Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Ultragenyx Germany GmbH, Friedrichstr. 191, 10117, Berlin, Germany
Life-threatening hypersensitivity (anaphylactic reaction) to the active substance or to any of the excipients listed in section 6.1 (see section 4.4).
The effects of treatment with vestronidase alfa should be periodically evaluated and discontinuation of treatment should be considered in cases where clear benefits (including stabilisation of disease manifestations) are not observed.
As end organ damage progresses over time, it is more difficult for the treatment to reverse the damage or to show improvements. It should be considered by the treating physician that the administration of vestronidase alfa does not affect the irreversible complications (e.g. skeletal deformities).
Vestronidase alfa, at the exposure observed in humans, is not expected to cross the blood-brain-barrier and therefore it is not likely to impact the neurological manifestations of the disease.
Serious hypersensitivity reactions, including anaphylaxis, have been reported with vestronidase alfa; therefore, appropriate medical support should be readily available when vestronidase alfa is administered.
Infusion should be avoided if the patient has an acute febrile or respiratory illness at the time.
It is recommended that premedication with non-sedating antihistamines with or without antipyretics be administered 30-60 minutes prior to the start of the infusion (see section 4.2).
It is important to administer vestronidase alfa according to the recommended infusion rate schedule (see Table 2 in section 6.6).
If severe hypersensitivity reactions occur, immediately stop the infusion of vestronidase alfa and initiate appropriate treatment. Management of hypersensitivity reactions should be based on the severity of the reaction and include temporary interruption or discontinuation of the infusion and/or administration of additional antihistamines, antipyretics, and/or corticosteroids for mild to moderate reactions. Consider rapid sodium chloride 9 mg/mL (0.9%) solution for infusion for decreased blood pressure and oxygen for hypoxia. Patients should be observed for a minimum of 60 minutes after completing the infusion of vestronidase alfa.
Patients should be informed of the signs and symptoms of hypersensitivity reactions and instructed to seek immediate medical care should such signs and symptoms occur. The risks and benefits of readministering vestronidase alfa should be considered following a severe hypersensitivity reaction.
Spinal or cervical cord compression is a known and serious complication of MPS VII. During enzyme replacement therapy, spinal cord injury can occur due to improved neck and spine mobility. Patients with MPS VII receiving vestronidase alfa should be monitored for signs and symptoms of spinal cord compression or neck instability including neck or back pain, weakness of limbs, changes in reflexes or urinary and faecal incontinence. Appropriate clinical treatment should be immediately sought.
This medicinal product contains 17.8 mg sodium per vial and is administered in sodium chloride 9 mg/mL (0.9%) solution for infusion (see section 6.6). For each vial dosed, including the corresponding diluent volume, the sodium intake is 35.5 mg sodium. This amount is equivalent to 1.8% of the WHO recommended maximum daily intake for sodium (2 g). Mepsevii is considered high in sodium. This should be taken into consideration during dilution of the medicinal product for patients on a controlled sodium diet or for those patients with congestive heart failure needing to restrict sodium and total water intake.
No interaction studies have been performed. Because it is a recombinant human protein and its enzyme action is within the lysosome, vestronidase alfa is not expected to interact with other medicinal products.
There are no data on the use of vetronidase alfa in pregnant women. Animal studies with vestronidase alfa do not indicate direct or indirect harmful effects with respect to pregnancy or embryo-foetal development (see section 5.3).
As a precautionary measure, it is preferable to avoid the use of vestronidase alfa during pregnancy, unless the potential benefit to the mother outweighs the potential theoretical risks to the foetus.
There are no data from studies in breast-feeding women. It is not known whether vestronidase alfa is excreted in human milk, but systemic exposure via breast-milk is not expected. Due to lack of human data, vestronidase alfa should only be administered to a breast-feeding woman if the potential benefit of vestronidase alfa to the mother and the benefit of breast-feeding to the infant outweighs the potential theoretical risks to the infant.
No human data are available on the effect of vestronidase alfa on fertility. Animal studies with vestronidase alfa do not indicate any impact on male or female fertility (see section 5.3).
Mepsevii has no or negligible influence on the ability to drive and use machines.
The assessment of adverse reactions was based on the exposure of 23 patients from 4 clinical trials, aged 5 months to 25 years, who received vestronidase alfa at doses up to 4 mg/kg once every two weeks for up to 132 weeks. Nineteen patients were younger than 18 years of age.
The most common adverse reactions from 4 clinical trials in 23 patients treated with vestronidase alfa were anaphylactoid reaction (13%), urticaria (13%), infusion site swelling (13%), infusion site extravasation (8.7%), pruritus (8.7%), diarrhoea (8.7%) and rash (8.7%). Most adverse reactions were mild to moderate in severity. There was a single adverse reaction of febrile convulsion observed in one patient (4.3%); the patient recovered without sequelae.
Table 1 lists the adverse reactions reported from 4 clinical trials in 23 patients treated with Mepsevii. Adverse reactions are presented by System Organ Class and frequency. Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1,000), and very rare (<1/10,000).
Table 1. Adverse reactions reported in patients treated with Mepsevii:
Very common: Anaphylactoid reaction
Common: Febrile convulsion*
Common: Diarrhoea
Very common: Urticaria
Common: Rash, Pruritus
Very common: Infusion site swelling**
Common: Infusion site extravasation
* Refer to description of selected adverse reactions for details on the febrile convulsion reported in 1 of 23 trial patients.
** One adverse reaction of Peripheral swelling is included within the frequency of Infusion site swelling as the event is classified as intravenous catheter issue.
One patient receiving a vestronidase alfa dose of 4 mg/kg experienced a febrile convulsion during treatment at the week 66, within 3 days of diphtheria, tetanus, pertussis vaccination. The infusion was stopped, the patient received anticonvulsants, antipyretics and antibiotics, and the febrile convulsion resolved. The patient subsequently was re-challenged without recurrence and continued on vestronidase alfa treatment. This event was assessed as possibly related to vestronidase alfa due to the temporal association with the infusion.
Sixteen out of 23 patients (70%) from 4 clinical trials developed anti-recombinant human betaglucuronidase (rhGUS) antibodies (ADA), nine of whom further developed neutralizing antibodies (NAb) on at least one occasion, but not consistently over time. There is no definitive correlation between the antibody titre and neutralizing antibody development. In most patients, a pattern of attenuated immunogenicity with chronic exposure was suggested by declining antibody titres over time on continuous treatment. The presence of ADA (non-NAb and NAb) does not appear to affect reduction in the pharmacodynamic marker, urinary glycosaminoglycans (uGAGs).
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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