These Highlights Do Not Include All The Information Needed To Use Lumizyme Safely And Effectively. See Full Prescribing Information For Lumizyme.

Hypersensitivity Reactions Including Anaphylaxis

Patients treated with enzyme replacement therapies have experienced life-threatening hypersensitivity reactions, including anaphylaxis. Anaphylaxis has occurred during the early course of enzyme replacement therapy and after extended duration of therapy. Initiate LUMIZYME in a healthcare setting with appropriate medical monitoring and support measures, including access to cardiopulmonary resuscitation equipment. If a severe hypersensitivity reaction (e.g., anaphylaxis) occurs, discontinue LUMIZYME and immediately initiate appropriate medical treatment, including use of epinephrine. Inform patients of the symptoms of life-threatening hypersensitivity reactions, including anaphylaxis and to seek immediate medical care should symptoms occur [see Warnings and Precautions (5.1)].

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.

Alglucosidase alfa is a hydrolytic lysosomal glycogen-specific enzyme encoded by the predominant of nine observed haplotypes of the human acid α-glucosidase (GAA) gene. Alglucosidase alfa is produced by recombinant DNA technology in a Chinese hamster ovary cell line. Alglucosidase alfa degrades glycogen by catalyzing the hydrolysis of α-1,4- and α-1,6- glycosidic linkages of lysosomal glycogen.

Alglucosidase alfa is a glycoprotein with a calculated mass of 99,377 Daltons for the polypeptide chain, and a total mass of approximately 109,000 Daltons, including carbohydrates. Alglucosidase alfa has a specific activity of 3.6 to 5.4 units/mg (one unit is defined as that amount of activity that results in the hydrolysis of 1 micromole of synthetic substrate per minute under specified assay conditions). Alglucosidase alfa is intended for intravenous infusion. It is supplied as a sterile, nonpyrogenic, white to off-white, lyophilized cake or powder for reconstitution with 10.3 mL Sterile Water for Injection, USP. Each 50 mg vial contains 52.5 mg alglucosidase alfa, 210 mg mannitol, 0.5 mg polysorbate 80, 9.9 mg sodium phosphate dibasic heptahydrate, and 31.2 mg sodium phosphate monobasic monohydrate. Following reconstitution as directed, each vial contains 10.5 mL reconstituted solution and a total extractable volume of 10 mL at 5 mg/mL alglucosidase alfa. Alglucosidase alfa does not contain preservatives; each vial is for single dose only.

The safety and effectiveness of LUMIZYME has been established in pediatric patients with Pompe disease [see Adverse Reactions (6.2)].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) [see Clinical Studies (14.1)] 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 [see Clinical Studies (14.2)].

Anaphylaxis, hypersensitivity reactions, and acute cardiorespiratory failure have occurred in pediatric patients [see Boxed Warning, Warnings and Precautions (5.1, 5.3)]. Additionally, cardiac arrhythmia and sudden cardiac death have occurred in pediatric patients during general anesthesia for central venous catheter placement [see Warnings and Precautions (5.4)].

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 [see Clinical Studies (14.1)].

The observed incidence of anti-drug antibodies (ADA) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADAs in the studies described below with the incidence of ADAs in other studies, including those of LUMIZYME or of other alglucosidase alfa products.

None.

The following serious adverse reactions are described below and elsewhere in the labeling:

• Hypersensitivity Reactions Including Anaphylaxis [see Warnings and Precautions (5.1)]

Clinical pharmacodynamic studies have not been conducted for alglucosidase alfa.

The pharmacokinetics of alglucosidase alfa was evaluated in 13 patients with infantile-onset Pompe disease, aged 1 month to 7 months, who received 20 mg/kg (approximately as a 4-hour infusion) or 40 mg/kg (approximately as a 6.5-hour infusion) of alglucosidase alfa every 2 weeks. The measurement of alglucosidase alfa plasma concentration was based on an activity assay using an artificial substrate. Systemic exposure was approximately dose proportional between the 20 and 40 mg/kg doses. Based on the pharmacokinetic blood samples collected for 12 hours after a 4-hour intravenous infusion of 20 mg/kg (n=5), the estimated mean AUC was 811 mcg∙hr/mL with 17% coefficient of variation [CV], C_max was 162 mcg/mL with 19% CV, clearance was 25 mL/hr/kg with 16% CV, and half-life was 2.3 hours with 17% CV.

The pharmacokinetics of alglucosidase alfa was also evaluated in a separate trial of 14 patients with infantile-onset Pompe disease, aged 6 months to 3.5 years, who received 20 mg/kg of alglucosidase alfa as a 4-hour infusion every 2 weeks. The pharmacokinetic parameters were similar to those observed for the infantile-onset Pompe disease patients aged 1 month to 7 months who received the 20 mg/kg dose.

