Fabrazyme: Package Insert and Label Information

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

1 INDICATIONS AND USAGE

Fabrazyme^® is indicated for use in patients with Fabry disease. Fabrazyme reduces globotriaosylceramide (GL-3) deposition in capillary endothelium of the kidney and certain other cell types.

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. The initial intravenous infusion rate is no more than 0.25 mg/min (15 mg/hour). Slow the infusion rate in the event of infusion-associated reactions [see Warnings and Precautions (5.2)].
• Administer antipyretics prior to infusion of Fabrazyme [see Warnings and Precautions (5.2)].
• 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 maximum infusion rate for patients weighing less than 30 kg, is 0.25 mg/minute (15 mg/hour).
• For patients weighing 30 kg or greater, the minimum infusion duration is 1.5 hours (based on individual patient tolerability).
• 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., 1/2 the therapeutic dose (0.5 mg/kg) at 1/25 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.

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

   Patient Weight (kg)	Minimum Total Volume (mL)
   ≤35	50
   35.1–70	100
   70.1–100	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

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 Allergic Reactions

Life-threatening anaphylactic and severe allergic 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.

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

If anaphylactic or severe allergic reactions occur, immediately discontinue the administration of Fabrazyme and initiate necessary emergency treatment. Because of the potential for severe allergic 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 allergic reaction should be considered. Extreme care should be exercised, with appropriate medical support measures readily available, if the decision is made to readminister the product [see Warnings and Precautions (5.4) and Clinical Studies (14)].

5.2 Infusion-associated Reactions

In clinical trials with Fabrazyme, 59% of patients experienced infusion-associated reactions during Fabrazyme administration, some of which were severe [see Warnings and Precautions (5.1)]. Severe infusion-associated reactions experienced by more than one patient in clinical studies with Fabrazyme included chills, vomiting, hypotension, and paresthesia. Other infusion-associated reactions included pyrexia, feeling hot or cold, dyspnea, nausea, flushing, headache, fatigue, pruritus, pain in extremity, hypertension, chest pain, throat tightness, abdominal pain, dizziness, tachycardia, nasal congestion, diarrhea, edema peripheral, myalgia, urticaria, bradycardia, and somnolence.

Most patients in clinical trials were pretreated with acetaminophen. In patients experiencing infusion-associated reactions, pretreatment with an antipyretic and antihistamine is recommended. Infusion-associated reactions occurred in some patients after receiving pretreatment with antipyretics, antihistamines, and oral steroids. Infusion-associated reactions tended to decline in frequency with continued use of Fabrazyme. However, infusion-associated reactions may still occur despite extended duration of Fabrazyme treatment. If an infusion-associated reaction occurs, decreasing the infusion rate, temporarily stopping the infusion, and/or administrating additional antipyretics, antihistamines, and/or steroids may ameliorate the symptoms. If severe infusion-associated reactions occur, immediate discontinuation of the administration of Fabrazyme should be considered and appropriate medical treatment should be initiated. Severe reactions are generally managed with administration of antihistamines, corticosteroids, intravenous fluids, and/or oxygen, when clinically indicated. Because of the potential for severe infusion-associated reactions, appropriate medical support measures should be readily available when Fabrazyme is administered. Patients who have experienced infusion-associated reactions should be treated with caution when readministering Fabrazyme.

5.3 Compromised Cardiac Function

Patients with advanced Fabry disease may have compromised cardiac function, which may predispose them to a higher risk of severe complications from infusion-associated reactions [see Warnings and Precautions (5.1, 5.2)]. Patients with compromised cardiac function should be monitored closely if the decision is made to administer Fabrazyme.

5.4 Immunogenicity and Rechallenge

In clinical trials with Fabrazyme, a few 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. Physicians should consider testing for IgE antibodies in patients who experienced suspected allergic reactions and consider the risks and benefits of continued treatment in patients with anti-Fabrazyme IgE antibodies [see Warnings and Precautions (5.1)].

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 [see Clinical Studies (14)]. 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)].

5.5 Monitoring: Laboratory Tests

There are no marketed tests for antibodies against Fabrazyme. If testing is warranted, contact your local Genzyme representative or Genzyme Corporation at 1-800-745-4447.

