FABRAZYME

Agalsidase beta is a recombinant human α-galactosidase A similar to agalsidase alfa.

While patients generally do not experience a clinically significant difference in outcomes between the two drugs, some patients may experience greater benefit with agalsidase beta. 1, 2 Use of agalsidase beta has decreased in Europe, in favor of agalsidase alfa, after a contamination event in 2009.

Agalsidase beta was granted

FDA approval on 24 April 2003.

Agalsidase beta is indicated in the treatment of Fabry disease.

Agalsidase beta is a recombinant human α-galactosidase A used as enzyme replacement therapy in the treatment of Fabry disease.

It has a long duration of action and a wide therapeutic index.

Patients should be counselled regarding the risk of infusion related reactions and hypersensitivity.

A 1 mg/kg dose of agalsidase beta with a mean infusion length of 115 minutes reaches a C max 5.0 ± 1.1 µg/mL with an AUC of 496 ± 137 µg*min/mL.

A 1 mg/kg dose of agalsidase beta with a mean infusion length of 115 minutes has a V SS of 112 ± 13 mL/kg.

Data regarding the metabolism of agalsidase beta is not readily available.

However, protein drugs are expected to be degraded by proteases and other catalytic enzymes to smaller peptides and amino acids.

After nonspecific proteolysis, the amino acids from protein drugs are reused for protein synthesis or further broken down and eliminated by the kidneys.

agalsidase beta has a half like of 67 ± 12 min for a 1 mg/kg dose with a mean infusion length of 115 minutes.

A 1 mg/kg dose of agalsidase beta with a mean infusion length of 115 minutes has a clearance of 2.1 ± 0.7 mL/min/kg.

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Data regarding overdoses of agalsidase beta are not readily available.

Patients experiencing an overdose of agalsidase beta may experience an increased incidence and severity of adverse effects.

Overdose can be managed through the use of symptomatic and supportive measures.

Administration of

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

The recommended dosage is 1 mg/kg body weight given every two weeks as an intravenous infusion.

See the full prescribing information for rechallenge, preparation, storage, and administration instructions. 2.1 Recommendations Prior to FABRAZYME Treatment Administration of FABRAZYME should be supervised by a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis.

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

Prior to

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

FABRAZYME must be reconstituted and diluted prior to use 2.2 Recommended Dosage and Administration The recommended dosage of FABRAZYME is 1 mg/kg body weight infused every two weeks as an intravenous infusion.

The initial recommended infusion rate is 0.25 mg/min (15 mg/hour) . 2.3 Rechallenge Instructions Patients who have had a positive skin test to FABRAZYME or who have tested positive for anti-FABRAZYME IgE may be successfully rechallenged with FABRAZYME.

The initial rechallenge administration should be a low dose at a lower infusion rate, e.g., one-half the therapeutic dose (0.5 mg/kg) at 1/25 th of the initial standard recommended rate (0.01 mg/min or 0.6 mg/hr).

Once a patient tolerates the infusion, the dose may be increased to reach the approved dose of 1 mg/kg and the infusion rate may be increased by slowly titrating upwards (doubled every 30 minutes up to a maximum rate of 0.25 mg/minute), as tolerated. 2.4 Preparation Instructions Use aseptic technique during preparation.

Reconstitute and dilute FABRAZYME in the following manner: Reconstitution Instructions 1.

Determine the number of 35 mg and 5 mg FABRAZYME vials to be reconstituted based on actual body weight (kg) and the recommended dose. 2.

Remove the required number of 35 mg and 5 mg FABRAZYME 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) before use. 3.

Reconstitute each vial by directing the diluent down the inside wall of each vial then gently tilt and roll each vial.

Use the following volumes for reconstitution: 7.2 mL of FABRAZYME Sterile Water for Injection into the 35 mg vial.

Total extractable amount per vial is 35 mg, 7 mL. 1.1 mL of Sterile Water for Injection into the 5 mg vial.

Total extractable amount per vial is 5 mg, 1 mL. 4.

Each reconstituted vial will yield a concentration of 5 mg/mL of agalsidase beta. 5.

Do not shake or agitate the product. 6.

