Elaprase

Follow your doctor's instructions about any restrictions on food, beverages, or activity.

Other drugs may interact with idursulfase, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

Before taking Elaprase, tell your doctor about all of your medical conditions. Especially tell your doctor if you:

• are allergic to Elaprase or to any of its ingredients
• have heart problems
• have lung problems
• are currently sick
• are pregnant or plan to become pregnant
• are breastfeeding or plan to breastfeed

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements.

WARNING: RISK OF ANAPHYLAXIS

Life-threatening anaphylactic reactions have occurred in some patients during and up to 24 hours after ELAPRASE infusions. Anaphylaxis, presenting as respiratory distress, hypoxia, hypotension, urticaria and/or angioedema of throat or tongue have been reported to occur during and after ELAPRASE infusions, regardless of duration of the course of treatment. Closely observe patients during and after ELAPRASE administration and be prepared to manage anaphylaxis. Inform patients of the signs and symptoms of anaphylaxis and have them seek immediate medical care should symptoms occur. Patients with compromised respiratory function or acute respiratory disease may be at risk of serious acute exacerbation of their respiratory compromise due to hypersensitivity reactions, and require additional monitoring.

Hunter Syndrome

Management of Hunter syndrome (mucopolysaccharidosis II, MPS II);1 2 4 5 6 designated an orphan drug by FDA for use in this condition.3

Hunter syndrome is an X-linked recessive disease characterized by a deficiency of the lysosomal enzyme iduronate-2-sulfatase.1 2 4 4 5 6

In patients with Hunter disease, reduced or absent iduronate-2-sulfatase activity results in progressive accumulation of glycosaminoglycans in the lysosomes of various cells, leading to cellular engorgement, organomegaly, tissue destruction, and organ system dysfunction.1 5 6

Idursulfase improves endurance (measured by increases in walking distance) in patients with Hunter syndrome.1 2 4 5 6

Administration

Administer by IV infusion.1

IV Administration

For solution compatibility and storage information, see Stability.

Administer by IV infusion using a 0.2-mcm filter.1

Do not infuse idursulfase infusions simultaneously through the same IV line with other drugs.1

Prior to infusion, dilute the appropriate dose of commercially available idursulfase concentrated solution (2 mg of the drug per mL) in 100 mL of 0.9% sodium chloride for injection according to the manufacturer’s instructions.1 Vials are for single use only; discard partially used vials of idursulfase solution.1

Withdraw the calculated volume providing the appropriate dose of idursulfase from the appropriate number of vials and dilute in 100 mL of 0.9% sodium chloride injection.1 Gently mix the solution in the infusion bag; do not shake.1 Consult the manufacturer’s labeling for additional information on dilution and administration of idursulfase.1

Administer by IV infusion at an initial infusion rate of 8 mL/hour for the first 15 minutes.1 May increase infusion rate in increments of 8 mL/hour every 15 minutes in order to administer the entire volume within the desired time, up to a maximum rate of 100 mL/hour.1 May administer the total volume of infusion in 1–3 hours; do not exceed 8 hours.1 May decrease infusion rate, temporarily discontinue infusion, or stop the infusion for the particular visit if infusion-related reactions occur.1

Dosage

The specific activity of idursulfase is 41–77 units/mg, with 1 unit defined as the amount of activity that results in the hydrolysis of 1 mcmol of heparin disaccharide substrate per hour under specified assay conditions.1

Pediatric Patients

Children ≥5 years of age: 0.5 mg/kg by IV infusion once weekly.1

Adults

0.5 mg/kg by IV infusion once weekly.1

Prescribing Limits

Pediatric Patients

Maximum infusion rate: 100 mL/hour.1

Adults

Maximum infusion rate: 100 mL/hour.1

Special Populations

No special population dosage recommendations at this time.1

Absorption

Plasma Concentrations

AUC values increased in a greater than dose proportional manner following single 1-hour IV infusion of idursulfase dosages ranging from 0.15–1.5 mg/kg.1

Distribution

Extent

Not known whether idursulfase is distributed into milk.1

Elimination

Half-life

44–48 minutes.1

• Importance of encouraging patients to participate in the Hunter Outcome Survey (http://www.elaprase.com or 866-888-0660) to understand the variability and progression of the disease and to continue to monitor and evaluate long-term treatment effects of idursulfase.1

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.1

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

• Importance of informing patients of other important precautionary information.1 (See Cautions.)

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur:

• Bone or muscle pain
• chest pain
• chills
• cough
• fast, pounding, or irregular heartbeat or pulse
• feeling of warmth
• fever
• headache
• hives or welts
• itching
• rash
• redness of the face, neck, arms, and occasionally, upper chest
• redness of the skin
• sneezing
• sore throat
• tightness in the chest
• unusual tiredness or weakness

• Blurred vision
• confusion
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• sweating

• Difficulty with swallowing
• dilated neck veins
• extreme fatigue
• heart stops
• irregular breathing
• no breathing
• no pulse or blood pressure
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• unconscious
• weight gain

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Change in hearing
• diarrhea
• ear drainage
• earache or pain in the ear

• Nausea
• vomiting

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

• It is used to treat Hunter syndrome.

• If you have an allergy to idursulfase or any other part of this medicine.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.

This medicine may interact with other drugs or health problems.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take Elaprase with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

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 practice.

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

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

In clinical trials, the most common adverse reactions (>10%) following Elaprase treatment were hypersensitivity reactions, and included rash, urticaria, pruritus, flushing, pyrexia, and headache. Most hypersensitivity reactions requiring intervention were ameliorated with slowing of the infusion rate, temporarily stopping the infusion, with or without administering additional treatments including antihistamines, corticosteroids or both prior to or during infusions.

In clinical trials, the most frequent serious adverse reactions following Elaprase treatment were hypoxic episodes. Other notable serious adverse reactions that occurred in the Elaprase-treated patients but not in the placebo-treated patients included one case each of: cardiac arrhythmia, pulmonary embolism, cyanosis, respiratory failure, infection, and arthralgia.

Clinical Trials in Patients 5 Years and Older

A 53-week, double-blind, placebo-controlled clinical trial of Elaprase was conducted in 96 male patients with Hunter syndrome, ages 5-31 years old. Of the 96 patients, 83% were White, non-Hispanic. Patients were randomized to three treatment groups, each with 32 patients: Elaprase 0.5 mg/kg once weekly, Elaprase 0.5 mg/kg every other week, or placebo. Hypersensitivity reactions were reported in 69% (22 of 32) of patients who received once-weekly treatment of Elaprase.

Table 1 summarizes the adverse reactions that occurred in at least 9% of patients (≥3 patients) in the Elaprase 0.5 mg/kg once weekly group and with a higher incidence than in the placebo group.

Additional adverse reactions that occurred in at least 9% of patients (≥3 patients) in the Elaprase 0.5 mg/kg every other week group and with a higher incidence than in the placebo group included: rash (19%), flushing (16%), fatigue (13%), tachycardia (9%), and chills (9%).

Extension Trial

An open-label extension trial was conducted in patients who completed the placebo-controlled trial. Ninety-four of the 96 patients who were enrolled in the placebo-controlled trial consented to participate in the extension trial. All 94 patients received Elaprase 0.5 mg/kg once weekly for 24 months. No new serious adverse reactions were reported. Approximately half (53%) of patients experienced hypersensitivity reactions during the 24-month extension trial. In addition to the adverse reactions listed in Table 1, common hypersensitivity reactions occurring in at least 5% of patients (≥ 5 patients) in the extension trial included: rash (23%), pyrexia (9%), flushing (7%), erythema (7%), nausea (5%), dizziness (5%), vomiting (5%), and hypotension (5%).

Clinical Trial in Patients 7 Years and Younger

A 53-week, open-label, single-arm, safety trial of once weekly Elaprase 0.5 mg/kg treatment was conducted in patients with Hunter syndrome, ages 16 months to 4 years old (n=20) and ages 5 to 7.5 years old (n=8) at enrollment. Patients experienced similar adverse reactions as those observed in clinical trials in patients 5 years and older, with the most common adverse reactions following Elaprase treatment being hypersensitivity reactions (57%). A higher incidence of the following common hypersensitivity reactions were reported in this younger age group: pyrexia (36%), rash (32%) and vomiting (14%). The most common serious adverse reactions occurring in at least 10% of patients (≥ 3 patients) included: bronchopneumonia/pneumonia (18%), ear infection (11%), and pyrexia (11%).

Twenty-seven patients had results of genotype analysis: 15 patients had complete gene deletion, large gene rearrangement, nonsense, frameshift or splice site mutations and 12 patients had missense mutations.

Safety results demonstrated that patients with complete gene deletion, large gene rearrangement, nonsense, frameshift, or splice site mutations are more likely to experience hypersensitivity reactions and have serious adverse reactions following Elaprase administration, compared to patients with missense mutations. Table 2 summarizes these findings.

