Naglazyme

Galsulfase is used to treat some of the symptoms of a genetic condition called Maroteaux-Lamy syndrome. Maroteaux-Lamy syndrome is also called mucopolysaccharidosis (MYOO-koe-pol-ee-SAK-a-rye-DOE-sis).

Maroteaux-Lamy syndrome is a metabolic disorder in which the body lacks the enzyme needed to break down certain sugars and proteins. These substances can build up in the body, causing enlarged organs, abnormal bone structure, changes in facial features, breathing problems, heart problems, vision or hearing loss, and changes in mental or physical abilities.

Galsulfase may improve walking and stair-climbing ability in people with this condition. However, this medication is not a cure for Maroteaux-Lamy syndrome.

Galsulfase may also be used for other purposes not listed in this medication guide.

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 observed in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

NAGLAZYME was studied in a randomized, double-blind, placebo-controlled trial in which 19 patients received weekly infusions of 1 mg/kg NAGLAZYME and 20 patients received placebo; of the 39 patients 66% were female, and 62% were White, non-Hispanic. Patients were aged 5 years to 29 years. NAGLAZYME-treated patients were approximately 3 years older than placebo-treated patients (mean age 13.7 years versus 10.7 years, respectively).

Serious adverse reactions experienced in this trial include apnea, pyrexia, and respiratory distress. Severe adverse reactions include chest pain, dyspnea, laryngeal edema, and conjunctivitis. The most common adverse reactions requiring interventions were infusion reactions.

Table 1 summarizes the adverse reactions that occurred in the placebo-controlled trial in at least 2 patients more in the NAGLAZYME-treated group than in the placebo-treated group.

Table 1: Adverse Reactions that Occurred in the Placebo-Controlled Trial in at least 2 Patients More in the NAGLAZYME Group than in the Placebo Group

Four open-label clinical trials were conducted in MPS VI patients aged 3 months to 29 years with NAGLAZYME administered at doses of 0.2 mg/kg (n = 2), 1 mg/kg (n = 55), and 2 mg/kg (n = 2). The mean exposure to the recommended dose of NAGLAZYME (1 mg/kg) was 138 weeks (range = 54 to 261 weeks). Two infants (12.1 months and 12.7 months) were exposed to 2 mg/kg of NAGLAZYME for 105 and 81 weeks, respectively.

In addition to those listed in Table 1, common adverse reactions observed in the open-label trials include pruritus, urticaria, pyrexia, headache, nausea, and vomiting. The most common adverse reactions requiring interventions were infusion reactions. Serious adverse reactions included laryngeal edema, urticaria, angioedema, and other allergic reactions. Severe adverse reactions included urticaria, rash, and abdominal pain.

Observed adverse events in four open-label studies (up to 261 weeks treatment) were not different in nature or severity to those observed in the placebo-controlled study. No patients discontinued during open-label treatment with NAGLAZYME due to adverse events.

Immunogenicity

Ninety-eight percent (53/54) of patients treated with NAGLAZYME and evaluable for the presence of antibodies to galsulfase developed anti-galsulfase IgG antibodies within 4 to 8 weeks of treatment (in four clinical studies). In 19 patients treated with NAGLAZYME from the placebo-controlled study, serum samples were evaluated for a potential relationship of anti-galsulfase antibody development to clinical outcome measures. All 19 patients treated with NAGLAZYME developed antibodies specific to galsulfase; however, the analysis revealed no consistent predictive relationship between total antibody titer, neutralizing or IgE antibodies, and infusion-associated reactions, urinary glycosaminoglycan (GAG) levels, or endurance measures. Antibodies were assessed for the ability to inhibit enzymatic activity but not cellular uptake.

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

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of NAGLAZYME. 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 addition to infusion reactions reported in clinical trials, serious reactions which occurred during NAGLAZYME infusion in the worldwide marketing experience include anaphylaxis, shock, hypotension, bronchospasm, and respiratory failure.

Additional infusion reactions included pyrexia, erythema, pallor, bradycardia, tachycardia, hypoxia, cyanosis, tachypnea, and paresthesia.

During postmarketing surveillance, there has been a single case of membranous nephropathy and rare cases of thrombocytopenia reported. In the case of membranous nephropathy, renal biopsy revealed galsulfase-immunoglobulin complexes in the glomeruli. With both membranous nephropathy and thrombocytopenia, patients have been successfully rechallenged and have continued to receive NAGLAZYME.

Read the entire FDA prescribing information for Naglazyme (Galsulfase)

• Biomarin Pharmaceutical. Inc.

Galsulfase is injected into a vein through an IV. You will most likely receive this injection in a clinic or hospital setting.

Galsulfase must be given slowly through an IV infusion, and can take at least 4 hours to complete.

Your doctor may also prescribe other medications to help prevent an allergic reaction to galsulfase. Take all of your medications as directed.

Galsulfase is usually given once per week. Follow your doctor's instructions.

Your doctor will need to check your progress while you are using galsulfase.

In the U.S.

• Naglazyme

Available Dosage Forms:

• Solution

Therapeutic Class: Endocrine-Metabolic Agent

Pharmacologic Class: Enzyme

• If you need to store Naglazyme at home, talk with your doctor, nurse, or pharmacist about how to store it.

Recommended Dose

The recommended dosage regimen of Naglazyme is 1 mg per kg of body weight administered once weekly as an intravenous infusion.

Pretreatment with antihistamines with or without antipyretics is recommended 30 to 60 minutes prior to the start of the infusion [see Warnings and Precautions (5.2)].

The total volume of the infusion should be delivered over a period of time of no less than 4 hours.  Naglazyme should be diluted with 0.9% Sodium Chloride Injection, USP, to a final volume of 250 mL and delivered by controlled intravenous infusion using an infusion pump.  The initial infusion rate should be 6 mL per hour for the first hour.  If the infusion is well tolerated, the rate of infusion may be increased to 80 mL per hour for the remaining 3 hours.  The infusion time can be extended up to 20 hours if infusion reactions occur.

For patients 20 kg and under or those who are susceptible to fluid volume overload, physicians may consider diluting Naglazyme in a volume of 100 mL [see Warnings and Precautions (5.1) and Adverse Reactions (6.3)]. The infusion rate (mL per hour) should be decreased so that the total infusion duration remains no less than 4 hours.

Each vial of Naglazyme provides 5 mg of galsulfase (expressed as protein content) in 5 mL of solution and is intended for single use only.  Do not use the vial more than one time.  The concentrated solution for infusion must be diluted with 0.9% Sodium Chloride Injection, USP, using aseptic techniques.  Prepare Naglazyme using low-protein-binding containers and administer the diluted Naglazyme solution to patients using a low-protein-binding infusion set equipped with a low-protein-binding 0.2 µm in-line filter. There is no information on the compatibility of diluted Naglazyme with glass containers.

Instructions for Use

Prepare and use Naglazyme according to the following steps. Use aseptic techniques.

1. Determine the number of vials to be used based on the patient's weight and the recommended dose of 1 mg per kg:
   
   Patient's weight (kg) x 1 mL/kg of Naglazyme = Total number of mL of Naglazyme
   
   Total number of mL of Naglazyme ÷ 5 mL per vial = Total number of vials
   
   Round up to the next whole vial. Remove the required number of vials from the refrigerator to allow them to reach room temperature. Do not allow vials to remain at room temperature longer than 24 hours prior to dilution. Do not heat or microwave vials.
   
   
2. Before withdrawing the Naglazyme solution from the vial, visually inspect each vial for particulate matter and discoloration.  The Naglazyme solution should be clear to slightly opalescent and colorless to pale yellow.  Some translucency may be present in the solution.  Do not use if the solution is discolored or if there is particulate matter in the solution.
   
   
3. From a 250 mL infusion bag of 0.9% Sodium Chloride Injection, USP, withdraw and discard a volume equal to the volume of Naglazyme solution to be added. If using a 100 mL infusion bag, this step is not necessary.
   
   
4. Slowly withdraw the calculated volume of Naglazyme from the appropriate number of vials using caution to avoid excessive agitation.  Do not use a filter needle, as this may cause agitation.  Agitation may denature Naglazyme, rendering it biologically inactive.
   
   
5. Slowly add the Naglazyme solution to the 0.9% Sodium Chloride Injection, USP, using care to avoid agitation of the solutions.  Do not use a filter needle.
   
   
6. Gently rotate the infusion bag to ensure proper distribution of Naglazyme.  Do not shake the solution.
   
   
7. Administer the diluted Naglazyme solution to patients using a low-protein-binding infusion set equipped with a low-protein-binding 0.2 µm in-line filter.

Naglazyme does not contain preservatives; therefore, after dilution with saline, the infusion bags should be used immediately.  If immediate use is not possible, the diluted solution must be stored refrigerated at 2°C to 8°C (36°F to 46°F) and administered within 48 hours from the time of dilution to completion of administration.  Other than during infusion, do not store the diluted Naglazyme solution at room temperature.  Any unused product or waste material must be discarded and disposed of in accordance with local requirements.

Naglazyme must not be infused with other products in the infusion tubing.  The compatibility of Naglazyme in solution with other products has not been evaluated.

Injection; 5 mL vials (5 mg per 5 mL).

A total of 56 patients with MPS VI, ages 5 years to 29 years, were enrolled in four clinical studies. The majority of patients had severe manifestations of the disease as evidenced by poor performance on a test of physical endurance.

In the randomized, double-blind, multicenter, placebo-controlled clinical trial, 38 patients with MPS VI received 1 mg/kg Naglazyme or placebo, once-weekly for 24 weeks.  The patients’ ages ranged from 5 to 29 years.  Enrollment was restricted to patients with a 12‑minute walk distance of 5 to 400 meters.  All patients were treated with antihistamines prior to each infusion.

The Naglazyme-treated group showed greater mean increases in the distance walked in 12 minutes (12‑minute walk test, 12‑MWT) and in the rate of stair climbing in a 3-minute stair climb test, compared with the placebo group (Table 3).

Following the 24-week placebo-controlled study period, 38 patients received open-label Naglazyme for 72 weeks.  Among the 19 patients who were initially randomized to Naglazyme and who continued to receive treatment for 72 weeks (total of 96 weeks), increases in the 12-MWT distance and in the rate of stair climbing were observed compared to the start of the open-label period (mean [ ± SD] change): 72 ± 116 meters and 5.6 ± 10.6 stairs/minute, respectively).  Among the 19 patients who were randomized initially to placebo for 24 weeks, and then crossed over to treatment with Naglazyme, the increases after 72 weeks of Naglazyme treatment compared to the start of the open-label period, (mean [ ± SD] change): were 118 ± 127 meters and 11.1 ± 10.0 stairs/minute, for the 12-MWT and the rate of stair climbing, respectively.

Bioactivity was evaluated with urinary GAG concentration.  Overall, 95% of patients showed at least a 50% reduction in urinary GAG levels after 72 weeks of treatment with Naglazyme.  No patient receiving Naglazyme reached the normal range for urinary GAG levels [see Clinical Pharmacology (12.2)].

In an additional open-label extension study, patients receiving Naglazyme showed maintenance of initial improvement in endurance for approximately 240 weeks.

Applies to galsulfase: intravenous solution

General

The most frequently reported adverse reactions included rash, pain, urticaria, pyrexia, pruritus, chills, headache, nausea, vomiting, abdominal pain, and dyspnea.

The most frequently reported adverse reactions requiring interventions are infusion-related reactions.[Ref]

Hypersensitivity

Frequency not reported: Anaphylaxis/anaphylactoid reaction, allergic reaction[Ref]

Dermatologic

Very common (10% or more): Rash (21%), angioedema, urticaria, pruritus
Common (1% to 10%): Erythema[Ref]

Gastrointestinal

Very common (10% or more): Abdominal pain (47%), gastroenteritis (11%), umbilical hernia (11%), nausea, vomiting[Ref]

Other

Very common (10% or more): Infusion reactions (56%), ear pain (42%), pain (32%), chills/rigors (21%), chest pain (16%), malaise (11%), hearing impairment (11%), pyrexia[Ref]

Infusion reactions, which occurred in 56% of patients across 5 clinical studies were defined as adverse reactions occurring during infusions or until the end of the infusion day. Infusion reactions were observed as early as week 1 and as late as week 146 of treatment and occurred during multiple infusions, however, not always in consecutive weeks. The most common signs/symptoms included pruritus, vomiting, abdominal pain, nausea, hypertension, headache, chest pain, erythema, cough, hypotension, angioedema, respiratory distress, tremor, conjunctivitis, malaise, bronchospasm, and arthralgia.[Ref]

Cardiovascular

Very common (10% or more): Hypertension (11%)
Common (1% to 10%): Hypotension
Frequency not reported: Pallor, bradycardia, tachycardia, cyanosis, shock[Ref]

Nervous system

Very common (10% or more): Areflexia (11%), headache
Common (1% to 10%): Tremor
Frequency not reported: Paresthesia[Ref]

Respiratory

Very common (10% or more): Dyspnea (21%), pharyngitis (11%), nasal congestion (11%)
Common (1% to 10%): Apnea, cough, respiratory distress, asthma, bronchospasm
Frequency not reported: Laryngeal edema, hypoxia, tachypnea, sleep apnea
Postmarketing reports: Respiratory failure[Ref]

Musculoskeletal

Very common (10% or more): Arthralgia (42%)[Ref]

Ocular

Very common (10% or more): Conjunctivitis (21%), corneal opacity (11%)[Ref]

Immunologic

Very common (10% or more): Development of antidrug antibodies (98%)[Ref]

During clinical trials, 53 out of 54 patients tested positive for antidrug IgG antibodies within 4 to 8 weeks of treatment. In the placebo controlled study, 19 patients were evaluated for a potential relationship between development of antidrug antibodies to clinical outcome measures. While all 19 patients developed antidrug antibodies, there was no consistent predictive relationship between total antibody titer, neutralizing or IgE antibodies, and infusion-associated reactions, urinary glycosaminoglycan (GAG) levels, or endurance measures.[Ref]

Renal

Postmarketing reports: Membranous nephropathy[Ref]

Hematologic

Postmarketing reports: Thrombocytopenia[Ref]

Some side effects of Naglazyme may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.