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

The reconstituted solution should be clear and colorless.

Discard if visible particulate matter is present or the solution is discolored.

Instructions 7.

Select an appropriate size 0.9% Sodium Chloride Injection infusion bag and prepare by removing a volume equal to the required FABRAZYME volume to achieve a total volume per Table 1. 8.

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

Discard any unused reconstituted solution remaining in the vial.

Table 1: Total Infusion Volume Based on Patient Weight Patient Weight (kg) Total Volume (mL) ≤35 50 35.1 to 70 100 70.1 to 100 250 >100 500 9.

Gently inject the

FABRAZYME reconstituted solution into the port of the 0.9% Sodium Chloride Injection infusion bag.

Do not inject into the airspace within the infusion bag. 10.

Gently invert the infusion bag to mix the solution.

Do not shake or agitate the product.

After dilution, the solution will have a final concentration of 0.2 to 0.7 mg/mL of agalsidase beta. 2.5 Storage Instructions for the Reconstituted and Diluted Product Dilute the reconstituted solution without delay and use immediately.

If immediate use is not possible, the reconstituted and diluted solution may be stored at 2°C to 8°C (36°F to 46°F) for up to 24 hours. 2.6 Administration Instructions The initial recommended infusion rate is 0.25 mg/min (15 mg/hour).

For patients weighing: 30 kg or more, in the absence of hypersensitivity and/or infusion-associated reactions (IARs), increase the infusion rate in increments of 0.05 to 0.08 mg/min (3 to 5 mg/hour) with each subsequent infusion.

The minimum infusion duration is 1.5 hours (based on individual patient tolerability) .

Less than 30 kg, the maximum infusion rate is 0.25 mg/minute (15 mg/hour) .

Do not infuse

FABRAZYME in the same intravenous line with other products.

FABRAZYME using an in-line low protein binding 0.2 µm filter.

(agalsidase beta) for injection is supplied as a sterile, nonpyrogenic, white to off-white lyophilized cake or powder in single-dose vials. 35 mg vial: NDC 58468-0040-1 5 mg vial: NDC 58468-0041-1 Refrigerate vials of FABRAZYME at 2°C to 8°C (36°F to 46°F).

Do not use

FABRAZYME after the expiration date on the vial.

This product contains no preservatives.

Reconstituted and diluted solutions of

FABRAZYME should be used immediately.

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

Refrigerate vials of

FABRAZYME at 2°C to 8°C (36°F to 46°F).

Do not use

FABRAZYME after the expiration date on the vial.

This product contains no preservatives.

Reconstituted and diluted solutions of

FABRAZYME should be used immediately.

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

Risk Summary Available data from a pregnancy sub-study within the Fabry Disease registry, post-marketing case reports, and case series with FABRAZYME use during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes.

Reproduction studies performed in rats at doses up to 68 times the human dose have revealed no evidence of effects on embryo-fetal development.

The background risk of major birth defects and miscarriage for 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.

Data Human Data Available data from a pregnancy sub-study within the Fabry Disease registry, post-marketing case reports, and case series with FABRAZYME use during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes.

Disease registry pregnancy sub-study, 33 pregnancies exposed to FABRAZYME prior to or during pregnancy had a known outcome; 5 were reported as exposed in the first trimester.

The effects of agalsidase beta on embryo-fetal development in rats were evaluated at doses of 3, 10, and 30 mg/kg/day (up to 68 times the human dose of 1 mg/kg every 2 weeks on a body surface area basis) during gestation days to 17.

Hepatocellular necrosis consistent with accumulation of test article was evident in maternal livers in the and 30 mg/kg/day groups (23 and 68 times the human dose on a body surface area basis).

There were no adverse effects of agalsidase beta on embryo-fetal development in rats.

The safety and effectiveness of

FABRAZYME have been established in pediatric patients based on adequate and well-controlled studies in adults, a single-arm, open-label study in 16 pediatric patients with Fabry disease aged to 16 years, and additional data in 24 patients with Fabry disease aged to 7 years.

The overall safety profile of

FABRAZYME was similar between the pediatric and the adult population.

Clinical studies of

FABRAZYME did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects.