MYOZYME

Aglucosidase alfa consists of the human enzyme acid alpha-glucosidase (GAA) which is essential for the degradation of glygogen to glucose in lysosomes.

It is encoded by the most predominant of nine observed haplotypes of this gene.

Aglucosidase alfa is produced by recombinant DNA technology in a Chinese hamster ovary cell line.

Alglucosidase alfa degrades glycogen by catalyzing the hydrolysis of a-1,4.

• and a-1,6.

• glycosidic linkages of lysosomal glycogen.

Structurally, Alglucosidase alfa is a glycoprotein with a calculated mass of 98,008 daltons for the 883 residue mature polypeptide chain, and a total mass of approximately 109,000 daltons, including carbohydrates.

It is used for the treatment of Pompe disease (GAA deficiency) in infants and pediatric patients.

For the treatment of

Pompe disease (GAA deficiency) in infants and pediatric patients.

Pompe disease (glycogen storage disease type II, GSD II, glycogenosis type II, acid maltase deficiency) is an inherited disorder of glycogen metabolism caused by the absence or marked deficiency of the lysosomal enzyme GAA.

In the infantile-onset form, Pompe disease results in intralysosomal accumulation of glycogen in various tissues, particularly cardiac and skeletal muscles, and hepatic tissues, leading to the development of cardiomyopathy, progressive muscle weakness, and impairment of respiratory function.

In the juvenile.

• and adult-onset forms, intralysosomal accumulation of glycogen is limited primarily to skeletal muscle, resulting in progressive muscle weakness.

Death in all forms is usually related to respiratory failure.

Alglucosidase alfa provides an exogenous source of GAA.

Binding to mannose-6-phosphate receptors on the cell surface has been shown to occur via carbohydrate groups on the GAA molecule, after which it is internalized and transported into lysosomes, where it undergoes proteolytic cleavage that results in increased enzymatic activity.

It then exerts enzymatic activity in cleaving glycogen.

Lysosomal alpha-glucosidase Substrate

Cation-dependent mannose-6-phosphate receptor Binder Cation-independent mannose-6-phosphate receptor Binder + 1 more target.

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There have been no reports of overdose with alglucosidase alfa.

Administration of

LUMIZYME should be supervised by a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis.

Recommended dosage is 20 mg/per kg body weight administered every 2 weeks as an intravenous infusion.

The initial infusion rate should be no more than 1 mg/kg/hour Reconstitute and dilute LUMIZYME prior to use.

See full prescribing information for storage of the reconstituted and diluted product and administration instructions 2.1 Recommendations prior to LUMIZYME Treatment Administration of LUMIZYME should be supervised by a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis.

LUMIZYME in a healthcare setting with appropriate medical monitoring and support measures, including access to cardiopulmonary resuscitation equipment.

Prior to

LUMIZYME administration, consider pretreating with antihistamines, antipyretics, and/or corticosteroids.

LUMIZYME must be reconstituted and diluted prior to use.

Appropriate medical monitoring and support measures, including cardiopulmonary resuscitation equipment, should be readily available during LUMIZYME administration. 2.2 Recommended Dosage and Administration The recommended dosage of LUMIZYME is 20 mg/kg body weight administered every 2 weeks as an intravenous infusion.

The initial infusion rate should be no more than 1 mg/kg/hour.

If one or more doses are missed, restart LUMIZYME treatment as soon as possible, maintaining the 2-week interval between infusions thereafter. 2.3 Reconstitution and Dilution Instructions Reconstitute and dilute LUMIZYME in the following manner.

Use aseptic technique during preparation.

Do not use filter needles during preparation.

Reconstitute the Lyophilized Powder Determine the number of LUMIZYME vials to be reconstituted based on the actual body weight in kg and the recommended dose of 20 mg/kg. Round the number of vials up to the next whole number.

Remove the required number of

LUMIZYME vials from the refrigerator and allow the vials to sit for approximately 30 minutes at room temperature 20°C to 25°C (68°F to 77°F) prior to reconstitution.

