通用中文 | 重组人α-甘露糖苷酶 | 通用外文 | Elmanase alfa |
品牌中文 | 品牌外文 | Lamzede | |
其他名称 | |||
公司 | Chiesi(Chiesi) | 产地 | 德国(Germany) |
含量 | 10mg/5ml | 包装 | 1支/盒 |
剂型给药 | 注射剂 | 储存 | 2度-8度(冰箱冷藏,禁止冷冻) |
适用范围 | 作为一种长期酶替代疗法可用于治疗成人、青少年及儿童的轻度至中度形式的α-甘露糖苷缺乏症 |
通用中文 | 重组人α-甘露糖苷酶 |
通用外文 | Elmanase alfa |
品牌中文 | |
品牌外文 | Lamzede |
其他名称 | |
公司 | Chiesi(Chiesi) |
产地 | 德国(Germany) |
含量 | 10mg/5ml |
包装 | 1支/盒 |
剂型给药 | 注射剂 |
储存 | 2度-8度(冰箱冷藏,禁止冷冻) |
适用范围 | 作为一种长期酶替代疗法可用于治疗成人、青少年及儿童的轻度至中度形式的α-甘露糖苷缺乏症 |
2018年1月26日,欧洲药品管理局(EMA)的人用药品委员会(CHMP)建议为Lamzede(velmanase alfa)授予上市许可,Lamzede作为一种长期酶替代疗法可用于治疗成人、青少年及儿童的轻度至中度形式的α-甘露糖苷缺乏症。
α-甘露糖苷缺乏症是一种罕见性遗传性酶代谢障碍,患者身体的许多器官和组织中富集了甘露糖的低聚糖从而引起细胞损伤。受此病影响的患者可能有智力障碍,肝脾肿大,面部特征和骨骼异常。α-甘露糖苷缺乏症的症状范围从轻度、中度到重度。重度患儿的生存期通产不会超过童年时期,而那些受轻度疾病影响的个体则可以存活到成年期。作为一种罕见病,据估计全世界大约有50万至1百万人患有这种疾病。
Lamzede是一种重组人α-甘露糖苷酶,作为静脉内酶替代疗法(ERT)用于治疗α-甘露糖苷缺乏症。 治疗目的是将该药物注入血液内,以取代体内缺乏酶的功能。ERT旨在使身体中的寡糖水平正常化,以防止疾病的发展,并改善患者的生存状况。然而,Lamzede不能穿过血脑屏障,因此该药物预计不会影响疾病的神经方面。
velmanase alfa
An overview of Lamzede and why it is authorised in the EU
Lamzede is a medicine used for patients with mild to moderate alpha-mannosidosis. It is used for treating effects of the disease that do not involve the brain (non-neurological effects).
Alpha-mannosidosis is an inherited disease with features that include learning disability, difficulty controlling movement, deafness, speaking difficulty, frequent infections, enlarged liver and spleen, bone abnormalities, and muscle pain and weakness.
Lamzede contains the active substance velmanase alfa.
Alpha-mannosidosis is rare, and Lamzede was designated an ‘orphan medicine’ (a medicine used in rare diseases) on 26 January 2005.
How is Lamzede used?
Lamzede can only be obtained with a prescription. Treatment should be supervised by a doctor experienced in treating alpha-mannosidosis or in giving enzyme replacement treatments for similar conditions.
Lamzede is given by infusion (drip) into a vein at a dose of 1 mg per kg of body weight once a week. The infusion is given over at least 50 minutes, using a pump to control the speed of infusion.
For more information about using Lamzede, see the package leaflet or contact your doctor or pharmacist.
How does Lamzede work?
Patients with alpha-mannosidosis lack an enzyme called alpha-mannosidase which is important for breaking down certain glycosides (substances that contain proteins and sugars). As a result, certain oligosaccharides (types of sugar) build up in the body and cause damage. The active substance in Lamzede, velmanase alfa, acts in the same way as alpha-mannosidase. In this way, Lamzede prevents worsening of some body functions (such as breathing and movement) caused by the build-up of oligosaccharides.
What benefits of Lamzede have been shown in studies?
One main study involving 25 patients with alpha-mannosidosis found Lamzede more effective than placebo (a dummy treatment) at treating non-neurological effects of alpha-mannosidosis. Two main measures of effectiveness were used: a change in the level of oligosaccharides in patients’ blood after a year of treatment and physical endurance measured as a change in the number of steps the patient could climb on a staircase. The levels of oligosaccharides decreased, on average, three times as much in patients receiving Lamzede compared with those receiving placebo. After treatment for one year, patients receiving Lamzede could climb about half a step more in 1 minute than they could previously, while patients receiving placebo could climb two steps less.
What are the risks associated with Lamzede?
The most common side effects with Lamzede (which may affect up to 1 in 10 people) are weight gain, infusion-related reactions (such as allergic reactions, nausea, vomiting, fever, chills, feeling unwell and itchiness), diarrhoea, headache, joint pain, pain in the arms and legs and increased appetite.
For the full list of side effects and restrictions with Lamzede, see the package leaflet.
Why is Lamzede authorised in the EU?
The European Medicines Agency decided that Lamzede’s benefits are greater than its risks and it can be authorised for use in the EU. Lamzede lowers the levels of oligosaccharides in the blood and it is better than placebo at slowing down the worsening of many disease effects. The Agency noted that the medicine does not appear to reach the brain and it does not improve effects such as loss of hearing or loss of control over movement. Lamzede’s side effects are manageable.
Lamzede has been authorised under ‘exceptional circumstances’. This is because it has not been possible to obtain complete information about Lamzede due to the rarity of the disease. Every year, the Agency will review any new information that becomes available and this overview will be updated as necessary.
