Lumizyme: Package Insert and Label Information

LUMIZYME- alglucosidase alfa injection, powder, for solution
Genzyme Corporation

WARNING: RISK OF ANAPHYLAXIS, HYPERSENSITIVITY AND IMMUNE-MEDIATED REACTIONS, AND RISK OF CARDIORESPIRATORY FAILURE

Life-threatening anaphylactic reactions and severe hypersensitivity reactions, presenting as respiratory distress, hypoxia, apnea, dyspnea, bradycardia, tachycardia, bronchospasm, throat tightness, hypotension, angioedema (including tongue or lip swelling, periorbital edema, and face edema), and urticaria, have occurred in some patients during and after alglucosidase alfa infusions. Immune-mediated reactions presenting as proteinuria, nephrotic syndrome, and necrotizing skin lesions have occurred in some patients following alglucosidase alfa treatment. Closely observe patients during and after alglucosidase alfa administration and be prepared to manage anaphylaxis and hypersensitivity reactions. Inform patients of the signs and symptoms of anaphylaxis, hypersensitivity reactions, and immune-mediated reactions and have them seek immediate medical care should signs and symptoms occur [see Warnings and Precautions (5.1, 5.2)].

Infantile-onset Pompe disease patients with compromised cardiac or respiratory function may be at risk of serious acute exacerbation of their cardiac or respiratory compromise due to fluid overload, and require additional monitoring [see Warnings and Precautions (5.3)].

1 INDICATIONS AND USAGE

LUMIZYME® (alglucosidase alfa) [see Description (11)] is a hydrolytic lysosomal glycogen-specific enzyme indicated for patients with Pompe disease (acid α-glucosidase [GAA] deficiency).

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dose

The recommended dosage of alglucosidase alfa is 20 mg/kg body weight administered every 2 weeks as an intravenous infusion.

2.2 Instructions for Use

Alglucosidase alfa does not contain any preservatives. Vials are single dose only. Discard any unused product.

The total volume of infusion is determined by the patient’s body weight and should be administered over approximately 4 hours. 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, alglucosidase alfa 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 alglucosidase alfa, and initiate appropriate medical treatment. See Table 1 below for the rate of infusion at each step, expressed as mL/hr based on the recommended infusion volume by patient weight.

Table 1: Recommended Infusion Volumes and Rates
Patient Weight Range (kg) Total infusion volume (mL) Step 11 mg/kg/hr(mL/hr) Step 23 mg/kg/hr(mL/hr) Step 35 mg/kg/hr(mL/hr) Step 47 mg/kg/hr(mL/hr)
1.25 to 2.5 25 1.25 3.75 6.25 6.6
2.6 to 10 50 3 8 13 18
10.1 to 20 100 5 15 25 35
20.1 to 30 150 8 23 38 53
30.1 to 35 200 10 30 50 70
35.1 to 50 250 13 38 63 88
50.1 to 60 300 15 45 75 105
60.1 to 100 500 25 75 125 175
100.1 to 120 600 30 90 150 210
120.1 to 140 700 35 105 175 245
140.1 to 160 800 40 120 200 280
160.1 to 180 900 45 135 225 315
180.1 to 200 1,000 50 150 250 350

2.3 Reconstitution, Dilution, and Administration

Alglucosidase alfa should be reconstituted, diluted, and administered by a healthcare professional.

Use aseptic technique during preparation. Do not use filter needles during preparation.

a.
Determine the number of vials to be reconstituted based on the individual patient’s weight and the recommended dose of 20 mg/kg.

Patient weight (kg) × dose (mg/kg) = patient dose (in mg)

Patient dose (in mg) divided by 50 mg/vial = number of vials to reconstitute. If the number of vials includes a fraction, round up to the next whole number.

Example: Patient weight (68 kg) × dose (20 mg/kg) = patient dose (1,360 mg)

1,360 mg divided by 50 mg/vial = 27.2 vials; therefore, 28 vials should be reconstituted.

Remove the required number of vials from the refrigerator and allow them to reach room temperature prior to reconstitution (approximately 30 minutes).

b.
Reconstitute each alglucosidase alfa vial by slowly injecting 10.3 mL of Sterile Water for Injection, USP to the inside wall of each vial. Each vial will yield a concentration of 5 mg/mL. The total extractable dose per vial is 50 mg per 10 mL. Avoid forceful impact of the water for injection on the powder and avoid foaming. This is done by slow drop-wise addition of the water for injection down the inside of the vial and not directly onto the lyophilized cake. Tilt and roll each vial gently. Do not invert, swirl, or shake.
c.
The reconstituted alglucosidase alfa solution should be protected from light.
d.
Perform an immediate visual inspection on the reconstituted vials for particulate matter and discoloration. If upon immediate inspection opaque particles are observed or if the solution is discolored do not use. The reconstituted solution may occasionally contain some alglucosidase alfa particles (typically less than 10 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 alglucosidase alfa 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.
e.
Alglucosidase alfa should be diluted in 0.9% Sodium Chloride for Injection, USP, immediately after reconstitution, to a final alglucosidase alfa concentration of 0.5 to 4 mg/mL. See Table 1 for the recommended total infusion volume based on patient weight.
f.
Slowly withdraw the reconstituted solution from each vial. Avoid foaming in the syringe.
g.
Remove airspace from the infusion bag to minimize particle formation due to the sensitivity of alglucosidase alfa to air-liquid interfaces.
h.
Add the reconstituted alglucosidase alfa solution slowly and directly into the sodium chloride solution. Do not add directly into airspace that may remain within the infusion bag. Avoid foaming in the infusion bag.
i.
Gently invert or massage the infusion bag to mix. Do not shake.
j.
Administer alglucosidase alfa using an in-line low protein binding 0.2 µm filter.
k.
Do not infuse alglucosidase alfa in the same intravenous line with other products.

The reconstituted and diluted solution should be administered without delay. 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). Storage of the reconstituted solution at room temperature is not recommended. The reconstituted and diluted alglucosidase alfa solution should be protected from light. Do not freeze or shake.

Alglucosidase alfa does not contain any preservatives. Vials are single dose only. Discard any unused product.

3 DOSAGE FORMS AND STRENGTHS

For injection: 50 mg of alglucosidase alfa is supplied as a sterile, nonpyrogenic, white to off-white, lyophilized cake or powder in a single-dose vial for reconstitution. After reconstitution, the resultant solution concentration is 5 mg/mL.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Anaphylaxis and Hypersensitivity Reactions

Anaphylaxis and hypersensitivity reactions have been observed in patients during and up to 3 hours after alglucosidase alfa infusion. Some of the reactions were life-threatening and included anaphylactic shock, cardiac arrest, respiratory arrest, respiratory distress, hypoxia, apnea, dyspnea, bradycardia, tachycardia, bronchospasm, throat tightness, hypotension, angioedema (including tongue or lip swelling, periorbital edema, and face edema), and urticaria. Other accompanying reactions included chest discomfort/pain, wheezing, tachypnea, cyanosis, decreased oxygen saturation, convulsions, pruritus, rash, hyperhidrosis, nausea, dizziness, hypertension/increased blood pressure, flushing/feeling hot, erythema, pyrexia, pallor, peripheral coldness, restlessness, nervousness, headache, back pain, and paresthesia. Some of these reactions were IgE-mediated.

If anaphylaxis or severe hypersensitivity reactions occur, immediately discontinue administration of alglucosidase alfa, and initiate appropriate medical treatment. Severe reactions are generally managed with infusion interruption, administration of antihistamines, corticosteroids, intravenous fluids, and/or oxygen, when clinically indicated. In some cases of anaphylaxis, epinephrine has been administered. Appropriate medical support, including cardiopulmonary resuscitation equipment, should be readily available when alglucosidase alfa is administered.

The risks and benefits of readministering alglucosidase alfa following an anaphylactic or hypersensitivity reaction should be considered. Some patients have been rechallenged and have continued to receive alglucosidase alfa under close clinical supervision. Extreme care should be exercised, with appropriate resuscitation measures available, if the decision is made to readminister the product [see Adverse Reactions (6.2)].

5.2 Immune-Mediated Reactions

Immune-mediated cutaneous reactions have been reported with alglucosidase alfa including necrotizing skin lesions [see Adverse Reactions (6.3)]. Systemic immune-mediated reactions, including possible type III immune-mediated reactions have been observed with alglucosidase alfa. These reactions occurred several weeks to 3 years after initiation of alglucosidase alfa infusions. Skin biopsy in one patient demonstrated deposition of anti-rhGAA antibodies in the lesion. Another patient developed severe inflammatory arthropathy in association with pyrexia and elevated erythrocyte sedimentation rate. Nephrotic syndrome secondary to membranous glomerulonephritis was observed in some Pompe disease patients treated with alglucosidase alfa who had persistently positive anti-rhGAA IgG antibody titers. In these patients, renal biopsy was consistent with immune complex deposition. Patients improved following treatment interruption. Therefore, patients receiving alglucosidase alfa should undergo periodic urinalysis [see Adverse Reactions (6.3)].

Patients should be monitored for the development of systemic immune-mediated reactions involving skin and other organs while receiving alglucosidase alfa. If immune-mediated reactions occur, consider discontinuation of the administration of alglucosidase alfa, and initiate appropriate medical treatment. The risks and benefits of readministering alglucosidase alfa following an immune-mediated reaction should be considered. Some patients have been able to be rechallenged and have continued to receive alglucosidase alfa under close clinical supervision. Immune tolerance induction administered in conjunction with LUMIZYME may also aide tolerability of alglucosidase alfa under the management of a clinical specialist knowledgeable in immune tolerance induction in pediatric Pompe disease.

5.3 Risk of Acute Cardiorespiratory Failure

Patients with acute underlying respiratory illness or compromised cardiac and/or respiratory function may be at risk of serious exacerbation of their cardiac or respiratory compromise during infusions. Appropriate medical support and monitoring measures should be readily available during alglucosidase alfa infusion, and some patients may require prolonged observation times that should be individualized based on the needs of the patient. Acute cardiorespiratory failure has been observed in infantile-onset Pompe disease patients with underlying cardiac hypertrophy, possibly associated with fluid overload with intravenous administration of alglucosidase alfa [see Dosage and Administration (2.2)].

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