Alglucosidase Alfa

LUMIZYME ® is a hydrolytic lysosomal glycogen-specific enzyme indicated for patients with Pompe disease (acid α-glucosidase [GAA] deficiency). LUMIZYME ® is a hydrolytic lysosomal glycogen-specific enzyme indicated for patients with Pompe disease (GAA deficiency). ( 1 )

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. For injection: 50 mg of LUMIZYME as lyophilized powder in a single-dose vial for reconstitution. ( 3 )

None. None. ( 4 )

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 )

5.1 Hypersensitivity Reactions Including Anaphylaxis Hypersensitivity Reactions Including Anaphylaxis Hypersensitivity reactions including anaphylaxis have been observed in patients during and up to 3 hours after a LUMIZYME infusion. Some of the hypersensitivity 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. In clinical trials, hypersensitivity reactions including anaphylaxis were managed with infusion interruption; decreased infusion rate; and administration of antihistamines, corticosteroids, intravenous fluids, and/or oxygen. In some cases of anaphylaxis, epinephrine was administered. Some LUMIZYME-treated patients who experienced a hypersensitivity reaction and who tested positive for alglucosidase alfa-specific IgE antibodies were successfully rechallenged with a slower infusion rate at a lower dosage of LUMIZYME and continued to receive LUMIZYME under close clinical supervision. Because LUMIZYME-treated patients who develop anti-IgE alglucosidase alfa antibodies appear to be at a higher risk for developing hypersensitivity reactions including anaphylaxis, these patients should be monitored more closely during LUMIZYME administration. Recommendations to Prevent, Mitigate, and Monitor for Hypersensitivity Reactions Prior to LUMIZYME administration, consider pretreating with antihistamines, antipyretics, and/or corticosteroids. Administration of LUMIZYME should be supervised by a healthcare provider knowledgeable in the management of 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. If a mild or moderate hypersensitivity reaction occurs, consider temporarily holding the LUMIZYME infusion or slowing the infusion rate. Consider the risks and benefits of readministering LUMIZYME following a hypersensitivity reaction including anaphylaxis. Patients may be rechallenged using slower infusion rates at a lower dosage than the recommended dosage [see Adverse Reactions (6.2) ] . Inform patients of the symptoms of life-threatening hypersensitivity reactions, including anaphylaxis and recommend they seek immediate medical care should these symptoms occur.

5.2 Infusion-Associated Reactions 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.

5.3 Immune-Mediated Reactions 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.

5.4 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 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) ] .

5.5 Risk of Cardiac Arrhythmia and Sudden Cardiac Death during General Anesthesia for Central Venous Catheter Placement 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.

5.6 Risk of Developing Anti-alglucosidase Alfa Antibodies 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. […]

The following serious adverse reactions are described below and elsewhere in the labeling: Hypersensitivity Reactions Including Anaphylaxis [see Warnings and Precautions (5.1) ] The most frequently reported adverse reactions (≥5%) in clinical trials 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. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Genzyme at 1-800-633-1610, option 1 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience 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. Adverse Reactions in Clinical Trials in Infantile-Onset and Juvenile-Onset Pompe Disease Two multicenter, open-label clinical trials (Trials 1 and 2) [see Clinical Studies (14.1) ] were conducted in 39 patients with infantile-onset Pompe disease (IOPD), aged 1 month to 3.5 years old. Approximately half of the patients (54%) were male. Patients were treated with intravenous alglucosidase alfa 20 or 40 mg/kg every other week for periods ranging from 1 to 106 weeks (mean: 61 weeks). The most serious adverse reactions reported with alglucosidase alfa treatment included anaphylaxis and acute cardiorespiratory failure. The most common adverse reactions requiring intervention in these clinical trials were hypersensitivity reactions, that occurred in 20 of 39 (51%) patients treated with alglucosidase alfa, and included rash, pyrexia, urticaria, flushing, decreased oxygen saturation, cough, tachypnea, tachycardia, hypertension/increased blood pressure, pallor, rigors, vomiting, cyanosis, agitation, and tremor. These reactions were more likely to occur with higher infusion rates or doses. Some patients who were pretreated with antihistamines, antipyretics and/or corticosteroids still experienced hypersensitivity reactions. Table 2 summarizes all adverse reactions that occurred in ≥5% of patients (2 or more patients) treated with alglucosidase alfa in clinical trials described above. Table 2: Adverse Reactions that Occurred in at Least 5% of Alglucosidase Alfa-Treated Infantile-Onset Patients in Trials 1 and 2 Number of Patients (N=39) n (%) Adverse Reaction 20 (51) Rash (including rash erythematous, rash macular and maculopapular) 7 (18) Pyrexia 6 (15) Urticaria 5 (13) Flushing 5 (13) Hypertension/Increased Blood Pressure 4 (10) Decreased Oxygen Saturation 3 (8) Cough 3 (8) Tachypnea 3 (8) Tachycardia 3 (8) Erythema 2 (5) Vomiting 2 (5) Rigors 2 (5) Pallor 2 (5) Cyanosis 2 (5) Agitation 2 (5) Tremor 2 (5) An open-label, single-center trial (Trial 3) was conducted in 18 treatment-naive patients with IOPD who were treated with alglucosidase alfa [see Clinical Studies (14.1) ] . Adverse reactions observed in these patients were similar to patients with IOPD who received alglucosidase alfa in other clinical trials. Additional hypersensitivity reactions observed in patients with IOPD treated with alglucosidase alfa in other clinical trials and expanded access programs included livedo reticularis, irritability, retching, increased lacrimation, ventricular extrasystoles, nodal rhythm, rales, respiratory tract irritation, and cold sweat. Safety was also evaluated in 99 patients (51 male, 48 females) with Pompe disease in an ongoing, open-label, prospective study in patients 12 months of age and older who were previously treated with another alglucosidase alfa product and switched to LUMIZYME. Patients were aged 1 to 18 years with a median duration of treatment of 437 days (range 13 to 466 days). No new safety findings were observed following the switch to 4000 L scale of alglucosidase alfa. Adverse Reactions in Clinical Trials in Late-Onset Pompe Disease Assessment of adverse reactions in patients with late-onset Pompe disease (LOPD) is based on the exposure of 90 patients (45 male, 45 female), aged 10 to 70 years, to intravenous infusions of 20 mg/kg alglucosidase alfa or placebo in a randomized, double-blind, placebo-controlled trial (Trial 4). All patients were naive to enzyme replacement therapy. Patients were randomized in a 2:1 ratio and received intravenous alglucosidase alfa or placebo every other week for 78 weeks (18 months). Two patients who received alglucosidase alfa discontinued the trial due to anaphylactic reactions. Serious adverse reactions reported with alglucosidase alfa included anaphylaxis, which presented as angioedema, throat tightness and chest pain/discomfort. One patient with a history of Wolff-Parkinson-White syndrome experienced a serious adverse reaction of supraventricular tachycardia. The most common adverse reactions (≥3%; 2 or more patients) observed in alglucosidase alfa-treated patients were hypersensitivity reactions and included anaphylaxis, headache, nausea, urticaria, dizziness, chest discomfort, vomiting, hyperhidrosis, flushing/feeling hot, increased blood pressure, paresthesia, pyrexia, local swelling, diarrhea, pruritus, rash, and throat tightness. Delayed-onset reactions, defined as adverse reactions that occurred 2 to 48 hours after completion of alglucosidase alfa infusion, that were observed in ≥3% more patients in the alglucosidase alfa-treated group compared to patients in the placebo-treated group in the controlled trial, included hyperhidrosis. Additional delayed-onset reactions that occurred in alglucosidase alfa-treated patients included fatigue, myalgia, and nausea. Table 3 summarizes the most common adverse reactions that occurred in at least 3% of alglucosidase alfa-treated patients and with a higher incidence than the placebo-treated patients in Trial 4 (patients with LOPD). Table 3: Adverse Reactions in Patients with LOPD (Trial 4) Adverse reactions that occurred in ≥3% of alglucosidase alfa-treated patients and with a higher incidence than placebo-treated patients Adverse Reaction Alglucosidase Alfa n=60 N (%) Placebo n=30 N (%) Hyperhidrosis 5 (8.3) 0 (0) Urticaria 5 (8.3) 0 (0) Anaphylaxis 4 (6.7) 0 (0) Chest Discomfort 4 (6.7) 1 (3.3) Muscle Twitching 4 (6.7) 1 (3.3) Myalgia 3 (5.0) 1 (3.3) Flushing/Feeling Hot 3 (5.0) 0 (0) Increased Blood Pressure 3 (5.0) 0 (0) Vomiting 3 (5.0) 0 (0) Edema, Peripheral 2 (3.3) 0 (0) Pruritus 2 (3.3) 0 (0) Rash Papular 2 (3.3) 0 (0) Throat Tightness 2 (3.3) 0 (0)

6.2 Postmarketing Experience 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) ] . […]

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to LUMIZYME during pregnancy. Pregnant women and women of reproductive potential should be encouraged to enroll in the Pompe patient registry. The registry will monitor the effect of LUMIZYME on pregnant women and their offspring. For more information, visit www.registrynxt.com or call 1-800-745-4447, extension 15500. Risk Summary Data from postmarketing reports and published case reports with alglucosidase alfa use in pregnant women have not identified a LUMIZYME-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. The continuation of treatment for Pompe disease during pregnancy should be individualized to the pregnant woman. Untreated Pompe disease may result in worsening disease symptoms in pregnant women (see Clinical Considerations ). Reproduction studies performed in mice and rabbits at doses resulting in exposures up to 0.4 or 0.5 times the human steady-state AUC (area under the plasma concentration-time curve), respectively, during the period of organogenesis revealed no evidence of effects on embryo-fetal development. In mice there was an increase in pup mortality during lactation at maternal exposures 0.4 times the human steady-state AUC (see Data ) . The background risk of major birth defects and miscarriage in 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. Clinical Considerations Disease-associated Maternal and/or Embryo-fetal Risk Untreated Pompe disease has been associated with worsening respiratory and musculoskeletal symptoms in some pregnant women. Data Animal Data All reproductive studies included pretreatment with diphenhydramine to prevent or minimize hypersensitivity reactions. The effects of alglucosidase alfa were evaluated based on comparison to a control group treated with diphenhydramine alone. Daily intravenous administration of alglucosidase alfa up to 40 mg/kg in mice and rabbits (0.4 and 0.5 times the human steady-state AUC, respectively, at the recommended biweekly dose) during the period of organogenesis had no effects on embryo-fetal development. Administration of 40 mg/kg intravenously every other day in mice (0.4 times the human steady-state AUC at the recommended biweekly dose) during the period of organogenesis through lactation produced an increase in mortality of offspring during the lactation period.

8.2 Lactation Risk Summary Available published literature suggests the presence of alglucosidase alfa in human milk. There are no reports of adverse effects of alglucosidase alfa on the breastfed infant. There is no information on the effects of alglucosidase alfa on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for LUMIZYME and any potential adverse effects on the breastfed child from LUMIZYME or from the underlying maternal condition. Lactating women with Pompe disease treated with LUMIZYME should be encouraged to enroll in the Pompe disease registry [see Use in Specific Populations (8.1) ] . Clinical Considerations A lactating woman may consider interrupting breastfeeding, pumping and discarding breast milk during treatment and for 24 hours after LUMIZYME administration in order to minimize drug exposure to a breastfed infant.

8.4 Pediatric Use 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) ] .

8.5 Geriatric Use 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) ] .

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.