What information is still awaited for Lamzede?
Since Lamzede has been authorised under exceptional circumstances, the company that markets the medicine will set up a registry of patients treated with Lamzede and provide additional information on the long-term effectiveness and safety of the medicine as well as the medicine’s effects on variants of the condition. The company will also provide results of a 2-year study looking at the safety and effectiveness of Lamzede in children aged up to 6 years.
What measures are being taken to ensure the safe and effective use of Lamzede?
Recommendations and precautions to be followed by healthcare professionals and patients for the safe and effective use of Lamzede have been included in the summary of product characteristics and the package leaflet.
As for all medicines, data on the use of Lamzede is continuously monitored. Side effects reported with Lamzede are carefully evaluated and any necessary action taken to protect patients.
Other information about Lamzede
Lamzede received a marketing authorisation valid throughout the EU on 23 March 2018.
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.
1. NAME OF THE MEDICINAL PRODUCT
Lamzede 10 mg powder for solution for infusion
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
One vial contains 10 mg of velmanase alfa*.
After reconstitution, one mL of the solution contains 2 mg of velmanase alfa (10 mg / 5 mL). For the full list of excipients, see section 6.1.
*Velmanase alfa is produced in mammalian Chinese Hamster Ovary (CHO) cells using recombinant DNA technology.
3. PHARMACEUTICAL FORM
Powder for solution for infusion. White to off-white powder.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Enzyme replacement therapy for the treatment of non-neurological manifestations in patients with mild to moderate alpha-mannosidosis. See sections 4.4 and 5.1.
4.2 Posology and method of administration
The treatment should be supervised by a physician experienced in the management of patients with alpha-mannosidosis or in the administration of other enzyme replacement therapies (ERT) for lysosomal storage disorder. Administration of Lamzede should be carried out by a healthcare professional with the ability to manage ERT and medical emergencies.
Posology
The recommended dose regimen is 1 mg/kg of body weight administered once every week by intravenous infusion at a controlled speed. For infusion rate see section “Method of administration”.
Special populations
Renal or hepatic impairment
No dose adjustment is necessary for patients with renal or hepatic impairment.
Elderly
No data are available and no relevant use in elderly patients is described.
Paediatric population
No dose adjustment is necessary for the paediatric population.
Method of administration
For intravenous infusion use only.
For instructions on reconstitution of the medicinal product before administration, see section 6.6.
The reconstituted solution of Lamzede should be administered using an infusion set equipped with a pump and an in-line low protein-binding 0.22 µm filter. The infusion duration should be calculated individually considering a maximum infusion rate of 25 mL/hour to control the protein load. The infusion duration should be a minimum of 50 minutes. A slower infusion rate may be prescribed when clinically appropriate according to the physician’s judgment, for example at the beginning of the treatment or in case of previous infusion-related reactions (IRRs).
For the calculation of the infusion rate and the infusion time based on body weight see the table in section 6.6.
The patient should be observed for IRRs for at least one hour after the infusion according to clinical conditions and the physician’s judgment. For further instructions, see section 4.4.
4.3 Contraindications
Severe allergic reaction to the active substance or to any of the excipients listed in section 6.1.
4.4 Special warnings and precautions for use
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 clinical studies at any time under treatment, 8 patients out of 33 (24%) developed IgG-class antibodies to velmanase alfa. 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. Sodium content
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.
4.5 Interaction with other medicinal products and other forms of interaction
No interaction studies have been performed.
4.6 Fertility, pregnancy and lactation
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.
4.7 Effects on ability to drive and use machines
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 (18%), IRRs (9%), diarrhoea (12%), headache (9%), arthralgia (9%), increased appetite (6%) and pain in extremity (6%).
All of these adverse reactions were non-serious. IRRs include hypersensitivity in 3 patients and anaphylactoid reaction in 1 patient. These reactions were non-serious and mild to moderate in intensity.
A total of 2 serious adverse reactions (loss of consciousness in 1 patient and acute renal failure in 1 patient) were observed. In both cases the patients recovered without sequelae.
Tabulated list of adverse reactions
The adverse reactions reflecting exposure of 33 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
System organ class |
Adverse reaction |
Frequency |
Immune system disorders |
Hypersensitivity(1) |
Common |
Anaphylactoid reaction(1) |
Common |
|
Metabolism and nutrition disorders |
Increased appetite |
Common |
Psychiatric disorders |
Psychotic behaviour |
Common |
Initial insomnia |
Common |
|
Nervous system disorders |
Confusional state |
Common |
Loss of consciousness(2) |
Common |
|
Syncope |
Common |
|
Tremor |
Common |
|
Dizziness |
Common |
|
Headache |
Common |
|
Eye disorders |
Eye irritation |
Common |
Eyelid oedema |
Common |
|
Ocular hyperaemia |
Common |
|
Cardiac disorders |
Bradycardia |
Common |
Respiratory, thoracic and mediastinal disorders |
Epistaxis |
Common |
Gastrointestinal disorders |
Diarrhoea |
Very common |
Abdominal pain |
Common |
|
Abdominal pain upper |
Common |
|
Nausea(1) |
Common |
|
Vomiting(1) |
Common |
|
Reflux gastritis |
Common |
|
Skin and subcutaneous tissue disorders |
Urticaria(1) |
Common |
Hyperhidrosis(1) |
Common |
|
Musculoskeletal and connective tissue disorders |
Arthralgia |
Common |
Back pain |
Common |
|
Joint stiffness |
Common |
|
Myalgia |
Common |
|
Pain in extremity |
Common |
System organ class |
Adverse reaction |
Frequency |
Renal and urinary disorders |
Renal failure acute(2) |
Common |
General disorder and administration site conditions |
Pyrexia(1) |
Very common |
Catheter site pain |
Common |
|
Chills(1) |
Common |
|
Feeling hot(1) |
Common |
|
Fatigue |
Common |
|
Malaise(1) |
Common |
|
Investigations |
Weight increase |
Very common |
Injury, poisoning and procedural complications |
Procedural headache |
Common |
(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, nausea, vomiting, pyrexia, chills, feeling hot, malaise, urticaria, anaphylactoid reaction and hyperhidrosis) were reported in 9% of the patients (3 out of 33 patients) in clinical studies. All were mild or moderate in severity and none 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
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.
