LAMZEDE Powder for solution for infusion Ref.[7641] Active ingredients: Velmanase alfa

The effects of treatment with velmanase alfa should be periodically evaluated and discontinuation of treatment considered in cases where no clear benefits could be observed.

As the accumulation of end organ damage progresses over time, it is more difficult for the treatment to reverse the damage or to show improvements. As with other enzyme replacement therapies, velmanase alfa does not cross the blood-brain-barrier. It should be considered by the treating physician that the administration of velmanase alfa does not affect the irreversible complications (i.e. skeletal deformities, disostosis multiplex, neurological manifestations and impaired cognitive function).

Hypersensitivity

Hypersensitivity reactions have been reported in patients in clinical studies. Appropriate medical support should be readily available when velmanase alfa is administered. If severe allergic or anaphylactic-type reactions occur, immediate discontinuation of velmanase alfa is recommended and current medical standards for emergency treatment are to be followed.

Infusion-related reaction

Administration of velmanase alfa may result in an IRR, including anaphylactoid reaction (see section 4.8). The IRRs observed in clinical studies of velmanase alfa were characterised by a rapid onset of symptoms and were of mild to moderate severity.

The management of IRRs should be based on the severity of the reaction and includes slowing the infusion rate, treatment with medicinal products such as antihistamines, antipyretics and/or corticosteroids, and/or stopping and resuming treatment with increased infusion time. Pre-treatment with antihistamines and/or corticosteroids may prevent subsequent reactions in those cases where symptomatic treatment was required. Patients were not routinely pre-medicated prior to infusion of velmanase alfa during clinical studies.

In case symptoms such as angioedema (tongue or throat swelling), upper airway obstruction or hypotension occur during or immediately after infusion, anaphylaxis or an anaphylactoid reaction should be suspected. In such a case, treatment with an antihistamine and corticosteroids should be considered as being appropriate. In the most severe cases, the current medical standards for emergency treatment are to be observed.

The patient should be kept under observation for IRRs for one hour or longer after the infusion, according to the treating physician’s judgement.

Immunogenicity

Antibodies may play a role in treatment-related reactions observed with the use of velmanase alfa. To further evaluate the relationship, in instances of development of severe IRRs or lack or loss of treatment effect, patients should be tested for the presence of anti-velmanase alfa antibodies. In case the patient’s condition deteriorates during ERT, cessation of treatment should be considered.

There is a potential for immunogenicity.

In the exploratory and pivotal clinical studies at any time under treatment, 8 patients out of 33 (24%) developed IgG-class antibodies to velmanase alfa.

In a paediatric clinical study in patients below 6 years, 4 patients out of 5 (80%) developed IgG-class antibodies to velmanase alfa. In this study, the immunogenicity test was performed with a different and more sensitive method and therefore the incidence of patients developing IgG-class antibodies to velmanase alfa was higher but not comparable to data of the previous studies.

No clear correlation was found between antibody titres (velmanase alfa IgG antibody level) and reduction in efficacy or occurrence of anaphylaxis or other hypersensitivity reactions.

The development of antibodies has not been shown to affect clinical efficacy or safety.

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

No interaction studies have been performed.

Pregnancy

There are no data from the use of velmanase alfa in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). As velmanase alfa aims at normalizing alpha-mannosidase in alpha-mannosidosis patients, Lamzede should be used during pregnancy only when strictly needed.

Breast-feeding

It is unknown whether velmanase alfa or its metabolites are excreted in human milk. Nevertheless, the absorption of any ingested milk-containing velmanase alfa in the breastfed child is considered to be minimal and no untoward effects are therefore anticipated. Lamzede can be used during breastfeeding.

Fertility

There are no clinical data on the effects of velmanase alfa on fertility. Animal studies do not show evidence of impaired fertility.

Lamzede has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

The most common adverse reactions observed were weight increase (15%), IRRs (13%), diarrhoea (10%), headache (7%), arthralgia (7%), increased appetite (5%) and pain in extremity (5%). The majority of these adverse reactions were non-serious. IRRs include hypersensitivity in 3 patients and anaphylactoid reaction in 1 patient. These reactions were mild to moderate in intensity. A total of 4 serious adverse reactions (loss of consciousness in 1 patient, acute renal failure in 1 patient, chills and hyperthermia in 1 patient) were observed. In all cases the patients recovered without sequelae.

Tabulated list of adverse reactions

The adverse reactions reflecting exposure of 38 patients treated with velmanase alfa in clinical studies are listed in the table 1 below. Adverse reactions are classified by system organ class and preferred term according to the MedDRA frequency convention. Frequency is defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1 000 to <1/100), rare (≥1/10 000 to <1/1 000), very rare (<1/10 000) or not known (cannot be estimated from the available data).

Table 1. Adverse reactions reported in clinical studies in patients with alpha-mannosidosis treated with velmanase alfa:

¹ Preferred terms considered as IRR as described in the section below
² Selected adverse reaction as described in the section below

Description of selected adverse reactions

Infusion-related reaction

IRRs (including hypersensitivity, cyanosis, nausea, vomiting, pyrexia, chills, feeling hot, malaise, urticaria, anaphylactoid reaction and hyperhidrosis) were reported in 13% of the patients (5 out of 38 patients) in clinical studies. All were mild or moderate in severity and 2 were reported as a serious adverse event. All patients who experienced IRRs recovered.

Acute renal failure

In the clinical studies, one patient experienced acute renal failure considered possibly related to the study treatment. Acute renal failure was of moderate severity leading to temporary discontinuation of the study treatment and fully resolved within 3 months. Concomitant long-term treatment with high doses of ibuprofen was noted as a potentially causative contributor to the occurrence of the event.

Loss of consciousness

In one patient, loss of consciousness considered related to the study treatment with recovery after a few seconds was reported. The patient received saline infusion in a hospital setting and was then discharged after 6-hour observation. The patient later experienced epileptic seizures that were considered not related.

Paediatric population

Children age below 6 years old

A total of 5 patients with alpha-mannosidosis below 6 years received velmanase alfa in a clinical study. The safety profile was similar to that observed in the previous studies, with similar frequency, type and severity of adverse events

Children age group 6 to 17 years old

The safety profile of velmanase alfa in clinical studies involving children and adolescents was similar to that observed in adult patients. Overall, 58% of patients (19 out of 33) with alpha-mannosidosis receiving velmanase alfa in clinical studies were aged 6 to 17 years at the start of the study.

Reporting of suspected adverse reactions

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.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.