Lumizyme: Package Insert and Label Information (Page 3 of 4)

6.3 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 postmarketing experience with alglucosidase alfa, 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)].

Recurrent reactions consisting of flu-like illness or a combination of events such as pyrexia, chills, myalgia, arthralgia, pain, or fatigue occurring after completion of infusions and lasting usually for 1 to 3 days have been observed in some patients treated with alglucosidase alfa. The majority of patients were able to be rechallenged with alglucosidase alfa using lower doses and/or pretreatment with anti-inflammatory drugs and/or corticosteroids and were able to continue treatment under close clinical supervision.

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)].

7 DRUG INTERACTIONS

7.1 Interference with other Drugs

No drug interaction or in vitro metabolism studies were performed.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

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 estimated 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.

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.

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 alglucosidase alfa have been established in pediatric patients with Pompe disease [see Adverse Reactions (6.2)].

The safety and effectiveness of alglucosidase alfa were assessed in 57 treatment-naive infantile-onset Pompe disease patients, aged 0.2 month to 3.5 years at first infusion, in three separate clinical trials [see Clinical Studies (14.1)].

The safety and effectiveness of alglucosidase alfa were assessed in pediatric patients with late (non-infantile) onset Pompe disease in a randomized, double-blind, placebo-controlled study in 90 patients, 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 patients [see Clinical Studies (14.1)].

11 DESCRIPTION

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.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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.

12.2 Pharmacodynamics

Clinical pharmacodynamic studies have not been conducted for alglucosidase alfa.

12.3 Pharmacokinetics

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], Cmax 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.

Nineteen of 21 patients who received treatment with alglucosidase alfa and had pharmacokinetics and antibody titer data available at Week 12 developed antibodies to alglucosidase alfa. Five patients with antibody titers ≥12,800 at Week 12 had an average increase in clearance of 50% (range 5% to 90%) from Week 1 to Week 12. The other 14 patients with antibody titers <12,800 at Week 12 had similar average clearance values at Week 1 and Week 12.

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 Cmax 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 Cmax was 307 mcg/mL with 47% CV.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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.

14 CLINICAL STUDIES

14.1 Clinical Trials in Infantile-Onset Pompe Disease

The safety and efficacy of alglucosidase alfa were assessed in 57 treatment-naive infantile-onset Pompe disease patients, aged 0.2 month to 3.5 years at first infusion, in three separate clinical trials.

Study 1 was an international, multicenter, open-label, clinical trial of 18 infantile-onset Pompe disease patients. This study was conducted between 2003 and 2005. Patients were randomized 1:1 to receive either 20 mg/kg or 40 mg/kg 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 study 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 infantile-onset Pompe disease patients with similar age and disease severity. In the historical cohort, 61 untreated patients with infantile-onset Pompe disease 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 study 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.

Study 2 was an international, multicenter, non-randomized, open-label clinical trial that enrolled 21 infantile-onset patients aged 3 months to 3.5 years at first infusion. Eighteen patients were CRIM positive and 3 patients were CRIM negative. All patients received 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.

Study 3 was an open-label, single-center trial in 18 infantile-onset Pompe disease patients who had a confirmed diagnosis of Pompe disease as identified through a newborn screening program. All patients were CRIM positive. Patients were treated with 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.

14.2 Clinical Trials in Late-Onset Pompe Disease

The safety and efficacy of alglucosidase alfa were assessed in 90 patients with late-onset Pompe disease, aged 10 to 70 years, in a randomized, double-blind, placebo-controlled trial. The youngest alglucosidase alfa-treated patient was 16 years of age, and the youngest placebo-treated patient was 10 years of age. All patients were naive to enzyme replacement therapy. Patients were allocated in a 2:1 ratio and received 20 mg/kg alglucosidase alfa (n=60) or placebo (n=30) every other week for 78 weeks (18 months). The study 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 study 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

Figure 1
(click image for full-size original)

At study 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

Figure 2
(click image for full-size original)

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