4.9 Overdose
There is no experience with overdose of velmanase alfa. The maximum dose of velmanase alfa in clinical studies was a single administration of 100 units/kg (approximately corresponding to
3.2 mg/kg). During the infusion with this higher dose, fever of mild intensity and short duration (5 hours) was observed in one patient. No treatment was administered.
For the management of adverse reactions, see sections 4.4 and 4.8.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Other alimentary tract and metabolism products, enzymes. ATC code: A16AB15.
Mechanism of action
Velmanase alfa, the active substance of Lamzede, is a recombinant form of human alpha-mannosidase. The amino acid sequence of the monomeric protein is identical to the naturally occurring human enzyme, alpha-mannosidase.
Velmanase alfa is intended to supplement or replace natural alpha-mannosidase, an enzyme that catalyses the sequential degradation of hybrid and complex high-mannose oligosaccharides in the lysosome, reducing the amount of accumulated mannose-rich oligosaccharides.
Clinical efficacy and safety
A total of 33 patients (20 males and 13 females, ranging in age from 6 to 35 years) were exposed to velmanase alfa in five clinical studies. Patients were diagnosed based on alpha-mannosidase activity
<10% of normal activity in blood leukocytes. Patients with the most severe rapidly progressing phenotype (with a deterioration within one year and central nervous system involvement) were excluded. Based on this criteria mild to moderate patients, presenting heterogeneous severity with ability to perform endurance tests, large variability of clinical manifestations and age of onset were enrolled.
Overall effects of treatment were evaluated in the domains of pharmacodynamics (reduction of serum oligosaccharides), functional (three-minute stair climbing test (3MSCT), six-minute walking test (6MWT), and forced vital capacity (FVC) % predicted) and quality of life (childhood health assessment questionnaire (CHAQ) disability index (DI) and CHAQ VAS pain (visual analogue scale)).
In the phase 3 pivotal multi-centre, double-blind, randomised, placebo-controlled, parallel group study rhLAMAN-05, the efficacy and safety of repeated administrations of velmanase alfa over 52 weeks at a dose of 1 mg/kg given weekly as intravenous infusion were investigated. A total of 25 patients were enrolled, including 12 paediatric subjects (age range: 6 to 17 years; mean: 10.9 years) and 13 adult subjects (age range: 18 to 35 years; mean: 24.6). All but one patient were naïve to the treatment with velmanase alfa. In total 15 patients (7 paediatrics and 8 adults) received active treatment and
10 patients received placebo (5 paediatrics and 5 adults). The results (serum oligosaccharide concentration, 3MSCT, 6MWT and FVC%) are presented in table 2. A pharmacodynamic effect with statistically significant decrease of serum oligosaccharides in comparison to placebo was demonstrated. The results observed in patients below 18 years of age showed an improvement. In patients over 18 years old a stabilisation has been demonstrated. The numerical improvement of most clinical endpoints over placebo (2 to 8 %) observed in the year of observation could be suggestive of the ability of velmanase alfa to slow down the existing disease progression.
|
Treatment with velmanase alfa for 12 months (n=15) |
Treatment with placebo for 12 months (n=10) |
Velmanase alfa vs. placebo |
||
Patients |
Baseline actual value Mean (SD) |
Absolute change from baseline Mean |
Baseline actual value Mean (SD) |
Absolute change from baseline Mean |
Adjusted mean difference |
Serum oligosaccharide concentration (μmol/l) |
|||||
Overall(1) |
6.8 (1.2) |
-5.11 |
6.6 (1.9) |
-1.61 |
-3.50 |
[95% CI] |
|
[-5.66; -4.56] |
|
[-2.28; -0.94] |
[-4.37; -2.62] |
p-value |
|
|
|
|
p<0.001 |
<18 years(2) |
7.3 (1.1) |
-5.2 (1.5) |
6.0 (2.4) |
-0.8 (1.7) |
- |
≥18 years(2) |
6.3 (1.1) |
-5.1 (1.0) |
7.2 (1.0) |
-2.4 (1.4) |
|
3MSCT (steps/min) |
|||||
Overall(1) |
52.9 (11.2) |
0.46 |
55.5 (16.0) |
-2.16 |
2.62 |
[95% CI] |
|
[-3.58; 4.50] |
|
[-7.12; 2.80] |
[-3.81; 9.05] |
p-value |
|
|
|
|
p=0.406 |
<18 years(2) |
56.2 (12.5) |
3.5 (10.0) |
57.8 (12.6) |
-2.3 (5.4) |
- |
≥18 years(2) |
50.0 (9.8) |
-1.9 (6.7) |
53.2 (20.1) |
-2.5 (6.2) |
|
6MWT (metres) |
|||||
Overall(1) |
459.6 (72.26) |
3.74 |
465.7 (140.5) |
-3.61 |
7.35 |
[95% CI] |
|
[-20.32; 27.80] |
|
[-33.10; 25.87] |
[-30.76; 45.46] |
p-value |
|
|
|
|
p=0.692 |
<18 years(2) |
452.4 (63.9) |
12.3 (43.2) |
468.8 (79.5) |
3.6 (43.0) |
- |
≥18 years(2) |
465.9 (82.7) |
-2.5 (50.4) |
462.6 (195.1) |
-12.8 (41.6) |
|
FVC (% of predicted) |
|||||
Overall(1) |
81.67 (20.66) |
8.20 |
90.44 (10.39) |
2.30 |
5.91 |
[95% CI] |
|
[1.79; 14.63] |
|
[-6.19; 10.79] |
[-4.78; 16.60] |
p-value |
|
|
|
|
p=0.278 |
<18 years(2) |
69.7 (16.8) |
14.2 (8.7) |
88.0 (10.9) |
8.0 (4.2) |
- |
≥18 years(2) |
93.7 (17.7) |
2.2 (7.2) |
92.4 (10.8) |
-2.8 (15.5) |
(1) For overall: adjusted mean change and adjusted mean difference estimated by ANCOVA model are presented
(2) By age: unadjusted mean and SD are presented.