The pharmacokinetics of alglucosidase alfa was evaluated in another trial of 10 adult and 10 pediatric patients with Pompe disease who received a single dose of 20 mg/kg of alglucosidase alfa as a 4-hour infusion. In pediatric patients, aged 7 months to 13.7 years, the estimated mean AUC was 1,110 mcg∙hr/mL with 68% CV and C_max was 204 mcg/mL with 46% CV. In adult patients, aged 19 to 57 years, the estimated mean AUC was 1,890 mcg∙hr/mL with 51% CV and C_max was 307 mcg/mL with 47% CV.

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

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

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.

• Infusion-Associated Reactions (IARs): If an IAR occurs, decreasing the infusion rate, temporarily stopping the infusion, and/or administration of antihistamines and/or antipyretics may ameliorate the symptoms. (5.2)
• Risk of Cardiac Arrhythmia and Sudden Cardiac Death during General Anesthesia for Central Venous Catheter Placement: Caution should be used when administering general anesthesia for the placement of a central venous catheter intended for LUMIZYME infusion. (5.5)
• Risk of Developing Anti-alglucosidase Alfa Antibodies: Patients with IOPD should have a cross-reactive immunologic material (CRIM) assessment early in their disease course and be managed by a clinical specialist knowledgeable in immune tolerance induction in Pompe disease. (5.6)

• Administration of LUMIZYME should be supervised by a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis. (2.1)
• 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 (2.2)
• Reconstitute and dilute LUMIZYME prior to use. (2.3)
• See full prescribing information for storage of the reconstituted and diluted product and administration instructions (2.4, 2.5)

For injection: 50 mg of LUMIZYME 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.

The following adverse reactions have been identified during post approval use of alglucosidase alfa. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

In the postmarketing experience with LUMIZYME, serious adverse reactions have been reported, including anaphylaxis [see Boxed Warning and Warnings and Precautions (5.1)]. Acute cardiorespiratory failure, possibly associated with fluid overload, has been reported in infantile-onset Pompe disease patients with pre-existing hypertrophic cardiomyopathy [see Boxed Warning and Warning and Precautions (5.3)].

Infusion associated reactions, including pyrexia, chills, fatigue, urticaria, rash, pruritus, erythema, dyspnea, hypotension, bradycardia, tachycardia, flushing, nausea, headache, and syncope have been reported with alglucosidase alfa.

In addition to the hypersensitivity reactions reported in clinical trials [see Adverse Reactions (6.1)], the following hypersensitivity reactions have been reported in at least 2 patients and included: anaphylactic shock, respiratory failure, respiratory arrest, cardiac arrest, hypoxia, dyspnea, wheezing, convulsions, peripheral coldness, restlessness, nervousness, back pain, stridor, pharyngeal edema, abdominal pain, apnea, muscle spasm, and conjunctivitis. In addition, one case of hyperparathyroidism has been reported.

Systemic and cutaneous immune-mediated reactions, including proteinuria and nephrotic syndrome secondary to membranous glomerulonephritis, and necrotizing skin lesions have been reported in postmarketing safety experience with alglucosidase alfa [see Warnings and Precautions (5.2)].

Immune-mediated cutaneous reactions have been reported with LUMIZYME including necrotizing skin lesions [see Adverse Reactions (6.2)]. Systemic immune-mediated reactions, including possible type III immune-mediated reactions have been observed with LUMIZYME. These reactions occurred several weeks to 3 years after initiation of LUMIZYME 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 LUMIZYME-treated patients with Pompe disease who had persistently positive anti-rhGAA IgG antibody titers. In these patients, renal biopsy was consistent with immune complex deposition. Patients improved following LUMIZYME treatment interruption [see Adverse Reactions (6.2)].

LUMIZYME treated patients should be monitored for the development of systemic immune-mediated reactions involving skin and other organs including periodic urinalysis. If immune-mediated reactions occur, consider discontinuing the LUMIZYME administration, and initiating appropriate medical treatment. The risks and benefits of readministering LUMIZYME following an immune-mediated reaction should be considered. Some patients have been able to be rechallenged and have continued to receive LUMIZYME under close clinical supervision. Immune tolerance induction administered in conjunction with LUMIZYME may also aide tolerability of LUMIZYME under the management of a clinical specialist knowledgeable in immune tolerance induction in pediatric patients with IOPD or LOPD.

