Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: BioMarin International Limited, Shanbally, Ringaskiddy, County Cork, P43 R298, Ireland
Severe or life-threatening hypersensitivity to the active substance or to any of the excipients, if hypersensitivity is not controllable.
Caution must be exercised in the management and treatment of patients with compromised airways by limitation or careful monitoring of antihistamine and other sedative medicinal product use. Institution of positive–airway pressure during sleep as well as potential tracheostomy in clinically appropriate situations should also be considered.
Patients who present with an acute febrile or respiratory illness may need to have their Naglazyme infusions delayed.
Patients treated with Naglazyme have developed infusion-associated reactions (IARs), defined as any adverse reactions occurring during the infusion or until the end of the infusion day (see section 4.8).
Based on data obtained during Naglazyme clinical trials, the majority of patients are expected to develop IgG antibodies to galsulfase within 4-8 weeks of treatment initiation.
In the Naglazyme clinical trials, IARs were usually manageable by interrupting or slowing the rate of infusion and by (pre-) treating the patient with antihistamines and/or antipyretics (paracetamol), thus enabling the patient to continue treatment.
As there is little experience on resumption of treatment following prolonged interruption, caution is to be used due to the theoretical increased risk of hypersensitivity reaction.
With administration of Naglazyme it is recommended that patients be administered pre-treatment medicinal products (antihistamines with or without antipyretics) approximately 30-60 minutes prior to the start of the infusion, to minimise the potential occurrence of IARs.
In case of a mild or moderate IAR, treatment with antihistamines and paracetamol should be considered and/or a reduction in the infusion rate to half the rate at which the reaction occurred.
In case of a single severe IAR, the infusion should be stopped until the symptoms are resolved and treatment with antihistamines and paracetamol should be considered. The infusion can be restarted with a reduction of the infusion rate to 50%–25% of the rate at which the reaction occurred. In case of a recurrent moderate IAR or re-challenge after a single severe IAR, pre-treatment should be considered (antihistamines and paracetamol and/or corticosteroids) and a reduction of the infusion rate to 50%–25% of the rate at which the previous reaction occurred.
As with any intravenous protein medicinal product, severe allergic-type hypersensitivity reactions are possible. If these reactions occur, immediate discontinuation of Naglazyme is recommended and appropriate medical treatment should be initiated. The current medical standards for emergency treatment are to be observed. In patients who have experienced 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. Severe, or potentially life-threatening hypersensitivity is a contraindication to rechallenge, if hypersensitivity is not controllable. See also section 4.3.
Spinal/cervical cord compression (SCC) with resultant myelopathy is a known and serious complication that can be due to MPS VI. There have been post-marketing reports of patients treated with Naglazyme who experienced the onset or worsening of SCC requiring decompression surgery. Patients 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 faecal incontinence) and given appropriate clinical care.
Caution should be exercised when administering Naglazyme to patients susceptible to fluid volume overload; such as in 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 occur. 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 section 4.2).
Type III immune complex-mediated reactions including membranous glomerulonephritis have been observed with Naglazyme. 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 (see section 4.2).
This medicinal product contains 0.8 mmol (18.4 mg) sodium per vial and is administered in sodium chloride 9 mg/ml solution for injection (see section 6.6). To be taken into consideration by patients on a controlled sodium diet.
No interaction studies have been performed.
For Naglazyme, no clinical data on exposed pregnancies are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy or embryo-foetal development (see section 5.3). Naglazyme should not be used during pregnancy unless clearly necessary.
It is not known whether galsulfase is excreted in milk, therefore breast-feeding should be stopped during Naglazyme treatment.
Reproduction studies have been performed in rats and rabbits at doses up to 3 mg/kg/day and have revealed no evidence of impaired fertility or harm to the embryo or foetus due to Naglazyme.
No studies on the effects on the ability to drive and use machines have been performed.
Due to the low number of patients in clinical trials, adverse event (AE) data from all Naglazyme studies have been pooled and reviewed in a single, clinical trial safety analysis.
All patients treated with NAGLAZYME (59/59) reported at least one AE. The majority (42/59; 71%) of patients experienced at least one Adverse Drug Reaction. The most common adverse reactions were pyrexia, rash, pruritus, urticaria, chills/rigors, nausea, headache, abdominal pain, vomiting and dypsnoea. Serious adverse reactions included laryngeal edema, apnoea, pyrexia, urticaria, respiratory distress, angioedema, asthma and anaphylactoid reaction.
Infusion reactions, defined as adverse reactions occurring during Naglazyme infusions or until the end of the infusion day, were observed in 33 (56%) of the 59 patients treated with Naglazyme across five clinical studies. Infusion reactions began as early as Week 1 and as late as Week 146 of Naglazyme treatment, and occurred during multiple infusions though not always in consecutive weeks. Very common symptoms of these infusion reactions were pyrexia, chills/rigors, rash, urticaria and dyspnoea. Common symptoms of infusion reactions were pruritus, vomiting, abdominal pain, nausea, hypertension, headache, chest pain, erythema, cough, hypotension, angioedema, respiratory distress, tremor, conjunctivitis, malaise, bronchospasm and arthralgia.
Adverse reactions are listed in Table 1 by System Organ Class.
The reactions are listed following the MedDRA frequency convention. Very common adverse reactions are those with a frequency of ≥1/10. Common reactions have a frequency of ≥1/100 to <1/10. Due to the small patient population, an adverse reaction in a single patient is classified as common.
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Adverse reactions reported during the Post Marketing period are included at a frequency category of “unknown”.
Overall, one case of sleep apnoea was experienced from all clinical studies.
Table 1. Frequency of adverse drug reactions with Naglazyme:
Unknown: Anaphylaxis, shock
Very common: Pharyngitis1, gastroenteritis1
Very common: Areflexia1, headache
Common: Tremor
Unknown: Paresthesia
Very common: Conjunctivitis1, corneal opacity1
Unknown: Bradycardia, tachycardia, cyanosis
Very common: Ear pain1, hearing impaired1
Very common: Hypertension1
Common: Hypotension
Unknown: Pallor
Very common: Dyspnoea1, nasal congestion1
Common: Apnoea1, cough, respiratory distress, asthma, bronchospasm
Unknown: Laryngeal oedema, hypoxia, tachypnoea
Very common: Abdominal pain1, umbilical hernia1, vomiting, nausea
Very common: Angioeodema1, rash1, urticaria, pruritus
Common: Erythema
Very common: Pain1, chest pain1, rigors1, malaise1, pyrexia
Very common: Arthralgia
1 Reactions reported more frequently in the active arm of the placebo-controlled study than the placebo arm; frequency determined from 39 patients of the blinded Phase 3 study.
Other reactions with known frequency were reported from 59 patients treated with Naglazyme from all five clinical trials.
Reactions of unknown frequency were reported post-marketing.
In four patients <1 year of age, the overall safety profile of a higher dose (2 mg/kg/week) did not differ in a clinically meaningful manner from that of the recommended 1 mg/kg/week dose, and was consistent with the safety profile of Naglazyme in older children.
Out of the 59 patients treated with Naglazyme in the clinical studies, 54 were tested for IgG antibodies. 53/54 patients (98%) were positive for IgG antibodies to galsulfase.
A comprehensive antibody analysis based on data from three clinical studies has been carried out in 48 patients.
Although a larger proportion of subjects with high total antibody titres experienced recurrent infusion reactions, neither frequency nor severity could be predicted based on the anti-galsulfase antibody titre. Likewise, antibody development is not predictive of decreased efficacy although subjects with limited response in endurance parameters or urinary glycosaminoglycans (GAGs) tended to have higher peak anti-galsulfase titres than those with good response.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
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