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in labeling:

• Anaphylaxis and Allergic Reactions [see Warnings and Precautions (5.1)]
• Infusion-associated Reactions [see Warnings and Precautions (5.2)]
• Compromised Cardiac Function [see Warnings and Precautions (5.3)]
• Immunogenicity and Rechallenge [see Warnings and Precautions (5.4)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trial of another drug and may not reflect the rates observed in patients in clinical practice.

The data described below reflect exposure of 80 patients, ages 16 to 61 years, to 1 mg/kg Fabrazyme every two weeks in two separate double-blind, placebo-controlled clinical trials, for periods ranging from 1 to 35 months (mean 15.5 months). All 58 patients enrolled in one of the two studies continued into an open-label extension study of Fabrazyme treatment for up to 54 additional months. Patients were treated with antipyretics and antihistamines prior to the infusions.

Most Common Adverse reactions

Table 2 enumerates adverse reactions that occurred during the double-blind treatment periods of the two placebo-controlled trials (Study 1 and Study 2) [see Clinical Studies (14)]. The most common adverse reactions reported with Fabrazyme were infusion-associated reactions, (Fabrazyme 59% vs placebo 27%) some of which were severe.

Common adverse reactions which occurred in ≥20% of patients treated with Fabrazyme and >2.5% compared to placebo are: upper respiratory tract infection, chills, pyrexia, headache, cough, paresthesia, fatigue, peripheral edema, dizziness and rash.

Table 2: Summary of Common Adverse Reactions * in Clinical Trials of Patients with Fabry Disease

Adverse Reaction	Fabrazyme(n=80 )%	Placebo(n=60)%
* Reported at rate of at least 5% in Fabrazyme-treated patients and greater than 2.5% compared to placebo-treated patients.
Upper respiratory tract infection	44	30
Chills	43	12
Pyrexia	39	22
Headache	39	28
Cough	33	25
Paresthesia	31	18
Fatigue	24	17
Peripheral edema	21	7
Dizziness	21	8
Rash	20	10
Pain in extremity	19	8
Nasal congestion	19	15
Lower respiratory tract infection	18	7
Pain	16	13
Back pain	16	10
Myalgia	14	5
Hypertension	14	5
Feeling cold	11	2
Pruritus	10	3
Tachycardia	9	3
Sinusitis	9	3
Excoriation	9	2
Increased blood creatinine	9	5
Tinnitus	8	3
Dyspnea	8	2
Respiratory tract congestion	8	2
Toothache	6	3
Pharyngitis	6	2
Fall	6	3
Burning sensation	6	0
Anxiety	6	3
Depression	6	2
Wheezing	6	0
Hypoacusis	5	0
Chest discomfort	5	2
Fungal infection	5	0
Viral infection	5	0
Muscle spasms	5	2
Hot flush	5	0

Serious and/or frequently occurring (≥5% incidence) related adverse reactions based on a pooled analysis of 150 patients treated with Fabrazyme consisted of one or more of the following: chills, pyrexia, feeling hot or cold, dyspnea, nausea, flushing, headache, vomiting, paresthesia, fatigue, pruritus, pain in extremity, hypertension, chest pain, throat tightness, abdominal pain, dizziness, tachycardia, nasal congestion, diarrhea, edema peripheral, myalgia, back pain, pallor, bradycardia, urticaria, hypotension, face edema, rash, and somnolence. The occurrence of somnolence can be attributed to clinical trial specified pretreatment with antihistamines. Most infusion-related reactions requiring intervention were ameliorated with slowing of the infusion rate, temporarily stopping the infusion, and/or administration of antipyretics, antihistamines, or steroids.

Other reported serious adverse events included stroke, pain, ataxia, bradycardia, cardiac arrhythmia, cardiac arrest, decreased cardiac output, vertigo, and nephrotic syndrome. These adverse events also occur as manifestations of Fabry disease; an alteration in frequency or severity cannot be determined from the small numbers of patients studied.

Adverse Reactions in Pediatric Patients

The safety profile of Fabrazyme in pediatric Fabry disease patients, ages 8 to 16 years, was found to be consistent with that seen in adults [see Use in Specific Populations (8.4) and Clinical Studies (14)]. The safety of Fabrazyme in patients younger than 8 years of age has not been evaluated.