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

In clinical trials, the most common adverse reactions (≥5%) following intravenous alglucosidase alfa treatment were hypersensitivity reactions, and included anaphylaxis, rash, pyrexia, flushing/feeling hot, urticaria, headache, hyperhidrosis, nausea, cough, decreased oxygen saturation, tachycardia, tachypnea, chest discomfort, dizziness, muscle twitching, agitation, cyanosis, erythema, hypertension/increased blood pressure, pallor, rigors, tremor, vomiting, fatigue, and myalgia.

• The total volume of infusion is determined by the patient's body weight and should be administered over approximately 4 hours.
• Administer 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. 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.
• Do not infuse LUMIZYME in the same intravenous line with other products. Discard any unused product.

Infusion-associated reactions (IARs) such as pyrexia, chills, flu-like illness, myalgia, arthralgia, pain, fatigue, urticaria, rash, pruritus, erythema, dyspnea, tachycardia, flushing, nausea, headache and syncope occurred in LUMIZYME-treated patients [see Adverse Reactions (6.2)].

If an IAR occurs, decreasing the infusion rate, temporarily stopping the infusion, and/or administering antihistamines and/or antipyretics may ameliorate the symptoms. Closely monitor patients who have experienced IARs when re-administering LUMIZYME.

LUMIZYME 50 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)

• 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 [see Dosage and Administration (2.5)].

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 LUMIZYME 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 LUMIZYME [see Dosage and Administration (2.2)].

Lumizyme^®

(alglucosidase alfa)

50 mg/vial

For Injection

For Intravenous Infusion Only

Rx only

Contains No Preservatives

SANOFI GENZYME

Reconstitute and dilute LUMIZYME in the following manner.

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

• Administration of LUMIZYME should be supervised by a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis [see Warnings and Precautions (5.1)].
• Initiate LUMIZYME in a healthcare setting with appropriate medical monitoring and support measures, including access to cardiopulmonary resuscitation equipment [see Warnings and Precautions (5.1)].
• Prior to LUMIZYME administration, consider pretreating with antihistamines, antipyretics, and/or corticosteroids [see Warnings and Precautions (5.1, 5.2)].
• LUMIZYME must be reconstituted and diluted prior to use [see Dosage and Administration (2.3)].
• Appropriate medical monitoring and support measures, including cardiopulmonary resuscitation equipment, should be readily available during LUMIZYME administration [see Warnings and Precautions (5.1)].

The safety and efficacy of alglucosidase alfa were assessed in 90 patients with late-onset Pompe disease (LOPD), aged 10 to 70 years, in a randomized, double-blind, placebo-controlled trial (Trial 4). All patients were naive to enzyme replacement therapy. Patients were allocated in a 2:1 ratio and received 20 mg/kg of intravenous alglucosidase alfa (n=60) or intravenous placebo (n=30) every other week for 78 weeks (18 months).

The youngest alglucosidase alfa-treated patient was 16 years of age, and the youngest placebo-treated patient was 10 years of age. The trial population included 34 males and 26 females (n=60) in the alglucosidase alfa group and 11 males and 19 females (n=30) in the placebo group. At baseline, all patients were ambulatory (some required assistive walking devices), did not require invasive ventilator support or non-invasive ventilation while awake and sitting upright, and had a forced vital capacity (FVC) between 30 and 79% of predicted in the sitting position. Patients who could not walk 40 meters in 6 minutes or were unable to perform appropriate pulmonary and muscle function testing were excluded from the study.

A total of 81 of 90 patients completed the trial. Of the 9 patients who discontinued, 5 were in the alglucosidase alfa group and 4 were in the placebo group. Three patients discontinued the study due to an adverse event; two patients were in the alglucosidase alfa treatment group and one patient was in placebo group.

At trial entry, the mean % predicted FVC in the sitting position among all patients was about 55%. After 78 weeks, the mean % predicted FVC increased to 56.2% for alglucosidase alfa-treated patients and decreased to 52.8% for placebo-treated patients indicating an alglucosidase alfa treatment effect of 3.4% (95% confidence interval: [1.3% to 5.5%]; p=0.004). Stabilization of % predicted FVC in the alglucosidase alfa-treated patients was observed (see Figure 1).

Figure 1: Mean FVC Upright (% Predicted) Over Time in Patients with LOPD (Trial 4)

At trial entry, the mean 6 minute walk test (6MWT) among all patients was about 330 meters. After 78 weeks, the mean 6MWT increased by 25 meters for alglucosidase alfa-treated patients and decreased by 3 meters for placebo-treated patients indicating an alglucosidase alfa treatment effect of 28 meters (95% confidence interval: [-1 to 52 meters]; p=0.06) (see Figure 2).

Figure 2: Mean Six Minute Walk Test Total Distance Walked Over Time in Patients with LOPD (Trial 4)

The safety and effectiveness of alglucosidase alfa in the treatment patients with infantile-onset Pompe disease (IOPD) were assessed in 57 treatment-naive infantile-onset Pompe disease patients, aged 0.2 month to 3.5 years at first alglucosidase alfa infusion, in three separate open-label, single-arm clinical trials (Trials 1, 2, and 3).

Long-term studies in animals to evaluate carcinogenic potential or studies to evaluate mutagenic potential have not been performed with alglucosidase alfa.

Intravenous administration of alglucosidase alfa every other day in mice at doses up to 40 mg/kg (0.4 times the human AUC at the recommended biweekly dose) had no effect on fertility and reproductive performance.

As shown from clinical trials and published literature, individualized immune tolerance induction regimen administered prior to and with initiation of LUMIZYME has been reported to aid tolerability of LUMIZYME and reduce the development of high ADA titers in CRIM-negative IOPD patients. Furthermore, CRIM status has been shown to be associated with immunogenicity and patients' responses to LUMIZYME. LUMIZYME-treated infants with IOPD who are CRIM-negative (indicating no endogenous enzyme is detected) have shown poorer clinical response (loss of motor function, ventilator dependence, or death) in the presence of high sustained IgG ADA titers and positive inhibitory antibodies compared to CRIM-positive infants [see Adverse Reactions (6.2)]. However, high and sustained ADA titers has also occurred in a limited number of CRIM-positive patients, generally with very low endogenous enzyme [see Clinical Pharmacology (12.6)]. Therefore, these patients must be managed by a clinical specialist knowledgeable in immune tolerance induction in Pompe disease.

Some alglucosidase alfa-treated patients who developed high sustained IgG ADA titers had reduced efficacy. Some alglucosidase alfa-treated patients with high IgG ADA titers had a higher incidence of IARs.

Patients with IOPD should have a cross-reactive immunologic material (CRIM) assessment early in their disease course.

Anti-alglucosidase alfa antibody (referred to as ADA) titers should be obtained during LUMIZYME treatment. Contact Genzyme Corporation at 1-800-745-4447 for information on ADA testing.

Recommend the following ADA testing:

• Baseline serum ADA sample collection prior to the first LUMIZYME infusion is strongly encouraged.
• For patients with:
  • IOPD, suggest regular ADA monitoring during first year of treatment (example: every 3 months).
  • LOPD, suggest ADA be monitored within six months of LUMIZYME initiation with subsequent monitoring as clinically warranted based on safety and efficacy considerations.
• If patients [see Adverse Reactions (6.2) and Clinical Pharmacology (12.6)]:
  • Develop hypersensitivity reactions, consider testing for IgG ADA, IgE ADA and other mediators.
  • Develop immune-mediated reactions that are not hypersensitivity reactions, consider testing for IgG ADA.
  • Lose or have a reduced clinical response, consider testing for IgG ADA and for inhibitory antibody activity.

• 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.

Administration of general anesthesia can be complicated by the presence of severe cardiac and skeletal (including respiratory) muscle weakness. Therefore, caution should be used when administering general anesthesia. Ventricular arrhythmias and bradycardia, resulting in cardiac arrest or death, or requiring cardiac resuscitation or defibrillation have been observed in patients with IOPD with cardiac hypertrophy during general anesthesia for central venous catheter placement.

WARNING: HYPERSENSITIVITY REACTIONS INCLUDING ANAPHYLAXIS, IMMUNE-MEDIATED REACTIONS, and RISK OF ACUTE CARDIORESPIRATORY FAILURE

See full prescribing information for complete boxed warning.

Hypersensitivity Reactions Including Anaphylaxis

Anaphylaxis has occurred during the early course of enzyme replacement therapy and after extended duration of therapy. Initiate LUMIZYME in a healthcare setting with appropriate medical monitoring and support measures, including access to cardiopulmonary resuscitation equipment. If a severe hypersensitivity reaction (e.g., anaphylaxis) occurs, discontinue LUMIZYME and immediately initiate appropriate medical treatment, including use of epinephrine. (5.1)

Immune-Mediated Reactions

Immune-mediated reactions presenting as proteinuria, nephrotic syndrome, and necrotizing skin lesions have occurred in some patients following LUMIZYME treatment. Monitor patients for the development of systemic immune-mediated reactions involving skin and other organs while receiving LUMIZYME. (5.3)

Risk of Acute Cardiorespiratory Failure

Infantile-onset Pompe disease (IOPD) 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. (5.4)

Hypersensitivity Reactions Including Anaphylaxis

Patients treated with enzyme replacement therapies have experienced life-threatening hypersensitivity reactions, including anaphylaxis. Anaphylaxis has occurred during the early course of enzyme replacement therapy and after extended duration of therapy. Initiate LUMIZYME in a healthcare setting with appropriate medical monitoring and support measures, including access to cardiopulmonary resuscitation equipment. If a severe hypersensitivity reaction (e.g., anaphylaxis) occurs, discontinue LUMIZYME and immediately initiate appropriate medical treatment, including use of epinephrine. Inform patients of the symptoms of life-threatening hypersensitivity reactions, including anaphylaxis and to seek immediate medical care should symptoms occur [see Warnings and Precautions (5.1)].

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.

Alglucosidase alfa is a hydrolytic lysosomal glycogen-specific enzyme encoded by the predominant of nine observed haplotypes of the human acid α-glucosidase (GAA) gene. Alglucosidase alfa is produced by recombinant DNA technology in a Chinese hamster ovary cell line. Alglucosidase alfa degrades glycogen by catalyzing the hydrolysis of α-1,4- and α-1,6- glycosidic linkages of lysosomal glycogen.

Alglucosidase alfa is a glycoprotein with a calculated mass of 99,377 Daltons for the polypeptide chain, and a total mass of approximately 109,000 Daltons, including carbohydrates. Alglucosidase alfa has a specific activity of 3.6 to 5.4 units/mg (one unit is defined as that amount of activity that results in the hydrolysis of 1 micromole of synthetic substrate per minute under specified assay conditions). Alglucosidase alfa is intended for intravenous infusion. It is supplied as a sterile, nonpyrogenic, white to off-white, lyophilized cake or powder for reconstitution with 10.3 mL Sterile Water for Injection, USP. Each 50 mg vial contains 52.5 mg alglucosidase alfa, 210 mg mannitol, 0.5 mg polysorbate 80, 9.9 mg sodium phosphate dibasic heptahydrate, and 31.2 mg sodium phosphate monobasic monohydrate. Following reconstitution as directed, each vial contains 10.5 mL reconstituted solution and a total extractable volume of 10 mL at 5 mg/mL alglucosidase alfa. Alglucosidase alfa does not contain preservatives; each vial is for single dose only.

The safety and effectiveness of LUMIZYME has been established in pediatric patients with Pompe disease [see Adverse Reactions (6.2)].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) [see Clinical Studies (14.1)] 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 [see Clinical Studies (14.2)].

Anaphylaxis, hypersensitivity reactions, and acute cardiorespiratory failure have occurred in pediatric patients [see Boxed Warning, Warnings and Precautions (5.1, 5.3)]. Additionally, cardiac arrhythmia and sudden cardiac death have occurred in pediatric patients during general anesthesia for central venous catheter placement [see Warnings and Precautions (5.4)].

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 [see Clinical Studies (14.1)].

The observed incidence of anti-drug antibodies (ADA) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADAs in the studies described below with the incidence of ADAs in other studies, including those of LUMIZYME or of other alglucosidase alfa products.

None.

The following serious adverse reactions are described below and elsewhere in the labeling:

• Hypersensitivity Reactions Including Anaphylaxis [see Warnings and Precautions (5.1)]

Clinical pharmacodynamic studies have not been conducted for alglucosidase alfa.

The pharmacokinetics of alglucosidase alfa was evaluated in 13 patients with infantile-onset Pompe disease, aged 1 month to 7 months, who received 20 mg/kg (approximately as a 4-hour infusion) or 40 mg/kg (approximately as a 6.5-hour infusion) of alglucosidase alfa every 2 weeks. The measurement of alglucosidase alfa plasma concentration was based on an activity assay using an artificial substrate. Systemic exposure was approximately dose proportional between the 20 and 40 mg/kg doses. Based on the pharmacokinetic blood samples collected for 12 hours after a 4-hour intravenous infusion of 20 mg/kg (n=5), the estimated mean AUC was 811 mcg∙hr/mL with 17% coefficient of variation [CV], C_max was 162 mcg/mL with 19% CV, clearance was 25 mL/hr/kg with 16% CV, and half-life was 2.3 hours with 17% CV.

The pharmacokinetics of alglucosidase alfa was also evaluated in a separate trial of 14 patients with infantile-onset Pompe disease, aged 6 months to 3.5 years, who received 20 mg/kg of alglucosidase alfa as a 4-hour infusion every 2 weeks. The pharmacokinetic parameters were similar to those observed for the infantile-onset Pompe disease patients aged 1 month to 7 months who received the 20 mg/kg dose.

The pharmacokinetics of alglucosidase alfa was evaluated in another trial of 10 adult and 10 pediatric patients with Pompe disease who received a single dose of 20 mg/kg of alglucosidase alfa as a 4-hour infusion. In pediatric patients, aged 7 months to 13.7 years, the estimated mean AUC was 1,110 mcg∙hr/mL with 68% CV and C_max was 204 mcg/mL with 46% CV. In adult patients, aged 19 to 57 years, the estimated mean AUC was 1,890 mcg∙hr/mL with 51% CV and C_max was 307 mcg/mL with 47% CV.

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

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

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.

• Infusion-Associated Reactions (IARs): If an IAR occurs, decreasing the infusion rate, temporarily stopping the infusion, and/or administration of antihistamines and/or antipyretics may ameliorate the symptoms. (5.2)
• Risk of Cardiac Arrhythmia and Sudden Cardiac Death during General Anesthesia for Central Venous Catheter Placement: Caution should be used when administering general anesthesia for the placement of a central venous catheter intended for LUMIZYME infusion. (5.5)
• Risk of Developing Anti-alglucosidase Alfa Antibodies: Patients with IOPD should have a cross-reactive immunologic material (CRIM) assessment early in their disease course and be managed by a clinical specialist knowledgeable in immune tolerance induction in Pompe disease. (5.6)

• Administration of LUMIZYME should be supervised by a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis. (2.1)
• 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 (2.2)
• Reconstitute and dilute LUMIZYME prior to use. (2.3)
• See full prescribing information for storage of the reconstituted and diluted product and administration instructions (2.4, 2.5)

For injection: 50 mg of LUMIZYME 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.

The following adverse reactions have been identified during post approval use of alglucosidase alfa. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

In the postmarketing experience with LUMIZYME, serious adverse reactions have been reported, including anaphylaxis [see Boxed Warning and Warnings and Precautions (5.1)]. Acute cardiorespiratory failure, possibly associated with fluid overload, has been reported in infantile-onset Pompe disease patients with pre-existing hypertrophic cardiomyopathy [see Boxed Warning and Warning and Precautions (5.3)].

Infusion associated reactions, including pyrexia, chills, fatigue, urticaria, rash, pruritus, erythema, dyspnea, hypotension, bradycardia, tachycardia, flushing, nausea, headache, and syncope have been reported with alglucosidase alfa.

In addition to the hypersensitivity reactions reported in clinical trials [see Adverse Reactions (6.1)], the following hypersensitivity reactions have been reported in at least 2 patients and included: anaphylactic shock, respiratory failure, respiratory arrest, cardiac arrest, hypoxia, dyspnea, wheezing, convulsions, peripheral coldness, restlessness, nervousness, back pain, stridor, pharyngeal edema, abdominal pain, apnea, muscle spasm, and conjunctivitis. In addition, one case of hyperparathyroidism has been reported.

Systemic and cutaneous immune-mediated reactions, including proteinuria and nephrotic syndrome secondary to membranous glomerulonephritis, and necrotizing skin lesions have been reported in postmarketing safety experience with alglucosidase alfa [see Warnings and Precautions (5.2)].

Immune-mediated cutaneous reactions have been reported with LUMIZYME including necrotizing skin lesions [see Adverse Reactions (6.2)]. Systemic immune-mediated reactions, including possible type III immune-mediated reactions have been observed with LUMIZYME. These reactions occurred several weeks to 3 years after initiation of LUMIZYME 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 LUMIZYME-treated patients with Pompe disease who had persistently positive anti-rhGAA IgG antibody titers. In these patients, renal biopsy was consistent with immune complex deposition. Patients improved following LUMIZYME treatment interruption [see Adverse Reactions (6.2)].

LUMIZYME treated patients should be monitored for the development of systemic immune-mediated reactions involving skin and other organs including periodic urinalysis. If immune-mediated reactions occur, consider discontinuing the LUMIZYME administration, and initiating appropriate medical treatment. The risks and benefits of readministering LUMIZYME following an immune-mediated reaction should be considered. Some patients have been able to be rechallenged and have continued to receive LUMIZYME under close clinical supervision. Immune tolerance induction administered in conjunction with LUMIZYME may also aide tolerability of LUMIZYME under the management of a clinical specialist knowledgeable in immune tolerance induction in pediatric patients with IOPD or LOPD.

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

In clinical trials, the most common adverse reactions (≥5%) following intravenous alglucosidase alfa treatment were hypersensitivity reactions, and included anaphylaxis, rash, pyrexia, flushing/feeling hot, urticaria, headache, hyperhidrosis, nausea, cough, decreased oxygen saturation, tachycardia, tachypnea, chest discomfort, dizziness, muscle twitching, agitation, cyanosis, erythema, hypertension/increased blood pressure, pallor, rigors, tremor, vomiting, fatigue, and myalgia.

• The total volume of infusion is determined by the patient's body weight and should be administered over approximately 4 hours.
• Administer 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. 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.
• Do not infuse LUMIZYME in the same intravenous line with other products. Discard any unused product.

Infusion-associated reactions (IARs) such as pyrexia, chills, flu-like illness, myalgia, arthralgia, pain, fatigue, urticaria, rash, pruritus, erythema, dyspnea, tachycardia, flushing, nausea, headache and syncope occurred in LUMIZYME-treated patients [see Adverse Reactions (6.2)].

If an IAR occurs, decreasing the infusion rate, temporarily stopping the infusion, and/or administering antihistamines and/or antipyretics may ameliorate the symptoms. Closely monitor patients who have experienced IARs when re-administering LUMIZYME.

LUMIZYME 50 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)

• 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 [see Dosage and Administration (2.5)].

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 LUMIZYME 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 LUMIZYME [see Dosage and Administration (2.2)].

Lumizyme^®

(alglucosidase alfa)

50 mg/vial

For Injection

For Intravenous Infusion Only

Rx only

Contains No Preservatives

SANOFI GENZYME

Reconstitute and dilute LUMIZYME in the following manner.

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

• Administration of LUMIZYME should be supervised by a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis [see Warnings and Precautions (5.1)].
• Initiate LUMIZYME in a healthcare setting with appropriate medical monitoring and support measures, including access to cardiopulmonary resuscitation equipment [see Warnings and Precautions (5.1)].
• Prior to LUMIZYME administration, consider pretreating with antihistamines, antipyretics, and/or corticosteroids [see Warnings and Precautions (5.1, 5.2)].
• LUMIZYME must be reconstituted and diluted prior to use [see Dosage and Administration (2.3)].
• Appropriate medical monitoring and support measures, including cardiopulmonary resuscitation equipment, should be readily available during LUMIZYME administration [see Warnings and Precautions (5.1)].

The safety and efficacy of alglucosidase alfa were assessed in 90 patients with late-onset Pompe disease (LOPD), aged 10 to 70 years, in a randomized, double-blind, placebo-controlled trial (Trial 4). All patients were naive to enzyme replacement therapy. Patients were allocated in a 2:1 ratio and received 20 mg/kg of intravenous alglucosidase alfa (n=60) or intravenous placebo (n=30) every other week for 78 weeks (18 months).

The youngest alglucosidase alfa-treated patient was 16 years of age, and the youngest placebo-treated patient was 10 years of age. The trial population included 34 males and 26 females (n=60) in the alglucosidase alfa group and 11 males and 19 females (n=30) in the placebo group. At baseline, all patients were ambulatory (some required assistive walking devices), did not require invasive ventilator support or non-invasive ventilation while awake and sitting upright, and had a forced vital capacity (FVC) between 30 and 79% of predicted in the sitting position. Patients who could not walk 40 meters in 6 minutes or were unable to perform appropriate pulmonary and muscle function testing were excluded from the study.

A total of 81 of 90 patients completed the trial. Of the 9 patients who discontinued, 5 were in the alglucosidase alfa group and 4 were in the placebo group. Three patients discontinued the study due to an adverse event; two patients were in the alglucosidase alfa treatment group and one patient was in placebo group.

At trial entry, the mean % predicted FVC in the sitting position among all patients was about 55%. After 78 weeks, the mean % predicted FVC increased to 56.2% for alglucosidase alfa-treated patients and decreased to 52.8% for placebo-treated patients indicating an alglucosidase alfa treatment effect of 3.4% (95% confidence interval: [1.3% to 5.5%]; p=0.004). Stabilization of % predicted FVC in the alglucosidase alfa-treated patients was observed (see Figure 1).

Figure 1: Mean FVC Upright (% Predicted) Over Time in Patients with LOPD (Trial 4)

At trial entry, the mean 6 minute walk test (6MWT) among all patients was about 330 meters. After 78 weeks, the mean 6MWT increased by 25 meters for alglucosidase alfa-treated patients and decreased by 3 meters for placebo-treated patients indicating an alglucosidase alfa treatment effect of 28 meters (95% confidence interval: [-1 to 52 meters]; p=0.06) (see Figure 2).

Figure 2: Mean Six Minute Walk Test Total Distance Walked Over Time in Patients with LOPD (Trial 4)

The safety and effectiveness of alglucosidase alfa in the treatment patients with infantile-onset Pompe disease (IOPD) were assessed in 57 treatment-naive infantile-onset Pompe disease patients, aged 0.2 month to 3.5 years at first alglucosidase alfa infusion, in three separate open-label, single-arm clinical trials (Trials 1, 2, and 3).

Long-term studies in animals to evaluate carcinogenic potential or studies to evaluate mutagenic potential have not been performed with alglucosidase alfa.

Intravenous administration of alglucosidase alfa every other day in mice at doses up to 40 mg/kg (0.4 times the human AUC at the recommended biweekly dose) had no effect on fertility and reproductive performance.

As shown from clinical trials and published literature, individualized immune tolerance induction regimen administered prior to and with initiation of LUMIZYME has been reported to aid tolerability of LUMIZYME and reduce the development of high ADA titers in CRIM-negative IOPD patients. Furthermore, CRIM status has been shown to be associated with immunogenicity and patients' responses to LUMIZYME. LUMIZYME-treated infants with IOPD who are CRIM-negative (indicating no endogenous enzyme is detected) have shown poorer clinical response (loss of motor function, ventilator dependence, or death) in the presence of high sustained IgG ADA titers and positive inhibitory antibodies compared to CRIM-positive infants [see Adverse Reactions (6.2)]. However, high and sustained ADA titers has also occurred in a limited number of CRIM-positive patients, generally with very low endogenous enzyme [see Clinical Pharmacology (12.6)]. Therefore, these patients must be managed by a clinical specialist knowledgeable in immune tolerance induction in Pompe disease.

Some alglucosidase alfa-treated patients who developed high sustained IgG ADA titers had reduced efficacy. Some alglucosidase alfa-treated patients with high IgG ADA titers had a higher incidence of IARs.

Patients with IOPD should have a cross-reactive immunologic material (CRIM) assessment early in their disease course.

Anti-alglucosidase alfa antibody (referred to as ADA) titers should be obtained during LUMIZYME treatment. Contact Genzyme Corporation at 1-800-745-4447 for information on ADA testing.

Recommend the following ADA testing:

• Baseline serum ADA sample collection prior to the first LUMIZYME infusion is strongly encouraged.
• For patients with:
  • IOPD, suggest regular ADA monitoring during first year of treatment (example: every 3 months).
  • LOPD, suggest ADA be monitored within six months of LUMIZYME initiation with subsequent monitoring as clinically warranted based on safety and efficacy considerations.
• If patients [see Adverse Reactions (6.2) and Clinical Pharmacology (12.6)]:
  • Develop hypersensitivity reactions, consider testing for IgG ADA, IgE ADA and other mediators.
  • Develop immune-mediated reactions that are not hypersensitivity reactions, consider testing for IgG ADA.
  • Lose or have a reduced clinical response, consider testing for IgG ADA and for inhibitory antibody activity.

• 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.

Administration of general anesthesia can be complicated by the presence of severe cardiac and skeletal (including respiratory) muscle weakness. Therefore, caution should be used when administering general anesthesia. Ventricular arrhythmias and bradycardia, resulting in cardiac arrest or death, or requiring cardiac resuscitation or defibrillation have been observed in patients with IOPD with cardiac hypertrophy during general anesthesia for central venous catheter placement.

WARNING: HYPERSENSITIVITY REACTIONS INCLUDING ANAPHYLAXIS, IMMUNE-MEDIATED REACTIONS, and RISK OF ACUTE CARDIORESPIRATORY FAILURE

See full prescribing information for complete boxed warning.

Hypersensitivity Reactions Including Anaphylaxis

Anaphylaxis has occurred during the early course of enzyme replacement therapy and after extended duration of therapy. Initiate LUMIZYME in a healthcare setting with appropriate medical monitoring and support measures, including access to cardiopulmonary resuscitation equipment. If a severe hypersensitivity reaction (e.g., anaphylaxis) occurs, discontinue LUMIZYME and immediately initiate appropriate medical treatment, including use of epinephrine. (5.1)

Immune-Mediated Reactions

Immune-mediated reactions presenting as proteinuria, nephrotic syndrome, and necrotizing skin lesions have occurred in some patients following LUMIZYME treatment. Monitor patients for the development of systemic immune-mediated reactions involving skin and other organs while receiving LUMIZYME. (5.3)

Risk of Acute Cardiorespiratory Failure

Infantile-onset Pompe disease (IOPD) 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. (5.4)