Reconstitute each vial by slowly injecting 10.3 mL of Sterile Water for Injection, down the inside wall of each vial.

Avoid adding the Sterile Water for

Injection to the vial forcefully or directly onto the lyophilized powder to minimize foaming.

Gently tilt and roll each vial.

Do not invert, swirl, or shake the vial.

Each vial will yield a concentration of 5 mg/mL of LUMIZYME.

The total extractable dose per vial is 50 mg per 10 mL.

Visually inspect the reconstituted solution in the vials for particulate matter and discoloration.

Discard if particles are present or the solution is discolored.

The reconstituted solution may occasionally contain some LUMIZYME particles (typically less than in a vial) in the form of thin white strands or translucent fibers subsequent to the initial inspection.

This may also happen following dilution for infusion.

These particles have been shown to contain LUMIZYME and may appear after the initial reconstitution step and increase over time.

Studies have shown that these particles are removed via in-line filtration without having a detectable effect on the purity or strength.

Select and prepare an appropriate size 0.9% Sodium Chloride for Injection infusion bag with quantity sufficient of 0.9% Sodium Chloride for Injection to obtain the recommended total infusion volume per table 1 based on patient weight and dilute.

Slowly withdraw the required volume of reconstituted solution from the LUMIZYME vial(s).

Avoid foaming in the syringe.

Discard any unused reconstituted solution remaining in the vial.

Remove airspace from the prepared 0.9% Sodium Chloride for Injection infusion bag to minimize particle formation due to the sensitivity of LUMIZYME to air-liquid interfaces.

Inject the

LUMIZYME reconstituted solution slowly and directly into the port of the prepared 0.9% Sodium Chloride for Injection infusion bag.

Avoid foaming and introducing air in the infusion bag.

Gently invert or massage the infusion bag to mix the solution.

Do not shake.

After dilution, the solution will have a final concentration of 0.5 to 4 mg/mL of LUMIZYME. 2.4 Storage Instructions for the Reconstituted and Diluted Product The reconstituted and diluted solution should be administered without delay.

Storage of the reconstituted solution at room temperature is not recommended.

If immediate use is not possible, the reconstituted and diluted solution is stable for up to 24 hours refrigerated at 2°C to 8°C (36°F to 46°F).

The reconstituted and diluted

LUMIZYME solution should be protected from light.

Do not freeze or shake. 2.5 Administration Instructions The total volume of infusion is determined by the patient's body weight and should be administered over approximately 4 hours.

LUMIZYME using an in-line low protein binding 0.2-micron filter.

Infusions should be administered in a step-wise manner using an infusion pump.

The initial infusion rate should be no more than 1 mg/kg/hr. The infusion rate may be increased by 2 mg/kg/hr every 30 minutes, after patient tolerance to the infusion rate is established, until a maximum rate of 7 mg/kg/hr is reached.

Vital signs should be obtained at the end of each step.

If the patient is stable, LUMIZYME may be administered at the maximum rate of 7 mg/kg/hr until the infusion is completed.

The infusion rate may be slowed or temporarily stopped in the event of mild to moderate hypersensitivity reactions.

In the event of anaphylaxis or severe hypersensitivity reaction, immediately discontinue administration of LUMIZYME and initiate appropriate medical treatment.

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

Do not infuse

LUMIZYME in the same intravenous line with other products.

Discard any unused product.

