Fabrazyme

FABRAZYME- agalsidase beta injection, powder, lyophilized, for solution
Genzyme Corporation

1 INDICATIONS AND USAGE

Fabrazyme^® is indicated for the treatment of adult and pediatric patients 2 years of age and older with confirmed Fabry disease.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage

• The recommended dosage of Fabrazyme is 1 mg/kg body weight infused every two weeks as an intravenous infusion.
• Infusion rate:

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  The initial intravenous infusion rate is 0.25 mg/min (15 mg/hour). Slow the infusion rate in the event of infusion-associated reactions [see Warnings and Precautions (5.2)].

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  For patients >30 kg, after patient tolerance to the infusion is well established, increase the infusion rate in increments of 0.05 to 0.08 mg/min (increments of 3 to 5 mg/hour) with each subsequent infusion. The minimum infusion duration is 1.5 hours (based on individual patient tolerability).

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  For patients weighing <30 kg, the maximum infusion rate is 0.25 mg/minute (15 mg/hour).

• Because of the potential for severe infusion-associated reactions, appropriate medical support measures should be readily available when Fabrazyme is administered [see Warnings and Precautions (5.2)].
• Administer antipyretics prior to infusion of Fabrazyme [see Warnings and Precautions (5.2)].
• Rechallenge: 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). 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 [see Adverse Reactions (6.2)].

2.2 Preparation and Administration Instructions

Fabrazyme does not contain any preservatives. Vials are for single use only. Discard any unused product.

Avoid shaking or agitating this product. Do not use filter needles during the preparation of the infusion.

Reconstitution and Dilution (using Aseptic Technique)

1. Allow Fabrazyme vials and diluent to reach room temperature prior to reconstitution (approximately 30 minutes). The number of 35 mg and 5 mg vials needed is based on the patient’s body weight (kg) and the recommended dose of 1 mg/kg.
   Select a combination of 35 mg and 5 mg vials so that the total number of mg is equal to or greater than the patient’s number of kg of body weight.
2. Reconstitute each 35 mg vial of Fabrazyme by slowly injecting 7.2 mL of Sterile Water for Injection, USP down the inside wall of each vial. Roll and tilt each vial gently. Each vial will yield a 5 mg/mL clear, colorless solution (total extractable amount per vial is 35 mg, 7 mL).Reconstitute each 5 mg vial of Fabrazyme by slowly injecting 1.1 mL of Sterile Water for Injection, USP down the inside wall of each vial. Roll and tilt each vial gently. Each vial will yield a 5 mg/mL clear, colorless solution (total extractable amount per vial is 5 mg, 1 mL).
3. Visually inspect the reconstituted vials for particulate matter and discoloration. Do not use the reconstituted solution if there is particulate matter or if it is discolored.
4. The reconstituted solution should be further diluted with 0.9% Sodium Chloride Injection, USP to a total volume based on patient weight specified in Table 1 below. Prior to adding the volume of reconstituted Fabrazyme required for the patient dose, remove an equal volume of 0.9% Sodium Chloride Injection, USP from the infusion bag.

   Table 1: Total Infusion Volume Based on Patient Weight

   Patient Weight (kg)	Minimum Total Volume (mL)
   ≤35	50
   35.1 to 70	100
   70.1 to 100	250
   >100	500

   
   Example: Patient dose = 80 mg
   80 mg ÷ 5 mg/mL = 16 mL of FabrazymeSlowly withdraw the reconstituted solution from each vial up to the total volume required for the patient dose. Inject the reconstituted Fabrazyme solution directly into the Sodium Chloride solution. Do not inject in the airspace within the infusion bag. Discard any vial with unused reconstituted solution.
5. Gently invert infusion bag to mix the solution, avoiding vigorous shaking and agitation.
6. Do not infuse Fabrazyme in the same intravenous line with other products.
7. Administer Fabrazyme using an in-line low protein binding 0.2 µm filter.

Storage of Reconstituted Solution

Use reconstituted and diluted solutions of Fabrazyme 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).

3 DOSAGE FORMS AND STRENGTHS

For injection: 5 mg or 35 mg of agalsidase beta as a white to off-white, lyophilized cake or powder in a single-dose vial for reconstitution.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Anaphylaxis and Hypersensitivity Reactions

In clinical trials and postmarketing safety experience with Fabrazyme, approximately 1% of patients developed anaphylactic or severe hypersensitivity reactions during Fabrazyme infusion.

In clinical trials with Fabrazyme, 10 of 238 patients developed IgE antibodies or skin test reactivity specific to Fabrazyme. Two of six patients in the rechallenge study discontinued treatment with Fabrazyme prematurely due to recurrent infusion-associated reactions. Four serious infusion-associated reactions occurred in three patients during Fabrazyme infusions, including bronchospasm, urticaria, hypotension, and development of Fabrazyme-specific antibodies. Other infusion-associated reactions occurring in more than one patient during the study included rigors, hypertension, nausea, vomiting, and pruritus.

Higher incidences of hypersensitivity reactions were observed in adult patients with persistent anti-Fabrazyme antibodies and in adult patients with high antibody titer compared to that in antibody-negative adult patients [see Adverse Reactions (6.2)].

Life-threatening anaphylactic and severe hypersensitivity reactions have been observed in patients during Fabrazyme infusions. Reactions have included localized angioedema (including swelling of the face, mouth, and throat), bronchospasm, hypotension, generalized urticaria, dysphagia, rash, dyspnea, flushing, chest discomfort, pruritus, and nasal congestion. Interventions have included cardiopulmonary resuscitation, oxygen supplementation, intravenous fluids, hospitalization, and treatment with inhaled beta-adrenergic agonists, epinephrine, and intravenous corticosteroids.

If anaphylactic or severe hypersensitivity reactions occur, immediately discontinue the administration of Fabrazyme and initiate necessary emergency treatment. Because of the potential for severe hypersensitivity reactions, appropriate medical support measures should be readily available when Fabrazyme is administered.

The risks and benefits of readministering Fabrazyme following an anaphylactic or severe hypersensitivity reaction should be considered. If a decision is made to readminister the product, ensure that appropriate medical emergency support is available [see Dosage and Administration (2.1) and Adverse Reactions (6.2)].

Physicians should consider testing for IgE antibodies in patients who experienced suspected hypersensitivity reactions and consider the risks and benefits of continued treatment in patients with anti-Fabrazyme IgE antibodies. There are no marketed tests for antibodies against Fabrazyme. If testing is warranted, contact Genzyme Corporation at 1-800-745-4447.

Patients who have had a positive skin test to Fabrazyme or who have tested positive for Fabrazyme-specific IgE antibody have been rechallenged with Fabrazyme using a rechallenge protocol. Rechallenge of these patients should only occur under the direct supervision of qualified personnel with appropriate medical support measures readily available [see Dosage and Administration (2.1) and Adverse Reactions (6.2)].