucosidase alfa-atga exposure in rat milk to cipaglucosidase alfa-atga exposure in rat plasma was <4%, and the ratio of miglustat exposure in rat milk to the miglustat exposure in rat plasma was 1.7.
The concentration of drug in animal milk does not necessarily predict the concentration of drug in human milk.

Females and Males of Reproductive Potential

POMBILITI in combination with Opfolda may cause embryo-fetal harm when administered to a pregnant female [see Use in Specific Populations (8.1)].

Pregnancy Testing

Verify the pregnancy status in females of reproductive potential prior to initiating treatment with POMBILITI in combination with Opfolda.

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with POMBILITI in combination with Opfolda and for at least 60 days after the last dose.

Infertility

Females

Based on preimplantation loss observed in female rats treated with intravenous cipaglucosidase alfa-atga (400 mg/kg) in combination with oral miglustat (60 mg/kg) every other day for 14 days prior to mating, and continuing through GD 7, POMBILITI in combination with Opfolda may impair human female fertility. A NOAEL for the combination was not identified. The LOAEL margins are 27-fold and 4-fold the MRHD for POMBILITI and Opfolda, respectively. It is not known whether this preimplantation loss in female rats would be sustained if dosing with the combination were discontinued prior to mating [see Nonclinical Toxicology (13.1)].

Males

Based on reversible increases in preimplantation loss in male rats treated with the combination every other day for 28 days prior to mating, POMBILITI in combination with Opfolda may impair human male fertility. A NOAEL for the combination was not identified. The LOAEL margins are 27-fold and 4-fold the MRHD for POMBILITI and Opfolda, respectively [see Nonclinical Toxicology (13.1)].

For additional information about male fertility with the use of Opfolda, see the Opfolda Prescribing Information.

Pediatric Use

Safety and effectiveness of POMBILITI in combination with Opfolda have not been established in pediatric patients with late-onset Pompe disease.

Geriatric Use

Of the total number of patients treated with POMBILITI in combination with Opfolda in clinical trials for LOPD, 17 (11%) were 65 to 74 years of age, and none were 75 years of age and older [see Clinical Studies (14)].

Clinical trials of POMBILITI in combination with Opfolda did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients.