NAGLAZYME: Package Insert and Label Information

NAGLAZYME- galsulfase solution
BioMarin Pharmaceutical Inc.

1 INDICATIONS AND USAGE

NAGLAZYME is indicated for patients with Mucopolysaccharidosis VI (MPS VI, Maroteaux-Lamy syndrome). NAGLAZYME has been shown to improve walking and stair-climbing capacity.

2 DOSAGE AND ADMINISTRATION

2.1 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 (5.5].

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 (5.3)]. 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.

2.2 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.

3 DOSAGE FORMS AND STRENGTHS

Injection: 5 mg/5 mL (1 mg/mL) as a colorless to pale yellow, clear to slightly opalescent solution single-dose vials

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Anaphylaxis and Hypersensitivity Reactions

Anaphylaxis and serious hypersensitivity reactions have been observed in patients during and up to 24 hours after NAGLAZYME infusion. Some of the reactions were life-threatening and included anaphylaxis, shock, respiratory distress, dyspnea, bronchospasm, laryngeal edema, and hypotension [see Adverse Reactions (6.1, 6.3)]. If anaphylaxis or other serious hypersensitivity reactions occur, NAGLAZYME should be immediately discontinued, and appropriate medical treatment should be initiated. In patients who have experienced anaphylaxis or other serious hypersensitivity reactions during infusion with NAGLAZYME, caution should be exercised upon rechallenge; appropriately trained personnel and equipment for emergency resuscitation (including epinephrine) should be available during infusion.

5.2 Immune-Mediated Reactions

Type III immune complex-mediated reactions, including membranous glomerulonephritis have been observed with NAGLAZYME, as with other enzyme replacement therapies. If immune-mediated reactions occur, discontinuation of the administration of NAGLAZYME should be considered, and appropriate medical treatment initiated. The risks and benefits of re-administering NAGLAZYME following an immune-mediated reaction should be considered. Some patients have successfully been rechallenged and have continued to receive NAGLAZYME under close clinical supervision [see Adverse Reactions (6.3)].

5.3 Risk of Acute Cardiorespiratory Failure

Caution should be exercised when administering NAGLAZYME to patients susceptible to fluid volume overload, such as patients weighing 20 kg or less, patients with acute underlying respiratory illness, or patients with compromised cardiac and/or respiratory function, because congestive heart failure may result. Appropriate medical support and monitoring measures should be readily available during NAGLAZYME infusion, and some patients may require prolonged observation times that should be based on the individual needs of the patient [see Adverse Reactions (6.3)].

5.4 Acute Respiratory Complications Associated with Administration

Sleep apnea is common in MPS VI patients and antihistamine pretreatment may increase the risk of apneic episodes. Evaluation of airway patency should be considered prior to initiation of treatment. Patients using supplemental oxygen or continuous positive airway pressure (CPAP) during sleep should have these treatments readily available during infusion in the event of an infusion reaction, or extreme drowsiness/sleep induced by antihistamine use.

Consider delaying NAGLAZYME infusions in patients who present with an acute febrile or respiratory illness because of the possibility of acute respiratory compromise during infusion of NAGLAZYME.

5.5 Infusion Reactions

Because of the potential for infusion reactions, patients should receive antihistamines with or without antipyretics prior to infusion. Despite routine pretreatment with antihistamines, infusion reactions, some severe, occurred in 33 of 59 (56%) patients treated with NAGLAZYME. Serious adverse reactions during infusion included laryngeal edema, apnea, pyrexia, urticaria, respiratory distress, angioedema, and anaphylactoid reaction. Severe adverse reactions included urticaria, chest pain, rash, dyspnea, apnea, laryngeal edema, and conjunctivitis [see Adverse Reactions (6.1, 6.3)].

The most common symptoms of drug-related infusion reactions were pyrexia, chills, rash, urticaria, dyspnea, nausea, vomiting, pruritis, erythema, abdominal pain, hypertension, and headache. Respiratory distress, chest pain, hypotension, angioedema, conjunctivitis, tremor, and cough were also reported. Infusion reactions began as early as Week 1 and as late as Week 146 of NAGLAZYME treatment. Twenty-three of 33 patients (70%) experienced recurrent infusion reactions during multiple infusions though not always in consecutive weeks.

Symptoms typically abated with slowing or temporary interruption of the infusion and administration of additional antihistamines, antipyretics, and occasionally corticosteroids. Most patients were able to complete their infusions. Subsequent infusions were managed with a slower rate of NAGLAZYME administration, treatment with additional prophylactic antihistamines, and, in the event of a more severe reaction, treatment with prophylactic corticosteroids.

If severe infusion reactions occur, immediately discontinue the infusion of NAGLAZYME and initiate appropriate treatment. The risks and benefits of re-administering NAGLAZYME following a severe reaction should be considered.

No factors were identified that predisposed patients to infusion reactions. There was no association between severity of infusion reactions and titer of anti-galsulfase antibodies.

5.6 Spinal or Cervical Cord Compression

Spinal or cervical cord compression (SCC) with resultant myelopathy is a known and serious complication of MPS VI. SCC is expected to occur in the natural history of the disease, including in patients on NAGLAZYME. There have been post-marketing reports of patients treated with NAGLAZYME who experienced the onset or worsening of SCC requiring decompression surgery. Patients with MPS VI should be monitored for signs and symptoms of spinal/cervical cord compression (including back pain, paralysis of limbs below the level of compression, urinary and fecal incontinence) and given appropriate clinical care.

6 ADVERSE REACTIONS

Serious and or clinically significant adverse reactions described elsewhere in labeling include:

  • Anaphylaxis and Hypersensitivity Reactions [see Warnings and Precautions (5.1)]
  • Immune-Mediated Reactions [see Warnings and Precautions (5.2)]
  • Risk of Acute Cardiorespiratory Failure [see Warnings and Precautions (5.3)]
  • Acute Respiratory Complications Associated with Administration [see Warnings and Precautions (5.4)]
  • Infusion Reactions [see Warnings and Precautions (5.5)]
  • Spinal or Cervical Cord Compression [see Warnings and Precautions (5.6)]

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 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
MedDRA Preferred Term NAGLAZYME (n = 19) Placebo (n = 20 * )
No. Patients (%) No. Patients (%)
*
One of the 20 patients in the placebo group dropped out after Week 4 infusion
All 19 (100) 20 (100)
Abdominal Pain 9 (47) 7 (35)
Ear Pain 8 (42) 4 (20)
Arthralgia 8 (42) 5 (25)
Pain 6 (32) 1 (5)
Conjunctivitis 4 (21) 0
Dyspnea 4 (21) 2 (10)
Rash 4 (21) 2 (10)
Chills 4 (21) 0
Chest Pain 3 (16) 1 (5)
Pharyngitis 2 (11) 0
Areflexia 2 (11) 0
Corneal Opacity 2 (11) 0
Gastroenteritis 2 (11) 0
Hypertension 2 (11) 0
Malaise 2 (11) 0
Nasal Congestion 2 (11) 0
Umbilical Hernia 2 (11) 0
Hearing Impairment 2 (11) 0

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 hypersensitivity 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.

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