Immunogenicity

Clinical Trials in Patients 5 Years and Older

As with all therapeutic proteins, there is potential for immunogenicity. In clinical trials in patients 5 years and older, 63 of the 64 patients treated with Elaprase 0.5 mg/kg once weekly or placebo for 53 weeks, followed by Elaprase 0.5 mg/kg once weekly in the extension trial, had immunogenicity data available for analysis. Of the 63 patients, 32 (51%) patients tested positive for anti-idursulfase IgG antibodies (Ab) at least one time (Table 2). Of the 32 Ab-positive patients, 23 (72%) tested positive for Ab at three or more different time points (persistent Ab). The incidence of hypersensitivity reactions was higher in patients who tested positive for Ab than those who tested negative.

Thirteen of 32 (41%) Ab-positive patients also tested positive for antibodies that neutralize idursulfase uptake into cells (uptake neutralizing antibodies, uptake NAb) or enzymatic activity (activity NAb) at least one time, and 8 (25%) of Ab-positive patients had persistent NAb. There was no clear relationship between the presence of either Ab or NAb and therapeutic response.

Clinical Trial in Patients 7 Years and Younger

In the clinical trial in patients 7 years and younger, 19 of 28 (68%) patients treated with Elaprase 0.5 mg/kg once weekly tested Ab-positive. Of the 19 Ab-positive patients, 16 (84%) tested positive for Ab at three or more different time points (persistent Ab). In addition, 15 of 19 (79%) Ab-positive patients tested positive for NAb, with 14 of 15 (93%) NAb-positive patients having persistent NAb.

All 15 patients with complete gene deletion, large gene rearrangement, nonsense, frameshift or splice site mutations tested positive for Ab (Table 2). Of these 15 patients, neutralizing antibodies were observed in 13 (87%) patients. The NAbs in these patients developed earlier (most reported to be positive at Week 9 rather than at Week 27, as reported in clinical trials in patients older than 5 years of age) and were associated with higher titers and greater in vitro neutralizing activity than in patients older than 5 years of age. The presence of Ab was associated with reduced systemic idursulfase exposure [see Clinical Pharmacology (12.3)].

The immunogenicity data reflect the percentage of patients whose test results were positive for antibodies to idursulfase in specific assays, and are highly dependent on the sensitivity and specificity of these assays. The observed incidence of positive antibody in an assay may be influenced by several factors, including sample handling, timing of sample collection, concomitant medication, and underlying disease. For these reasons, comparison of the incidence of antibodies to idursulfase with the incidence of antibodies to other products may be misleading.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of Elaprase. 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 post-marketing experience, late-emergent symptoms and signs of anaphylactic reactions have occurred up to 24 hours after initial treatment and recovery from an initial anaphylactic reaction. In addition, patients experienced repeated anaphylaxis over a two- to four-month period, up to several years after initiating Elaprase treatment [ see Warnings and Precautions (5.1)].

A seven year-old male patient with Hunter syndrome, who received Elaprase at twice the recommended dosage (1 mg/kg weekly) for 1.5 years, experienced two anaphylactic events after 4.5 years of treatment. Treatment has been withdrawn [ see Overdosage (10)].

Serious adverse reactions that resulted in death included cardiorespiratory arrest, respiratory failure, respiratory distress, cardiac failure, and pneumonia.

Elaprase is a formulation of idursulfase, a purified form of human iduronate-2-sulfatase, a lysosomal enzyme. Idursulfase is produced by recombinant DNA technology in a human cell line. Idursulfase is an enzyme that hydrolyzes the 2-sulfate esters of terminal iduronate sulfate residues from the glycosaminoglycans dermatan sulfate and heparan sulfate in the lysosomes of various cell types.

Idursulfase is a 525-amino acid glycoprotein with a molecular weight of approximately 76 kilodaltons. The enzyme contains eight asparagine-linked glycosylation sites occupied by complex oligosaccharide structures. The enzyme activity of idursulfase is dependent on the post-translational modification of a specific cysteine to formylglycine. Idursulfase has a specific activity ranging from 46 to 74 units/mg of protein (one unit is defined as the amount of enzyme required to hydrolyze 1 µmole of heparin disaccharide substrate per hour under the specified assay conditions).

