NAGLAZYME® (galsulfase) safety and tolerability

Safety and tolerability data were collected from 59 patients in 4 open‐label clinical trials and postmarketing surveys conducted in patients aged 3 months to 29 years.1 The mean exposure was 138 weeks. Two infants were exposed to 2 mg/kg of NAGLAZYME® (galsulfase) for 105 and 81 weeks, respectively1.

Immune-related reactions

The most common adverse events requiring interventions related to the use of NAGLAZYME occurred during administration of the drug through IV infusion1.

Infusion‐associated reactions

Despite routine pretreatment with antihistamines, infusion reactions, some severe, occurred in 33 of 59 patients treated with NAGLAZYME. The most common symptoms of drug‐related infusion reactions were pyrexia, chills, rash, urticaria, dyspnea, nausea, vomiting, pruritus, 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.1

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. Twenty‐three of 33 patients (70%) experienced recurrent infusion reactions during multiple infusions, though not always in consecutive weeks.1

Adverse events

The most common serious adverse events related to the use of NAGLAZYME occurred during infusions and included apnea, pyrexia, and respiratory distress. Severe adverse reactions included chest pain, dyspnea, laryngeal edema, and conjunctivitis. The most common adverse reactions in clinical studies were rash, pain, urticaria, pyrexia, pruritus, chills, headache, nausea, vomiting, abdominal pain, and dyspnea. The most common adverse reactions requiring interventions were infusion‐related reactions.1

The table below enumerates adverse events reported during the 6‐month placebo‐controlled trial that occurred more frequently in the NAGLAZYME group than in the placebo group. Each event listed occurred in at least 2 more patients treated with NAGLAZYME than patients treated with placebo. Observed adverse events in the phase 1, phase 2, and open‐label extension studies were not different in nature or severity.1

 
NAGLAZYME (n=19)
Placebo (n=20)a
Adverse Event
No.of patient (%)
No.of patient (%)
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
aOne of the 20 patients in the placebo group dropped out after week 4 infusion.

 

Immune‐related reactions

Type III immune complex–mediated reactions have been observed with NAGLAZYME, as with other enzyme replacement therapies. If immune‐mediated reactions occur, initiate appropriate medical treatment and consider discontinuation of NAGLAZYME. The risks and benefits of re‐administering NAGLAZYME following an immune‐mediated reaction should be considered. Some patients have successfully continued to receive NAGLAZYME under close clinical supervision.1

Warnings and precautions

Life‐threatening anaphylactic reactions have been observed in some patients during NAGLAZYME infusions and up to 24 hours after infusion. If anaphylaxis or other severe allergic reactions occur, immediately discontinue infusion and initiate appropriate treatment, which may include resuscitation, epinephrine, administering additional antihistamines, antipyretics, or corticosteroids.1

Caution should be exercised when administering NAGLAZYME to patients susceptible to fluid volume overload, because congestive heart failure may result. Appropriate medical support and monitoring measures should be readily available during NAGLAZYME infusion. Some patients may require prolonged observation times.1

Sleep apnea is common in MPS VI patients and antihistamine pretreatment may increase the risk of an apneic episode. Evaluation of airway patency should be considered prior to initiation of treatment. Patients using supplemental oxygen or continuous positive airway pressure 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.1

Spinal/cervical cord compression is a known and serious complication that is expected to occur during the natural course of MPS VI. Signs and symptoms of spinal/cervical cord compression include back pain, paralysis of limbs below the level of compression, and urinary or fecal incontinence. Patients should be evaluated for spinal/cervical cord compression prior to initiation of NAGLAZYME to establish a baseline and risk profile. Patients treated with NAGLAZYME should be regularly monitored for the development or progression of spinal/cervical cord compression and be given appropriate clinical care.1

Immunogenicity

Ninety‐eight percent (53/54) of patients treated with NAGLAZYME® (galsulfase) developed anti‐galsulfase (IgG) antibodies. Initial evidence of antibody development typically appeared following 4 to 8 weeks of treatment. Nineteen patients treated with NAGLAZYME from the placebo‐controlled study 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 levels, or endurance measures. 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.1

Full dosing and infusion directions »

Reference: 1. NAGLAZYME [package insert]. Novato, CA: BioMarin Pharmaceutical Inc; 2013.

Important Safety Information

Indication

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

Important Safety Information

Life-threatening anaphylactic reactions and severe allergic reactions have been observed in some patients during NAGLAZYME (galsulfase) infusions and up to 24 hours after infusion. If these reactions occur, immediate discontinuation of NAGLAZYME is recommended and appropriate medical treatment should be initiated, which may include resuscitation, epinephrine, administering additional antihistamines, antipyretics or corticosteroids. In patients who have experienced anaphylaxis or other severe allergic 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 infusions.

As with other enzyme replacement therapies, immune-mediated reactions, including membranous glomerulonephritis have been observed. In clinical trials, nearly all patients developed antibodies as a result of treatment with NAGLAZYME; 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.

Caution should be exercised when administering NAGLAZYME to patients susceptible to fluid volume overload because congestive heart failure may result. Consider a decreased total infusion volume and infusion rate when administering NAGLAZYME to these patients.

Consideration to delay NAGLAZYME infusion should be given when treating patients who present with an acute febrile or respiratory illness. 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 the 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.

Pretreatment with antihistamines with or without antipyretics is recommended prior to the start of infusion to reduce the risk of infusion reactions. If infusion reactions occur, decreasing the infusion rate, temporarily stopping the infusion, or administering additional antihistamines and/or antipyretics is recommended.

During infusion, serious adverse reactions included laryngeal edema, apnea, pyrexia, urticaria, respiratory distress, angioedema, and anaphylactoid reaction; severe adverse reactions included urticaria, chest pain, rash, abdominal pain, dyspnea, apnea, laryngeal edema, and conjunctivitis. The most common adverse events (=10%) observed in clinical trials in patients treated with NAGLAZYME were rash, pain, urticaria, pyrexia, pruritus, chills, headache, nausea, vomiting, abdominal pain and dyspnea. The most common adverse reactions requiring interventions are infusion-related reactions.

Spinal/cervical cord compression is a known and serious complication that is expected to occur during the natural course of MPS VI. Signs and symptoms of spinal/cervical cord compression include back pain, paralysis of limbs below the level of compression, and urinary or fecal incontinence. Patients should be evaluated for spinal/cervical cord compression prior to initiation of NAGLAZYME to establish a baseline and risk profile. Patients treated with NAGLAZYME should be regularly monitored for the development or progression of spinal/cervical cord compression and be given appropriate clinical care.

To report SUSPECTED ADVERSE REACTIONS contact BioMarin Pharmaceutical Inc. at 1-866-906-6100, or FDA at 1-800-FDA-1088 or go to www.fda.gov/medwatch.

Please see full Prescribing Information.