Cipaglucosidase Alfa-atga (Monograph)

Brand name: Pombiliti
Drug class: Enzymes

Introduction

Cipaglucosidase alfa-atga is a hydrolytic lysosomal glycogen-specific recombinant human glucosidase (rhGAA) enzyme.

Uses for Cipaglucosidase Alfa-atga

Cipaglucosidase alfa-atga has the following uses:

Cipaglucosidase alfa-atga is indicated, in combination with miglustat, an enzyme stabilizer, for the treatment of adult patients with late-onset Pompe disease (lysosomal acid alpha-glucosidase [GAA] deficiency) weighing ≥40 kg and who are not improving on their current enzyme replacement therapy (ERT).

Cipaglucosidase Alfa-atga Dosage and Administration

General

Cipaglucosidase alfa-atga is available in the following dosage form(s) and strength(s):

For injection: 105 mg of cipaglucosidase alfa-atga as a lyophilized powder in a single-dose vial for reconstitution and dilution.

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

• Verify pregnancy status in females of reproductive potential prior to initiating treatment.

• Cipaglucosidase alfa-atga (Pombilti) must be administered in combination with miglustat (Opfolda). If the miglustat dose is missed, cipaglucosidase alfa should not be administered. Refer to the miglustat (Opfolda) Prescribing Information for dosage and administration recommendations.

• Consider administering antihistamines, antipyretics, and/or corticosteroids prior to cipaglucosidase alfa administration.

• Recommended cipaglucosidase alfa-atga dosage is 20 mg/kg (of actual body weight) administered every other week as an IV infusion over approximately 4 hours.

• Start cipaglucosidase alfa in combination with miglustat 2 weeks after the last ERT dose.

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

• See the full prescribing information for dosage modifications due to hypersensitivity reactions or infusion-associated reactions (IARs).

• Must be reconstituted and diluted prior to use.

• See the full prescribing information for additional details on preparation and administration.

Related/similar drugs

Nexviazyme, Pombiliti, miglustat, Lumizyme, Opfolda

Cautions for Cipaglucosidase Alfa-atga

Contraindications

Pregnancy.

Warnings/Precautions

Hypersensitivity Reactions

Prior to cipaglucosidase alfa-atga administration, consider pretreating with antihistamines, antipyretics, and/or corticosteroids. Appropriate medical support measures, including cardiopulmonary resuscitation equipment, should be readily available during cipaglucosidase alfa-atga administration.

If a severe hypersensitivity reaction (e.g., anaphylaxis) occurs, cipaglucosidase alfa should be discontinued immediately, and appropriate medical treatment should be initiated. The risks and benefits of readministering the drug following severe hypersensitivity reaction (including anaphylaxis) should be considered. Patients may be rechallenged using slower infusion rates. In patients with severe hypersensitivity reaction, desensitization measures to cipaglucosidase alfa may be considered. If the decision is made to readminister the drug, ensure the patient tolerates the infusion. If the patient tolerates the infusion, the dosage (dose and/or the rate) may be increased to reach the approved recommended dosage.

If a mild or moderate hypersensitivity reaction occurs, the infusion rate may be slowed or temporarily stopped.

Life-threatening hypersensitivity reactions, including anaphylaxis, have been reported in patients receiving cipaglucosidase alfa-atga. In clinical trials, 41 (27%) cipaglucosidase alfa-treated patients experienced hypersensitivity reactions, including 4 (3%) patients who reported severe hypersensitivity reactions and 4 (3%) additional patients who experienced anaphylaxis (fulfilling at least one of the Sampson criteria). Three of the 4 (2%) patients experiencing anaphylaxis discontinued from the trial. Two of the 4 patients who experienced anaphylaxis developed high anti-cipaglucosidase alfa-atga antibody titers. Anaphylaxis signs and symptoms included dyspnea, rash, hypotension, bronchospasm, edema, pharyngeal edema, and tongue swelling. Symptoms of severe hypersensitivity reactions included urticaria, pruritus, and flushing.

Infusion-associated Reactions

Antihistamines, antipyretics, and/or corticosteroids can be given prior to cipaglucosidase alfa-atga administration to reduce the risk of infusion-associated reactions (IARs). However, IARs may still occur in patients after receiving pretreatment.

If severe IARs occur, immediately discontinue the cipaglucosidase alfa infusion, initiate appropriate medical treatment, and assess the benefits and risks of readministering the drug following severe IARs. Patients may be rechallenged using slower infusion rates. Once a patient tolerates the infusion, the infusion rate may be increased to reach the recommended infusion rate.

In clinical trials, IARs were reported to occur at any time during and/or within a few hours after the cipaglucosidase alfa infusion and were more likely to occur with higher infusion rates. IARs were reported in 48 (32%) cipaglucosidase alfa-atga treated patients in clinical trials. In these trials, 4 (3%) cipaglucosidase alfa-atga treated patients reported 11 severe IARs including symptoms of pharyngeal edema, anaphylactic reaction, urticaria, pruritus, chills, dyspnea, and flushing. The majority of IARs were assessed as mild to moderate. IARs that led to treatment discontinuation were urticaria, anaphylactic reaction, chills, and hypotension.

Patients with an acute underlying illness at the time of cipaglucosidase alfa infusion may be at greater risk for IARs. Patients with advanced Pompe disease may have compromised cardiac and respiratory function, which may predispose them to a higher risk of severe complications from IARs.

Risk of Acute Cardiorespiratory Failure in Susceptible Patients

Patients susceptible to fluid volume overload, or those with acute underlying respiratory illness or compromised cardiac or respiratory function for whom fluid restriction is indicated may be at risk of serious exacerbation of their cardiac or respiratory status during the cipaglucosidase alfa infusion. More frequent monitoring of vitals should be performed during the infusion in these patients. Some patients may require prolonged observation times.

Embryo-fetal Toxicity

Based on findings from animal reproduction studies, cipaglucosidase alfa in combination with miglustat 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 oral miglustat at 16-fold and 3-fold, respectively, the maximum recommended human dose (MRHD) based on plasma AUC exposure.

Verify the pregnancy status in females of reproductive potential prior to initiating treatment with cipaglucosidase alfa in combination with miglustat. Advise females of reproductive potential to use effective contraception during treatment with the combination therapy and for at least 60 days after the last dose.

Risks Associated with Miglustat

Cipaglucosidase alfa must be administered in combination with miglustat (Opfolda). Refer to the Opfolda Prescribing Information for a description of additional risks including, but not limited to, the warnings and precautions for miglustat.

Specific Populations

Pregnancy

Based on findings from animal reproduction studies, cipaglucosidase alfa in combination with miglustat 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 cipaglucosidase alfa and miglustat 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 cipaglucosidase alfa 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 cipaglucosidase alfa and miglustat were 21- and 4-fold, respectively, based on plasma AUC exposure.

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

In a pre-and post-natal development study in rats, cipaglucosidase alfa-atga (75, 150, or 400 mg/kg) was administered IV 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 IV 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 cipaglucosidase alfa MRHD margin). A NOAEL was not identified for the combination, for which LOAEL margins at the MRHD of cipaglucosidase alfa and miglustat were 21-fold and 4-fold, respectively, based on plasma AUC exposure.

Lactation

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 is present in animal milk. 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 cipaglucosidase alfa in combination with miglustat may lead to serious adverse reactions in breastfed infants. Advise females that breastfeeding is not recommended while on treatment with the combination therapy.

Females and Males of Reproductive Potential

Cipaglucosidase alfa in combination with miglustat may cause embryo-fetal harm when administered to a pregnant female.

Verify the pregnancy status in females of reproductive potential prior to initiating treatment with cipaglucosidase alfa in combination with miglustat.

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

Based on preimplantation loss observed in female rats treated with IV 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, the combination therapy may impair human female fertility. A NOAEL for the combination was not identified. The LOAEL margins are 21-fold and 4-fold the MRHD for cipaglucosidase alfa and miglustat, 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.

Based on reversible increases in preimplantation loss in male rats treated with the combination every other day for 28 days prior to mating, cipaglucosidase alfa in combination with miglustat may impair human male fertility. A NOAEL for the combination was not identified. The LOAEL margins are 21-fold and 4-fold the MRHD for cipaglucosidase alfa and miglustat, respectively.

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

Pediatric Use

Safety and effectiveness of cipaglucosidase alfa-atga in combination with miglustat have not been established in pediatric patients with late-onset Pompe disease.

Geriatric Use

Of the total number of patients treated with cipaglucosidase alfa-atga in combination with miglustat in clinical trials for late-onset Pompe disease, 17 (11%) were 65 to 74 years of age, and none were 75 years of age and older.

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

Common Adverse Effects

Most common adverse reactions ≥ 5% are headache, diarrhea, fatigue, nausea, abdominal pain, and pyrexia.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Please see product labeling for drug interaction information.

Actions

Mechanism of Action

Pompe disease (also known as glycogen storage disease type II, acid maltase deficiency, and glycogenosis type II) is an inherited disorder of glycogen metabolism caused by a deficiency of lysosomal acid alpha-glucosidase (GAA) that degrades glycogen to glucose in the lysosome. GAA deficiency results in intra-lysosomal accumulation of glycogen in various tissues.

Cipaglucosidase alfa provides an exogenous source of GAA. The bis-M6P on cipaglucosidase alfa mediates binding to M6P receptors on the cell surface with high affinity. After binding, it is internalized and transported into lysosomes where it undergoes proteolytic cleavage and N-glycans trimming which are both required to yield the most mature and active form of GAA. Cipaglucosidase alfa then exerts enzymatic activity in cleaving glycogen.

Miglustat binds with, stabilizes, and reduces inactivation of cipaglucosidase alfa in the blood after infusion.

Advice to Patients

• Cipaglucosidase alfa-atga (Pombiliti) must be administered in combination with miglustat (Opfolda). Refer to the Opfolda Prescribing Information for miglustat patient counseling information.

• Advise the patient and caregiver to follow the timeline recommendations for taking miglustat prior to the IV infusion with cipaglucosidase alfa.

• Advise the patient and caregiver that reactions related to the infusion may occur during and after cipaglucosidase alfa in combination with miglustat treatment, including anaphylactic reactions, other serious or severe hypersensitivity reactions, and infusion-associated reactions (IARs). Inform the patient and caregiver of the signs and symptoms of hypersensitivity reactions and IARs and to seek medical care should signs and symptoms occur.

• Advise the patient and caregiver that a patient with underlying respiratory illness or compromised cardiac or respiratory function may be at risk of acute cardiorespiratory failure from volume overload during cipaglucosidase alfa infusion.

• Cipaglucosidase alfa in combination with miglustat may cause embryo-fetal harm. Advise a female patient and caregiver to inform their healthcare provider of a known or suspected pregnancy.

• Advise a female of reproductive potential to use effective contraception during treatment with cipaglucosidase alfa in combination with miglustat and for at least 60 days after the last dose.

• Advise a lactating female not to breastfeed during treatment with cipaglucosidase alfa in combination with miglustat.

• Advise the male or female of reproductive potential that cipaglucosidase alfa in combination with miglustat may impair fertility.

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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