Cipaglucosidase alfa (Monograph)

Drug class: Enzymes

Medically reviewed by Drugs.com on Sep 10, 2024. Written by ASHP.

Warning

Patients treated with cipaglucosidase alfa-atga have experienced life-threatening hypersensitivity reactions, including anaphylaxis.
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-atga should be discontinued immediately, and appropriate medical treatment should be initiated.
In patients with severe hypersensitivity reaction, desensitization measures to cipaglucosidase alfa-atga may be considered.

Patients treated with cipaglucosidase alfa-atga have experienced severe infusion-associated reactions.
If severe infusion-associated reactions occur, immediately discontinue the cipaglucosidase alfa-atga infusion, initiate appropriate medical treatment, and assess the benefits and risks of readministering cipaglucosidase alfa-atga.
Patients with an acute underlying illness at the time of cipaglucosidase alfa-atga infusion may be at greater risk for infusion-associated reactions.
Patients with advanced Pompe disease may have compromised cardiac and respiratory function, which may predispose them to a higher risk of severe complications from infusion-associated reactions.

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 cipaglucosidase alfa-atga infusion.
More frequent monitoring of vitals should be performed during cipaglucosidase alfa-atga infusion in such patients.

Introduction

Hydrolytic lysosomal glycogen-specific enzyme.

Uses for Cipaglucosidase alfa

Pompe Disease

Treatment of late-onset Pompe Disease in combination with miglustat in adult patients weighing ≥40 kg who are not improving on current enzyme replacement therapy (ERT); designated an orphan drug by FDA for this use.

The standard of care is supportive in nature, with administration of ERT in the form of recombinant human acid α-glucosidase.

Cipaglucosidase alfa Dosage and Administration

General

Pretreatment Screening

Verify pregnancy status of females of reproductive potential prior to initiation.

Patient Monitoring

Monitor for hypersensitivity reactions, including anaphylaxis, during administration. Appropriate medical support measures, including cardiopulmonary resuscitation equipment, should be readily available.

Premedication and Prophylaxis

Consider pretreating with antihistamines, antipyretics, and/or corticosteroids. If premedication was used with previous enzyme replacement therapy, pretreat with antihistamines, antipyretics, and/or corticosteroids.
Cipaglucosidase alfa-atga must be used in combination with miglustat. Refer to the prescribing information for miglustat for dosage and administration recommendations.
Cipaglucosidase alfa-atga IV infusion should be initiated approximately 1 hour after oral administration of miglustat. If the cipaglucosidase alfa-atga infusion cannot be started within 3 hours of miglustat, reschedule cipaglucosidase alfa-atga in combination with miglustat at least 24 hours after miglustat was last taken. If both drugs are missed, restart treatment as soon as possible.

Administration

Start cipaglucosidase alfa-atga and miglustat combination therapy 2 weeks after last dose of enzyme replacement therapy.

Administer IV as an infusion by healthcare professional. Ensure appropriate medical support available to manage hypersensitivity and infusion-associated reactions during administration.

Reconstitution and Dilution

Requires reconstitution and dilution prior to IV administration. Required number of vials to be reconstituted determined based on recommended weight-based dosage; each vial contains 105 mg.

Allow vials to come to room temperature for approximately 30 minutes prior to preparation. Using aseptic technique, reconstitute each vial by slowly injecting 7.2 mL of sterile water for injection down the inside wall of vial to avoid foaming. Roll and tilt each vial to allow lyophilized powder to dissolve completely (typically takes 2 minutes); do not invert, swirl, or shake the vials. Each vial will yield a concentration of 15 mg/mL. Inspect each reconstituted vial for particulate matter and discoloration; should be clear to opalescent, colorless to yellowish solution.

After reconstitution, remove both airspace and volume equivalent to total volume of the dose of reconstituted drug from a 0.9% sodium chloride bag (see Table 1 for recommended total infusion volume). Slowly withdraw 7 mL from each vial until total dose is obtained; discard remaining solution. Add reconstituted drug slowly and directly into infusion bag. To prevent foaming, gently invert infusion bag to mix and avoid vigorous shaking or agitation. After dilution, solution final concentration should be 0.5-4 mg/mL. Do not use pneumatic tube to transport.

Rate of Administration

Prior to administration, inspect bag for foaming. If foaming present, let foam dissipate before administering. If the diluted solution was refrigerated, allow to equilibrate to room temperature for 30 minutes prior to administration. Use an administration set with in-line low protein binding 0.2-micron filter; change filter if blocked. Do not infuse in same IV line with other products.

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

In event of severe hypersensitivity reaction (including anaphylaxis) or a severe infusion-associated reaction, immediately discontinue infusion and initiate appropriate treatment. In event of mild to moderate hypersensitivity reaction or moderate infusion-associated reaction, consider temporarily holding or slowing rate and initiating appropriate medical treatment. If symptoms persist despite temporarily holding or slowing infusion, stop infusion for 30 to 60 minutes, monitor patient, and consider resuming at reduced rate if symptoms improve. If symptoms persist, discontinue infusion and consider re-initiating within 7 to 14 days with appropriate premedication. If symptoms subside following holding or slowing infusion, increase infusion rate to rate at which reaction occurred and consider increasing rate every 30 minutes in stepwise manner up to target infusion rate. Closely monitor patient.

Table 1. Recommended Infusion Volume and Rate Based on Patient Weight1
Patient Weight Range (kg)	Total Infusion Volume (mL)	Step 1 1 mg/kg per hour (mL/hour)	Step 2 3 mg/kg per hour (mL/hour)	Step 3 5 mg/kg per hour (mL/hour)	Step 4 7 mg/kg per hour (mL/hour)
40–50	250	13	38	63	88
50.1–60	300	15	45	75	105
60.1–100	500	25	75	125	175
100.1–120	600	30	90	150	210
120.1–140	700	35	105	175	245

Dosage

Adults

Pompe Disease

IV

Dosage based on actual body weight.

For patients weighing ≥40 kg: 20 mg/kg every other week by IV infusion over approximately 4 hours.

Special Populations

Hepatic Impairment

No specific population dosage recommendations at this time.

Renal Impairment

No specific population dosage recommendations at this time.

Geriatric Patients

No specific population dosage recommendations at this time.

Cautions for Cipaglucosidase alfa

Contraindications

Pregnancy.

Warnings/Precautions

Warnings

Hypersensitivity Reactions Including Anaphylaxis

Life-threatening hypersensitivity reactions, including anaphylaxis, reported (see Boxed Warning). Anaphylaxis signs and symptoms include dyspnea, rash, hypotension, bronchospasm, edema, pharyngeal edema, and tongue swelling. Symptoms of severe hypersensitivity reactions include urticaria, pruritus, and flushing.

If severe hypersensitivity reaction (e.g., anaphylaxis) occurs, discontinue immediately and initiate appropriate medical treatment. Risks and benefits of readministering following severe hypersensitivity reaction (including anaphylaxis) should be considered. May rechallenge using slower infusion rates. After severe hypersensitivity reaction, desensitization measures may be considered. If mild or moderate hypersensitivity reaction occurs, infusion rate may be slowed or temporarily stopped.

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

Infusion-Associated Reactions

Infusion-associated reactions reported at any time during and/or within a few hours after infusion and are more likely to occur with higher infusion rates (see Boxed Warning). Severe infusion-associated reactions include symptoms of pharyngeal edema, anaphylactic reaction, urticaria, pruritus, chills, dyspnea, and flushing. Patients with underlying illness at time of infusion may be at greater risk. Patients with advanced Pompe disease may have compromised cardiac and respiratory function, which may predispose them to higher risk of severe complications from infusion-associated reactions.

Pretreatment with antihistamines, antipyretics, and/or corticosteroids can be given to reduce risk of infusion-associated reactions. However, infusion-associated reactions may still occur after pretreatment.

If severe infusion-associated reactions occur, immediately discontinue infusion, initiate appropriate medical treatment, and assess benefits and risks of readministering. May rechallenge using slower infusion rates. If mild or moderate infusion-associated reactions occur regardless of pretreatment, decreasing infusion rate or temporarily stopping infusion may ameliorate symptoms.

Risk of Acute Cardiorespiratory Failure in Susceptible Patients

Patients susceptible to fluid volume overload or 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 cardiac or respiratory status during infusion (see Boxed Warning). More frequent monitoring of vitals should be performed. Some patients may require prolonged observation times.

Other Warnings/Precautions

Embryo-Fetal Toxicity

Based on findings from animal reproduction studies, may cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy.

Verify pregnancy status in females of reproductive potential prior to initiation. Advise females of reproductive potential to use effective contraception during treatment and for at least 60 days after last dose.

Immunogenicity

At the end of week 52 of the trial with cipaglucosidase alfa-atga, 89% of enzyme replacement therapy-experienced patients had anti-drug and neutralizing antibodies. Because of the small number of patients with negative anti-drug antibodies, effect of anti-drug antibodies on effectiveness is unknown. There was no clinically significant effect of anti-drug antibodies on pharmacokinetics or pharmacodynamics over a treatment duration of 52 weeks. There is no clear trend in infusion-associated reaction occurrence with development of anti-cipaglucosidase alfa-atga IgE antibodies. Antibodies against cipaglucosidase alfa-atga are cross-reactive to alglucosidase alfa.

Risks Association with Miglustat

Must be administered in combination with miglustat. Refer to miglustat (Opfolda) prescribing information for description of additional risks including, but not limited to, warnings and precautions.

Specific Populations

Pregnancy

Insufficient evidence in pregnant women to evaluate drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Based on findings from animal reproduction studies, may cause embryo-fetal harm and is contraindicated during pregnancy.

Lactation

No data on presence of cipaglucosidase alfa-atga (alone or in combination with miglustat) in human milk, effects on breast-fed child, or effects on milk production. Based on findings in animal studies, may lead to serious adverse reactions in breast-fed infants.

Advise females that breastfeeding is not recommended while receiving cipaglucosidase alfa-atga treatment.

Females and Males of Reproductive Potential

May cause embryo-fetal harm when administered to a pregnant female. Verify pregnancy status in females of reproductive potential prior to initiating treatment.

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

Based on animal studies, may impair human male and female fertility.

Pediatric Use

Safety and effectiveness in pediatric patients not established. r1

Geriatric Use

Clinical studies did not include sufficient numbers of subjects ≥65 years of age to determine whether they respond differently than younger subjects.

Hepatic Impairment

Safety and effectiveness in patients with hepatic impairment not established.

Renal Impairment

Safety and effectiveness in patients with renal impairment not established; unlikely to be filtered by kidney or excreted in urine.

Common Adverse Effects

Most common adverse effects (≥5%): headache, diarrhea, fatigue, nausea, abdominal pain, pyrexia.

Drug Interactions

No formal drug interaction studies conducted; unlikely to be involved in CYP or transporter-mediated drug interactions.

Cipaglucosidase alfa Pharmacokinetics

Absorption

Bioavailability

100%.

Distribution

Extent

Not known whether distributes into human milk.

Plasma Protein Binding

Not characterized.

Elimination

Metabolism

Not characterized; expected to be metabolized into small peptides and amino acids via catabolic pathways.

Elimination Route

Secretion into bile not significant; unlikely to be filtered by kidney or excreted in urine.

Half-life

2.1 hours (in combination with miglustat).

Special Populations

Age (18 to 74 years) and sex had no clinically meaningful effects on pharmacokinetics of cipaglucosidase alfa-atga.

Stability

Storage

Parenteral

Powder for IV Infusion

Store vials of unreconstituted powder for injection at 2-8ºC in original carton to protect from light. Do not freeze.

If reconstituted vials not used immediately, store at 2-8°C for up to 24 hours. Do not freeze.

If diluted solution not administered immediately, store at 2-8°C for up to 16 hours. Storage at room temperature not recommended. Do not freeze. Discard diluted solution if refrigerated >16 hours or if diluted solution not completely infused within 6 hours after removal from refrigerator.

Actions

Hydrolytic lysosomal glycogen-specific recombinant human acid α-glucosidase (GAA) enzyme; provides an exogenous source of GAA for patients with Pompe disease.
Bis-mannose-6-phosphate on cipaglucosidase alfa-atga mediates binding to mannose-6-phosphate receptors on cell surface with high affinity.
After binding, internalized and transported into lysosomes where it undergoes proteolytic cleavage and N-glycans trimming to yield most mature and active form of GAA, then exerts enzymatic activity in cleaving glycogen.
Must be given in combination with miglustat; miglustat binds with, stabilizes, and reduces inactivation of cipaglucosidase alfa-atga in blood after infusion.

Advice to Patients

Advise the patient and their caregiver that cipaglucosidase alfa-atga must be administered in combination with miglustat. Advise the patient and caregiver to follow the timeline recommendations for taking oral miglustat prior to the IV infusion of cipaglucosidase alfa-atga.
Advise the patient and their caregiver that if a dose of miglustat is missed, cipaglucosidase alfa-atga should not be administered and treatment should be rescheduled at least 24 hours after miglustat was last taken. If both miglustat and cipaglucosidase alfa-atga are missed, restart the treatment as soon as possible.
Advise the patient and their caregiver that reactions related to the infusion may occur during and after administration of cipaglucosidase alfa-atga in combination with miglustat, including anaphylactic reactions, other serious or severe hypersensitivity reactions, and infusion-associated reactions. Inform the patient and caregiver of the signs and symptoms of hypersensitivity reactions and infusion-associated reactions and advise them 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-atga infusion.
Advise females of reproductive potential that cipaglucosidase alfa-atga in combination with miglustat may cause fetal harm and to inform their clinician of a known or suspected pregnancy. Inform females of reproductive potential that their clinician will verify pregnancy status prior to initiating treatment with cipaglucosidase alfa-atga. Advise females of reproductive potential to use effective contraception during treatment with cipaglucosidase alfa-atga in combination with miglustat and for at least 60 days after the last dose.
Advise females that breastfeeding is not recommended while on treatment with cipaglucosidase alfa-atga in combination with miglustat.
Advise males and females of reproductive potential that cipaglucosidase alfa-atga in combination with miglustat may impair fertility.
Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary and herbal supplements, as well as any concomitant illnesses.
Inform patients of other important precautionary information.
Refer to the prescribing information available from the manufacturer of miglustat for additional patient counseling information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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.