Table 1: Recommended LUMIZYME Infusion Volumes and Incremental Rate Steps by Patient Weight Patient Weight Range Total infusion volume Step 1 1 mg/kg/hr Step 2 3 mg/kg/hr Step 3 5 mg/kg/hr Step 4 7 mg/kg/hr Infusion Rate in mL/hr 1.25 to 2.5 kg 25 mL 1.25 3.75 6.25 6.6 2.6 to 10 kg 50 mL 3 8 13 18 10.1 to 20 kg 100 mL 5 15 25 35 20.1 to 30 kg 150 mL 8 23 38 53 30.1 to 35 kg 200 mL 10 30 50 70 35.1 to 50 kg 250 mL 13 38 63 88 50.1 to 60 kg 300 mL 15 45 75 105 60.1 to 100 kg 500 mL 25 75 125 175 100.1 to 120 kg 600 mL 30 90 150 210 120.1 to 140 kg 700 mL 35 105 175 245 140.1 to 160 kg 800 mL 40 120 200 280 160.1 to 180 kg 900 mL 45 135 225 315 180.1 to 200 kg 1,000 mL 50 150 250 350.

mg vials are supplied as a sterile, nonpyrogenic, preservative-free, white to off-white lyophilized cake or powder in single-dose vials.

NDC 58468-0160-1 (Carton of one single-dose vial) NDC 58468-0160-2 (Carton of ten single-dose vials) Store LUMIZYME under refrigeration between 2°C and 8°C (36°F and 46°F).

Do not use

LUMIZYME after the expiration date on the vial.

LUMIZYME under refrigeration between 2°C and 8°C (36°F and 46°F).

Do not use

LUMIZYME after the expiration date on the vial.

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to LUMIZYME during pregnancy.

Pregnant women and women of reproductive potential should be encouraged to enroll in the Pompe patient registry.

The registry will monitor the effect of LUMIZYME on pregnant women and their offspring.

For more information, visit or call 1-800-745-4447, extension 15500.

Data from postmarketing reports and published case reports with alglucosidase alfa use in pregnant women have not identified a LUMIZYME-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

The continuation of treatment for

Pompe disease during pregnancy should be individualized to the pregnant woman.

Pompe disease may result in worsening disease symptoms in pregnant women.

Reproduction studies performed in mice and rabbits at doses resulting in exposures up to 0.4 or 0.5 times the human steady-state AUC (area under the plasma concentration-time curve), respectively, during the period of organogenesis revealed no evidence of effects on embryo-fetal development.

In mice there was an increase in pup mortality during lactation at maternal exposures 0.4 times the human steady-state AUC.

The 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.

Maternal and/or Embryo-fetal Risk Untreated Pompe disease has been associated with worsening respiratory and musculoskeletal symptoms in some pregnant women.

All reproductive studies included pretreatment with diphenhydramine to prevent or minimize hypersensitivity reactions.

The effects of alglucosidase alfa were evaluated based on comparison to a control group treated with diphenhydramine alone.

Daily intravenous administration of alglucosidase alfa up to 40 mg/kg in mice and rabbits (0.4 and 0.5 times the human steady-state AUC, respectively, at the recommended biweekly dose) during the period of organogenesis had no effects on embryo-fetal development.

Administration of 40 mg/kg intravenously every other day in mice (0.4 times the human steady-state AUC at the recommended biweekly dose) during the period of organogenesis through lactation produced an increase in mortality of offspring during the lactation period.

The safety and effectiveness of

LUMIZYME has been established in pediatric patients with Pompe disease.The use of LUMIZYME for this pediatric indication is supported by evidence from an adequate and well-controlled trial in 57 treatment-naive pediatric patients with IOPD treated with alglucosidase alfa, aged 0.2 month to 3.5 years at first infusion, (Trials 1, 2, and 3) and 90 adult and pediatric patients with LOPD in a randomized, double-blind, placebo-controlled trial including 2 patients 16 years of age or less.

Anaphylaxis, hypersensitivity reactions, and acute cardiorespiratory failure have occurred in pediatric patients.

Additionally, cardiac arrhythmia and sudden cardiac death have occurred in pediatric patients during general anesthesia for central venous catheter placement.

The randomized, double-blind, placebo-controlled study of alglucosidase alfa did not include sufficient numbers (n=4) of patients aged 65 years and over to determine whether they respond differently from younger adult patients.