Elaprase is administered as an intravenous infusion and supplied as a sterile, nonpyrogenic clear to slightly opalescent, colorless solution that must be diluted prior to administration in 0.9% Sodium Chloride Injection, USP. Each vial contains an extractable volume of 3 mL with an idursulfase concentration of 2 mg/mL at a pH of approximately 6. Each vial contains 6 mg idursulfase, sodium chloride (24 mg), sodium phosphate monobasic monohydrate (6.75 mg), sodium phosphate dibasic heptahydrate (2.97 mg), and polysorbate 20 (0.66 mg). Elaprase does not contain preservatives. Each vial is for single use only.

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 Elaprase.

Elaprase at intravenous doses up to 5 mg/kg administered twice weekly (about 1.6 times the recommended human weekly dose based on body surface area) had no effect on fertility and reproductive performance in male rats.

Clinical Trials in Patients 5 Years and Older

The safety and efficacy of Elaprase were evaluated in a 53-week, randomized, double-blind, placebo-controlled clinical trial of 96 patients with Hunter syndrome. The trial included patients with deficiency in iduronate-2-sulfatase enzyme activity and a percent predicted forced vital capacity (% predicted FVC) less than 80%. The age of patients ranged from 5 to 31 years. Patients received Elaprase 0.5 mg/kg once per week (n=32), Elaprase 0.5 mg/kg once every other week (n=32), or placebo (n=32).

The primary efficacy outcome assessment was a two-component composite score based on the sum of the ranks of the change from baseline to Week 53 in distance walked in six minutes (6-minute walk test) and the ranks of the change in % predicted FVC. This two-component composite primary endpoint differed statistically significantly between the three groups, and the difference was greatest between the placebo group and the once weekly treatment group (once weekly Elaprase vs. placebo, p=0.0049).

Examination of the individual components of the composite score showed that, in the adjusted analysis, the weekly Elaprase-treated group experienced a 35 meter greater mean increase in the distance walked in six minutes compared to placebo. The changes in %-predicted FVC were not statistically significant (Table 5).

Pharmacodynamic assessments included urinary GAG levels and changes in liver and spleen size. Urinary GAG levels were elevated in all patients at baseline. Following 53 weeks of treatment, mean urinary GAG levels were reduced in the Elaprase once weekly group, although GAG levels still remained above the upper limit of normal in half of the Elaprase-treated patients. Urinary GAG levels remained elevated and essentially unchanged in the placebo group. Sustained reductions in both liver and spleen volumes were observed in the Elaprase once weekly group through Week 53 compared to placebo. There were essentially no changes in liver and spleen volumes in the placebo group.

Extension Trial

Patients who participated in the placebo-controlled trial were eligible to continue treatment in an open-label extension trial. During the extension trial, all patients received Elaprase 0.5mg/kg once weekly for 24 months.

Patients who were treated with Elaprase once weekly and every other week in the placebo-controlled trial demonstrated improvement in distance walked in the 6-minute walk test for an additional 8 months of treatment in the extension trial. There was no change in mean %-predicted FVC in all Hunter syndrome patients after 6 months of treatment in the extension trial; however, a slight decrease in mean %-predicted FVC was demonstrated through to month 24 of the extension trial. The long-term effect of Elaprase on pulmonary function in Hunter syndrome patients is unclear.

There were no further reductions in mean urinary GAG levels in patients initially treated with Elaprase once weekly; however, the patients treated with Elaprase every other week during the placebo-controlled trial experienced further reductions in mean urinary GAG levels after changing to a more frequent dosing regimen during the extension trial. The persistence of reduced urinary GAG levels did not correlate with the long term effect demonstrated by the 6-minute walk test distance or %-predicted FVC.

Clinical Trial in Patients 7 Years and Younger

A 53-week, open-label, multicenter, single-arm trial was conducted to assess the safety, pharmacokinetics, and pharmacodynamics of Elaprase 0.5 mg/kg once weekly in male Hunter syndrome patients aged 7 years and younger. Safety results demonstrated that patients with complete gene deletion or large gene rearrangement mutations are more likely to develop antibodies, including neutralizing antibodies, and to experience hypersensitivity reactions with Elaprase administration [ see Adverse Reactions (6.1, 6.2)]. In patients who remained antibody negative, the pharmacokinetic profile, reduction in urinary GAG excretion levels, and reduction in spleen volume were similar to those of adults and children 5 years and older. In patients who were persistently antibody positive, the presence of anti-idursulfase antibody was associated with reduced systemic exposure of idursulfase and a less pronounced decrease in urinary GAG levels [ see Clinical Pharmacology (12.2, 12.3)].