Missed Dose

If one or more doses are missed, restart LUMIZYME treatment as soon as possible, maintaining the 2-week interval between infusions thereafter.

Reconstitute the Lyophilized Powder

• Determine the number of LUMIZYME vials to be reconstituted based on the actual body weight in kg and the recommended dose of 20 mg/kg. Round the number of vials up to the next whole number.
• Remove the required number of LUMIZYME vials from the refrigerator and allow the vials to sit for approximately 30 minutes at room temperature 20°C to 25°C (68°F to 77°F) prior to reconstitution.
• Reconstitute each vial by slowly injecting 10.3 mL of Sterile Water for Injection, down the inside wall of each vial. Avoid adding the Sterile Water for Injection to the vial forcefully or directly onto the lyophilized powder to minimize foaming.
• Gently tilt and roll each vial. Do not invert, swirl, or shake the vial. Each vial will yield a concentration of 5 mg/mL of LUMIZYME. The total extractable dose per vial is 50 mg per 10 mL.
• Visually inspect the reconstituted solution in the vials for particulate matter and discoloration. Discard if particles are present or the solution is discolored. The reconstituted solution may occasionally contain some LUMIZYME 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 LUMIZYME 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.

Dilute the Reconstituted Solution

• Select and prepare an appropriate size 0.9% Sodium Chloride for Injection infusion bag with quantity sufficient of 0.9% Sodium Chloride for Injection to obtain the recommended total infusion volume per table 1 based on patient weight and dilute.
• Slowly withdraw the required volume of reconstituted solution from the LUMIZYME vial(s). Avoid foaming in the syringe. Discard any unused reconstituted solution remaining in the vial.
• Remove airspace from the prepared 0.9% Sodium Chloride for Injection infusion bag to minimize particle formation due to the sensitivity of LUMIZYME to air-liquid interfaces.
• Inject the LUMIZYME reconstituted solution slowly and directly into the port of the prepared 0.9% Sodium Chloride for Injection infusion bag. Avoid foaming and introducing air in the infusion bag.
• Gently invert or massage the infusion bag to mix the solution. Do not shake. After dilution, the solution will have a final concentration of 0.5 to 4 mg/mL of LUMIZYME.

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 severehypersensitivity 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.

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.

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).

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

Data

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.

Immunogenicity in Patients with Infantile-onset Pompe Disease

Thirty-nine patients with infantile-onset Pompe disease (IOPD), aged 1 month to 3.5 years, were treated with 20 or 40 mg/kg of intravenous alglucosidase alfa every other week for periods that ranged from 1 to 106 weeks (mean: 61 weeks) in two open-label clinical trials (Trials 1 and 2) [see Clinical Studies (14.1, 14.2)]. In Trials 1 and 2, 34/38 (89%) of alglucosidase alfa-treated patients tested positive for anti-alglucosidase alfa antibodies (referred to as ADA).

Immunogenicity in Patients with Late-onset Pompe Disease

Ninety patients with late-onset Pompe disease (LOPD), aged 10 to 70 years, were administered 20 mg/kg of intravenous alglucosidase alfa or intravenous placebo every other week (2:1 ratio) for 78 weeks in a randomized, double-blinded, placebo-controlled trial (Trial 4) [see Clinical Studies (14.2)]. In Trial 4, 59/59 (100%) of alglucosidase alfa-treated patients with available samples developed ADA. These patients were all cross-reactive immunologic material (CRIM) positive. Most patients who developed ADA did so within the first three months of exposure (median time to seroconversion was four weeks).

Antibody titers for cellular uptake inhibition were present in 18 of 59 (31%) alglucosidase alfa-treated patients by Week 78. Patients who tested positive for cellular uptake inhibition tended to have higher IgG titers than patients who tested negative for cellular uptake inhibition. None of the 59 evaluable patients tested positive for inhibition of enzyme activity.

Immunogenicity in Patients with Infantile-onset Pompe Disease or Late-onset Pompe Disease

Some patients with IOPD or LOPD who were ADA positive in Trials 1, 2 and 4 tested positive for inhibition of enzyme activity and/or uptake in in vitro assays. However, the clinical relevance of this in vitro inhibition is unclear.

Negative CRIM status (indicating no endogenous enzyme is detected) is a risk factor for LUMIZYME-treated patients to develop high and sustained ADA titers. However, high and sustained ADA titers have also occurred in a limited number of CRIM-positive patients, generally with very low endogenous enzyme.

Anti-Drug Antibody Effects on Pharmacokinetics

In Trials 1 and 2, 19 of 21 (90%) alglucosidase alfa-treated patients with IOPD - who had pharmacokinetics (PK) and antibody titer data available at Week 12 - developed ADA. Of these 19 patients, 5 patients with antibody titers ≥12,800 at Week 12 had a 50% mean increase in clearance (range 5% to 90%) from Week 1 to Week 12, while the 14 patients with antibody titers <12,800 at Week 12 had no significant change in the mean clearance values at Week 1 and Week 12.

In Trial 4, 5/32 (16%) of alglucosidase alfa-treated patients with LOPD that had evaluable PK samples tested positive for cellular uptake inhibition. An approximately 1.2-fold to 1.8- fold greater clearance was observed at Week 52 in 4 of 5 patients that tested positive for antibodies that inhibit the cellular uptake of enzyme in an in vitro assay compared to Week 0. PK in 4 of these 5 patients over time indicated an increase in clearance with increase in IgG titer.

Anti-Drug Antibody Effects on Safety and Efficacy

A small number of alglucosidase alfa-treated patients with LOPD who tested positive for alglucosidase alfa-specific IgE antibodies experienced anaphylactic reactions [see Warnings and Precautions (5.1)].

Some alglucosidase alfa-treated patients who developed high sustained ADA titers had reduced efficacy. Furthermore, CRIM-negative infants have shown reduced clinical effect in the presence of high sustained ADA titers with inhibitory activity [see Warnings and Precautions (5.6)].

There was no identified clinically significant effect of high ADA titers on the development of IARs in LUMIZYME-treated patients.

Trial 1 (Patients with IOPD)

Trial 1 was an international, multicenter, open-label, clinical trial of 18 patients with IOPD. This trial was conducted between 2003 and 2005. Patients were randomized 1:1 to receive either 20 mg/kg or 40 mg/kg of intravenous alglucosidase alfa every two weeks, with length of treatment ranging from 52 to 106 weeks. Enrollment was restricted to patients 7 months of age or younger at first infusion with clinical signs of Pompe disease and cardiac hypertrophy, and who did not require ventilatory support at trial entry. Fourteen patients were cross reactive immunologic material (CRIM) positive, and 4 patients were CRIM negative.

Efficacy was assessed by comparing the proportions of alglucosidase alfa-treated patients who died or needed invasive ventilator support at 18 months of age with the mortality experience of a historical cohort of untreated patients with IOPD with similar age and disease severity. In the historical cohort, 61 untreated patients with IOPD diagnosed by age 6 months, born between 1982 and 2002, were identified by a retrospective review of medical charts. By 18 months of age, 15 of 18 (83%) alglucosidase alfa-treated patients were alive without invasive ventilatory support and 3 (17%) required invasive ventilator support, whereas only one of the 61 (2%) historical control patients was alive. No differences in outcome were observed between patients who received 20 mg/kg versus 40 mg/kg.

Other outcome measures in this trial included unblinded assessments of motor function by the Alberta Infant Motor Scale (AIMS), a measure of infant motor performance that assesses motor maturation of the infant through age 18 months. Although gains in motor function were noted in 13 patients, the motor function was substantially delayed compared to normal infants of comparable age in the majority of patients. Two of 9 patients who had initially demonstrated gains in motor function after 12 months of alglucosidase alfa treatment regressed despite continued treatment.

Changes from baseline to Month 12 in left ventricular mass index (LVMI), a measure of pharmacodynamic effect, were evaluated by echocardiography. Fifteen patients who underwent both baseline and Month 12 echocardiograms demonstrated decreases from baseline in LVMI (mean decrease 118 g/m2, range 45 to 193 g/m2). However, the magnitude of the decrease in LVMI did not correlate with the clinical outcome measure of ventilator-free survival.

Trial 2 (Patients with IOPD)

Trial 2 was an international, multicenter, non-randomized, open-label clinical trial that enrolled 21 patients with IOPD aged 3 months to 3.5 years at first infusion. Eighteen patients were CRIM positive and 3 patients were CRIM negative. All patients received intravenous 20 mg/kg alglucosidase alfa every other week for up to 104 weeks. Five of 21 patients were receiving invasive ventilatory support at the time of first infusion.

The primary outcome measure was the proportion of patients alive at the conclusion of treatment. At the 52-week interim analysis, 16 of 21 patients were alive. Sixteen patients were free of invasive ventilatory support at the time of first infusion; of these, 4 died, 2 required invasive ventilatory support, and 10 were free of invasive ventilatory support after 52 weeks of treatment. For the 5 patients who were receiving invasive ventilatory support at baseline, 1 died, and 4 remained on invasive ventilatory support at Week 52.

Trial 3 (Patients with IOPD)

Trial 3 was an open-label, single-center trial in 18 patients with IOPD who had a confirmed diagnosis of Pompe disease as identified through a newborn screening program. All patients were CRIM positive. Patients were treated with intravenous alglucosidase alfa prior to 6 months of age (0.2 to 5.8 months at first infusion). Sixteen patients reached 18 months of age at the time of analysis, and all (100%) were alive without invasive ventilator support.