The long-term efficacy and safety of velmanase alfa was investigated in the uncontrolled, open label, phase 3 clinical study rhLAMAN-10 in 33 subjects (19 paediatrics and 14 adults, from 6 to 35 years at treatment initiation) who previously participated in velmanase alfa studies. An integrated database was created by pooling cumulative databases from all studies with velmanase alfa. Statistically significant improvements were detected in serum oligosaccharide levels, 3MSCT, pulmonary function, serum IgG
and EQ-5D-5L (euro quality of life-5 dimensions) over time, up to the last observation (table 3). The effects of velmanase alfa were more evident in patients younger than 18 years.
Table 3: Change of clinical endpoints from baseline to the last observation in rhLAMAN-10 study (source data: rhLAMAN-10)
Parameter |
Patients n=33 |
Baseline actual value Mean (SD) |
Last observation % change from baseline (SD) |
p-value [95% CI] |
Serum oligosaccharide concentration (µmol/L) |
Overall |
6.90 (2.30) |
-62.8 (33.61) |
<0.001 [-74.7; -50.8] |
3MSCT (steps/min) |
Overall |
53.60 (12.53) |
13.77 (25.83) |
0.004 [4.609; 22.92] |
6MWT (metres) |
Overall |
466.6 (90.1) |
7.1 (22.0) |
0.071 [-0.7; 14.9] |
FVC (% of predicted) |
Overall |
84.9 (18.6) |
10.5 (20.9) |
0.011 [2.6; 18.5] |
Data suggest that the beneficial effects of the treatment with velmanase alfa diminish with the increase of disease burden and disease-related respiratory infections.
A post-hoc multiparametric responders analysis supports the benefit of longer treatment with velmanase alfa in 87.9% of responders in at least 2 domains at last observation (table 4).
Table 4: Multiparametric responder analysis: MCID(1) Responders Rates by Endpoints and Domains (source data: rhLAMAN-05; rhLAMAN-10)
Domain |
Criterion |
Responders Rates |
||
rhLAMAN-05 study n=25 |
rhLAMAN-10 study n=33 |
|||
Placebo 12 months |
Lamzede 12 months |
Lamzede Last Observation |
||
Pharmacodynamic |
Oligosaccharides |
20.0% |
100% |
91.0% |
Pharmacodynamic Domain Response |
Oligosaccharides |
20.0% |
100% |
91.0% |
Functional |
3MSCT |
10.0% |
20.0% |
48.5% |
6MWT |
10.0% |
20.0% |
48.5% |
|
FVC (%) |
20.0% |
33.3% |
39.4% |
|
Functional Domain Response |
Combined |
30.0% |
60.0% |
72.7% |
Quality of Life |
CHAQ-DI |
20.0% |
20.0% |
42.2% |
CHAQ-VAS |
33.3% |
40.0% |
45.5% |
|
QoL Domain |
Combined |
40.0% |
40.0% |
66.7% |
Overall response |
Three domains |
0 |
13.3% |
45.5% |
Two domains |
30.0% |
73.3% |
42.4% |
|
One domain |
30.0% |
13.3% |
9.1% |
|
No domains |
40.0% |
0 |
3.0% |
(1) MCID: minimal clinically important difference Paediatric population
Use of velmanase alfa in the age group 6 to 17 years is supported by evidence from clinical studies in paediatric (19 out of 33 patients) and adult patients. No clinical data are available in children below the age of 6 years.
The European Medicines Agency has deferred the obligation to submit the results of studies with Lamzede in one or more subsets of the paediatric population in the treatment of alpha-mannosidosis disease (see section 4.2 for information on paediatric use).
This medicinal product has been authorised under ‘exceptional circumstances’. This means that due to the rarity of the disease, it has not been possible to obtain complete information on this medicinal product.
The European Medicines Agency will review any new information which may become available every year and this SmPC will be updated as necessary.
5.2 Pharmacokinetic properties
There were no apparent pharmacokinetic gender differences in patients with alpha-mannosidosis disease.
Absorption
Lamzede is administered through intravenous infusion. At steady-state after weekly infusion administration of 1 mg/kg of velmanase alfa, the mean maximum plasma concentration was about 8 µg/mL and was reached at 1.8 hours after the start of administration corresponding to the mean infusion duration time.
Distribution
As expected for a protein of this size, the steady-state volume of distribution was low (0.27 L/kg), indicating distribution confined to plasma. The clearance of velmanase alfa from plasma (mean
6.7 mL/h/kg) is consistent with a rapid cellular uptake of velmanase alfa via mannose receptors.
Biotransformation
The metabolic pathway of velmanase alfa is predicted to be similar to other natural occurring proteins that degrade into small peptides and finally into amino acids.
Elimination
After the end of the infusion, velmanase alfa plasma concentrations fell in a biphasic fashion with a mean terminal elimination half-life of about 30 hours.
Linearity/(Non)linearity
Velmanase alfa exhibited a linear (i.e. first-order) pharmacokinetic profile, and Cmax and AUC increased proportionally to the dose with doses ranging from 0.8 to 3.2 mg/kg (corresponding to 25 and 100 units/kg).
Special populations
Velmanase alfa is a protein and is predicted to be metabolically degraded into amino acids. Proteins larger than 50,000 Da, such as velmanase alfa, are not eliminated renally. Consequently hepatic and renal impairment are not expected to affect the pharmacokinetic of velmanase alfa. As no patients older than 41 years have been identified across Europe, no relevant use in elderly patients is expected.
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, juvenile toxicity and toxicity to reproduction and development.
6.1 List of excipients
Disodium phosphate dihydrate
Sodium dihydrogen phosphate dihydrate Mannitol
Glycine
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
6.3 Shelf life
2 years.
Reconstituted solution for infusion
Chemical and physical in-use stability has been demonstrated for 24 hours at 2°C - 8°C.
From a microbiological point of view, the medicinal product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C.
6.4 Special precautions for storage
Store and transport refrigerated (2°C - 8°C).
Store in the original package in order to protect from light.
For storage conditions after reconstitution of the medicinal product, see section 6.3.
6.5 Nature and contents of container
10 mL vial (Type I glass) with a bromobutyl rubber stopper, an aluminium seal and a polypropylene flip off cap.
Each vial contains 10 mg of velmanase alfa.
Pack sizes of 1, 5 or 10 vials per carton. Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Lamzede requires reconstitution and is intended for intravenous infusion only. Each vial is for single use only.
Instructions for reconstitution and administration
Lamzede should be reconstituted and administrated by a healthcare professional.
Aseptic technique is to be used during preparation. Filter needles must not be used during preparation.
a) The number of vials to be used should be calculated based on the individual patient’s weight. The recommended dose of 1 mg/kg is determined using the following calculation:
- Patient’s weight (kg) × dose (mg/kg) = Patient dose (in mg)
- Patient dose (in mg) divided by 10 mg/vial (content of one vial) = number of vials to reconstitute. If the number of calculated vials includes a fraction, it should be rounded up to the next whole number.
- Approximately 30 minutes prior to reconstitution, the required number of vials should be removed from the refrigerator. The vials should reach ambient temperature (between 15°C and 25°C) prior to reconstitution.
Each vial is reconstituted by slowly injecting 5 mL of water for injections to the inside of the wall of each vial. Each mL of reconstituted solution contains 2 mg of velmanase alfa. Only the volume corresponding to the recommended dose should be administered.
Example:
- Patient’s weight (44 kg) × dose (1 mg/kg) = Patient dose (44 mg)
- 44 mg divided by 10 mg/vial = 4.4 vials, therefore, 5 vials should be reconstituted.
- From the total reconstituted volume, only 22 mL (corresponding to 44 mg) should be administered.
b) The powder should be reconstituted in the vial by a slow drop-wise addition of the water for injections down the inside of the vial and not directly onto the lyophilised powder. Forcefully ejecting the water for injections from the syringe onto the powder should be avoided to minimise foaming. The reconstituted vials should stand on the table for about 5-10 minutes. Thereafter each vial should be tilted and rolled gently for 15-20 seconds to enhance the dissolution process. The vial should not be inverted, swirled, or shaken.
c) An immediate visual inspection of the solution for particulate matter and discoloration should be performed after reconstitution. The solution should be clear and not used if opaque particles are observed or if the solution is discoloured. Due to the nature of the medicinal product, the reconstituted solution may occasionally contain some proteinaceous particles in form of thin white strands or translucent fibers which will be removed by the in-line filter during infusion (see point e).
d) The reconstituted solution is to be slowly withdrawn from each vial with caution to avoid foaming in the syringe. If the volume of the solution exceeds one syringe capacity, the required number of syringes should be prepared in order to replace the syringe quickly during the infusion.
e) The reconstituted solution should be administered using an infusion set equipped with a pump and an in-line low protein-binding 0.22 μm filter.
The total volume of infusion is determined by the patient’s weight and should be administrated over a minimum of 50 minutes. For patients weighing less than 18 kg, and receiving less than 9 mL reconstituted solution, the infusion rate should be calculated so that the infusion time is
≥50 minutes. The maximum infusion rate is 25 mL/hour (see section 4.2). The infusion time can be calculated from the following table:
Patient weight (kg) |
Dose (mL) |
Maximum infusion rate (mL/h) |
Minimum infusion time (min) |
|
Patient weight (kg) |
Dose (mL) |
Maximum infusion rate (mL/h) |
Minimum infusion time (min) |
5 |
2.5 |
3 |
50 |
53 |
26.5 |
25 |
64 |
|
6 |
3 |
3.6 |
50 |
54 |
27 |
25 |
65 |
|
7 |
3.5 |
4.2 |
50 |
55 |
27.5 |
25 |
67 |
|
8 |
4 |
4.8 |
50 |
56 |
28 |
25 |
67 |
|
9 |
4.5 |
5.4 |
50 |
57 |
28.5 |
25 |
68 |
|
10 |
5 |
6 |
50 |
58 |
29 |
25 |
70 |
|
11 |
5.5 |
6.6 |
50 |
59 |
29.5 |
25 |
71 |
|
12 |
6 |
7.2 |
50 |
60 |
30 |
25 |
72 |
|
13 |
6.5 |
7.8 |
50 |
61 |
30.5 |
25 |
73 |
|
14 |
7 |
8.4 |
50 |
62 |
31 |
25 |
74 |
|
15 |
7.5 |
9 |
50 |
63 |
31.5 |
25 |
76 |
|
16 |
8 |
9.6 |
50 |
64 |
32 |
25 |
77 |
Patient weight (kg) |
Dose (mL) |
Maximum infusion rate (mL/h) |
Minimum infusion time (min) |
|
Patient weight (kg) |
Dose (mL) |
Maximum infusion rate (mL/h) |
Minimum infusion time (min) |
17 |
8.5 |
10.2 |
50 |
65 |
32.5 |
25 |
78 |
|
18 |
9 |
10.8 |
50 |
66 |
33 |
25 |
79 |
|
19 |
9.5 |
11.4 |
50 |
67 |
33.5 |
25 |
80 |
|
20 |
10 |
12 |
50 |
68 |
34 |
25 |
82 |
|
21 |
10.5 |
12.6 |
50 |
69 |
34.5 |
25 |
83 |
|
22 |
11 |
13.2 |
50 |
70 |
35 |
25 |
84 |
|
23 |
11.5 |
13.8 |
50 |
71 |
35.5 |
25 |
85 |
|
24 |
12 |
14.4 |
50 |
72 |
36 |
25 |
86 |
|
25 |
12.5 |
15 |
50 |
73 |
36.5 |
25 |
88 |
|
26 |
13 |
15.6 |
50 |
74 |
37 |
25 |
89 |
|
27 |
13.5 |
16.2 |
50 |
75 |
37.5 |
25 |
90 |
|
28 |
14 |
16.8 |
50 |
76 |
38 |
25 |
91 |
|
29 |
14.5 |
17.4 |
50 |
77 |
38.5 |
25 |
92 |
|
30 |
15 |
18 |
50 |
78 |
39 |
25 |
94 |
|
31 |
15.5 |
18.6 |
50 |
79 |
39.5 |
25 |
95 |
|
32 |
16 |
19.2 |
50 |
80 |
40 |
25 |
96 |
|
33 |
16.5 |
19.8 |
50 |
81 |
40.5 |
25 |
97 |
|
34 |
17 |
20.4 |
50 |
82 |
41 |
25 |
98 |
|
35 |
17.5 |
21 |
50 |
83 |
41.5 |
25 |
100 |
|
36 |
18 |
21.6 |
50 |
84 |
42 |
25 |
101 |
|
37 |
18.5 |
22.2 |
50 |
85 |
42.5 |
25 |
102 |
|
38 |
19 |
22.8 |
50 |
86 |
43 |
25 |
103 |
|
39 |
19.5 |
23.4 |
50 |
87 |
43.5 |
25 |
104 |
|
40 |
20 |
24 |
50 |
88 |
44 |
25 |
106 |
|
41 |
20.5 |
24.6 |
50 |
89 |
44.5 |
25 |
107 |
|
42 |
21 |
25 |
50 |
90 |
45 |
25 |
108 |
|
43 |
21.5 |
25 |
52 |
91 |
45.5 |
25 |
109 |
|
44 |
22 |
25 |
53 |
92 |
46 |
25 |
110 |
|
45 |
22.5 |
25 |
54 |
93 |
46.5 |
25 |
112 |
|
46 |
23 |
25 |
55 |
94 |
47 |
25 |
113 |
|
47 |
23.5 |
25 |
56 |
95 |
47.5 |
25 |
114 |
|
48 |
24 |
25 |
58 |
96 |
48 |
25 |
115 |
|
49 |
24.5 |
25 |
59 |
97 |
48.5 |
25 |
116 |
|
50 |
25 |
25 |
60 |
98 |
49 |
25 |
118 |
|
51 |
25.5 |
25 |
61 |
99 |
49.5 |
25 |
119 |
|
52 |
26 |
25 |
62 |
|
f) When the last syringe is empty, the dosage syringe is replaced with a 20 mL syringe filled with sodium chloride 9 mg/mL (0.9%) solution for injection. A volume of 10 mL sodium chloride solution should be administered through the infusion system to infuse the remaining fraction of Lamzede in the line to the patient.
Disposal
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Chiesi Farmaceutici S.p.A. Via Palermo 26/A
43122 Parma Italy
8. MARKETING AUTHORISATION NUMBER
EU/1/17/1258/001 EU/1/17/1258/002 EU/1/17/1258/003
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: {DD/MM/YYYY}
10. DATE OF REVISION OF THE TEXT
{MM/YYYY}
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.
ANNEX II
A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
E. SPECIFIC OBLIGATION TO COMPLETE POST- AUTHORISATION MEASURES FOR THE MARKETING AUTHORISATION UNDER EXCEPTIONAL CIRCUMSTANCES
A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
Name and address of the manufacturer of the biological active substance
Rentschler Biopharma SE Erwin-Rentschler-Strasse 21
88471 Laupheim Germany
Name and address of the manufacturer responsible for batch release
Chiesi Farmaceutici S.p.A. Via San Leonardo, 96 43122 Parma
Italy
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product Characteristics, section 4.2).
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
· Periodic Safety Update Reports
The requirements for submission of periodic safety update reports for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal.
The marketing authorisation holder shall submit the first periodic safety update report for this product within 6 months following authorisation.
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
· Risk Management Plan (RMP)
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent updates of the RMP.
An updated RMP should be submitted:
· At the request of the European Medicines Agency;
· Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached.
This being an approval under exceptional circumstances and pursuant to Article 14(8) of Regulation (EC) No 726/2004, the MAH shall conduct, within the stated timeframe, the following measures:
Description |
Due date |
In order to obtain long-term data on effectiveness and safety of treatment with Lamzede and to characterize the entire alpha-mannosidosis population, including variability of clinical manifestation, progression and natural history, the MAH is requested to submit the results of a study based on adequate source of data deriving from a registry of patients with alpha-mannosidosis. |
Annual reports to be submitted as part of the annual re- assessment |
Paediatric Study rhLAMAN-08. A 24 month multi-center, open label phase II trial investigating the safety and efficacy of repeated velmanase alfa (recombinant human alpha-mannosidase) treatment in paediatric patients <6 years of age with alpha-mannosidosis. |
Final Study report: November 2020 |
ANNEX III
LABELLING AND PACKAGE LEAFLET
A. LABELLING
Lamzede 10 mg powder for solution for infusion velmanase alfa
|
One vial contains 10 mg of velmanase alfa.
After reconstitution, one mL of the solution contains 2 mg of velmanase alfa (10 mg / 5 mL).
|
Disodium phosphate dihydrate
Sodium dihydrogen phosphate dihydrate Mannitol
Glycine
Powder for solution for infusion 1 vial
5 vials 10 vials
|
Read the package leaflet before use. Intravenous use.
|
Keep out of the sight and reach of children.
|
EXP
Store and transport refrigerated.
Store in the original package in order to protect from light.
After reconstitution, the medicinal product should be used immediately. If not used immediately, the reconstituted solution should be stored in a refrigerator for no longer than 24 hours.
|
|
Chiesi Farmaceutici S.p.A. Via Palermo 26/A
43122 Parma Italy
|
EU/1/17/1258/001 EU/1/17/1258/002 EU/1/17/1258/003
|
Lot
|
|
|
Justification for not including Braille accepted.
|
2D barcode carrying the unique identifier included.
|
PC: {number} SN: {number} NN: {number}
|
Lamzede 10 mg powder for solution for infusion velmanase alfa
Intravenous use
|
Read the package leaflet before use
|
EXP
|
Lot
|
10 mg velmanase alfa
|
B. PACKAGE LEAFLET
Package leaflet: Information for the patient
Lamzede 10 mg powder for solution for infusion
velmanase alfa
This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects.
Read all of this leaflet carefully before you start using this medicine because it contains important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
- If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this leaflet. See section 4.
What is in this leaflet
1. What Lamzede is and what it is used for
2. What you need to know before Lamzede is used
3. How Lamzede is used
4. Possible side effects
5. How Lamzede is stored
6. Contents of the pack and other information
1. What Lamzede is and what it is used for
Lamzede contains the active substance velmanase alfa which belongs to a group of medicines known as enzyme replacement therapies. It is used to treat patients with mild to moderate alpha-mannosidosis disease. It is given for the treatment of non-neurological symptoms of the disease.
Alpha-mannosidosis disease is a rare genetic disorder caused by a lack of an enzyme named
alpha-mannosidase, which is needed to break down certain sugar compounds (called ‘mannose-rich oligosaccharides’) in the body. When this enzyme is missing or does not work properly, these sugar compounds build up inside cells and cause the signs and symptoms of the disease. The typical manifestations of the disease include distinctive facial features, mental retardation, difficulty in controlling movements, difficulties in hearing and speaking, frequent infections, skeletal problems, muscle pain and weakness.
Velmanase alfa is designed to replace the missing enzyme in patients with alpha-mannosidosis disease. This may improve the symptoms of the disease.
2. What you need to know before Lamzede is used Lamzede must not be used:
- if you are allergic to velmanase alfa or any of the other ingredients of this medicine (listed in section 6).
Warnings and precautions
Talk to your doctor before Lamzede is used.
If you are treated with Lamzede, you may experience a side effect during or immediately following the drip (infusion) used to give the medicine (see section 4). This is known as an infusion-related reaction and can sometimes be severe.
- Infusion-related reactions include dizziness, headache, nausea, low blood pressure, tiredness and fever. If you experience an infusion-related reaction, you must tell your doctor immediately.
- If you have an infusion-related reaction you may be given additional medicines to treat or help prevent future reactions. These medicines may include medicines used to treat allergies (antihistamines), medicines used to treat fever (antipyretics) and medicines to control inflammation (corticosteroids).
- If the infusion-related reaction is severe, your doctor will stop the infusion immediately and start giving you appropriate medical treatment.
- If the infusion-related reactions are severe and/or there is a loss of effect from this medicine, your doctor will perform a blood test to check for antibodies that might affect the outcome of your treatment.
- Most of the time you can still be given Lamzede even if you experience an infusion-related reaction.
Other medicines and Lamzede
Tell your doctor if you are taking, have recently taken or might take any other medicines.
Pregnancy and breast-feeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before this medicine is used.
Lamzede should be used during pregnancy only when medically necessary. It is not known whether velmanase alfa passes into breast milk. Lamzede can be used during breast-feeding.
Driving and using machines
Lamzede has no or negligible influence on the ability to drive and use machines.
Lamzede contains sodium
This medicine contains less than 1 mmol sodium (23 mg) per dosage unit, that is to say essentially ‘sodium-free’.
3. How Lamzede is used
This medicine is only to be used under the supervision of a doctor experienced in the treatment of alpha-mannosidosis or other similar diseases and should only be given by a healthcare professional.
Dosage
The recommended dose of Lamzede is 1 mg/kg of body weight given once every week.
Use in children and adolescents
Lamzede may be given to children and adolescents at the same dose and frequency as in adults. There is no experience with patients younger than 6 years of age.
Administration
Lamzede is supplied in a vial as a powder for infusion which will be made up with water for injections before being given.
Once it has been made up, the medicine will be given by infusion pump (drip) into a vein over a period of at least 50 minutes under your doctor’s supervision.
If you have any further questions on the use of this medicine, ask your doctor.
Like all medicines, this medicine can cause side effects, although not everybody gets them. Most side effects occur during the infusion or shortly after (“infusion-related reaction”, see section 2 Warnings and precautions).
While under treatment with Lamzede, you may experience some of the following reactions:
Serious side effects
Common side effects (may affect up to 1 in 10 people)
- loss of consciousness (fainting, which may be preceded by feeling dizzy, lightheaded or confused)
- acute renal insufficiency (kidney problems which can be recognised from fluid retention, swelling in legs, ankles or feet, drowsiness, shortness of breath or fatigue)
- hypersensitivity and serious allergic reaction (symptoms including localised or diffuse skin itching, dizziness, difficulty breathing, chest pain, gastrointestinal symptoms such as nausea, vomiting, diarrhea or intestinal pain, swelling of the throat, face, lips or tongue)
If you experience any side effect like these, please tell your doctor immediately. Other side effects
Very common side effects (may affect more than 1 in 10 people)
- diarrhoea
- weight increase
- fever/increased body temperature
Common side effects (may affect up to 1 in 10 people)
- low heart beat (bradycardia)
- psychotic behaviour (mental illness with hallucinations, difficulty in thinking clearly and understanding reality, anxiety), initial difficulty in sleeping
- confused state, fainting, tremor, dizziness, headache
- intestinal (abdominal) pain, irritation of the stomach caused by digestive acids (reflux gastritis), nausea, vomiting
- pain at the site the infusion is given, chills, feeling hot, malaise, tiredness (fatigue)
- skin rashes (urticaria), increased sweating (hyperhidrosis)
- nosebleed
- joint pain, back pain, joint stiffness, muscle pain, pain in extremity (hands, feet)
- eye irritation, eyelid swelling (eyelid oedema), eye redness
- increased appetite
Reporting of side effects
If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.
5. How Lamzede is stored
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the label and the carton after ‘EXP’. The expiry date refers to the last day of that month.
Store and transport refrigerated (2°C - 8°C).
Store in the original package in order to protect from light.
After reconstitution, the medicine should be used immediately. If not used immediately, the reconstituted solution may be stored up to 24 hours at 2°C to 8°C.
This medicine must not be used if the reconstituted solution contains opaque particles or is discoloured.
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.
6. Contents of the pack and other information What Lamzede contains
- The active substance is velmanase alfa.
One vial contains 10 mg of velmanase alfa.
After reconstitution, one mL of the solution contains 2 mg of velmanase alfa (10 mg / 5 mL).
- The other ingredients are: disodium phosphate dihydrate, sodium dihydrogen phosphate dihydrate, mannitol and glycine.
What Lamzede looks like and contents of the pack
Lamzede is a white to off-white powder for solution for infusion, supplied in a glass vial. Each carton contains 1, 5 or 10 vials.
Not all pack sizes may be marketed.
Marketing Authorisation Holder
Chiesi Farmaceutici S.p.A. Via Palermo 26/A
43122 Parma Italy
Manufacturer
Chiesi Farmaceutici S.p.A. Via San Leonardo, 96 43122 Parma
Italy
For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder:
België/Belgique/Belgien Chiesi sa/nv Tél/Tel: + 32 (0)2 788 42 00 |
Lietuva Chiesi Pharmaceuticals GmbH Tel: + 43 1 4073919 |
България Chiesi Bulgaria EOOD Teл.: + 359 29201205 |
Luxembourg/Luxemburg Chiesi sa/nv Tél/Tel: + 32 (0)2 788 42 00 |
Česká republika Chiesi CZ s.r.o. Tel: + 420 261221745 |
Magyarország Chiesi Hungary Kft. Tel.: + 36-1-429 1060 |
Danmark Chiesi Pharma AB Tlf: + 46 8 753 35 20 |
Malta Chiesi Farmaceutici S.p.A. Tel: + 39 0521 2791 |
Deutschland Chiesi GmbH Tel: + 49 40 89724-0 |
Nederland Chiesi Pharmaceuticals B.V. Tel: + 31 88 501 64 00 |
Eesti Chiesi Pharmaceuticals GmbH Tel: + 43 1 4073919 |
Norge Chiesi Pharma AB Tlf: + 46 8 753 35 20 |
Ελλάδα Chiesi Hellas AEBE Τηλ: + 30 210 6179763 |
Österreich Chiesi Pharmaceuticals GmbH Tel: + 43 1 4073919 |
España Chiesi España, S.A.U. Tel: + 34 93 494 8000 |
Polska Chiesi Poland Sp. z.o.o. Tel.: + 48 22 620 1421 |
France Chiesi S.A.S. Tél: + 33 1 47688899 |
Portugal Chiesi Farmaceutici S.p.A. Tel: + 39 0521 2791 |
Hrvatska Chiesi Pharmaceuticals GmbH Tel: + 43 1 4073919 |
România Chiesi Romania S.R.L. Tel: + 40 212023642 |
Ireland Chiesi Ltd Tel: + 44 (0)161 488 5555 |
Slovenija Chiesi Slovenija d.o.o. Tel: + 386-1-43 00 901 |
Ísland Chiesi Pharma AB Sími: +46 8 753 35 20 |
Slovenská republika Chiesi Slovakia s.r.o. Tel: + 421 259300060 |
Italia Chiesi Farmaceutici S.p.A. Tel: + 39 0521 2791 |
Suomi/Finland Chiesi Pharma AB Puh/Tel: +46 8 753 35 20 |
Κύπρος Chiesi Farmaceutici S.p.A. Τηλ: + 39 0521 2791 |
Sverige Chiesi Pharma AB Tel: +46 8 753 35 20 |
Latvija Chiesi Pharmaceuticals GmbH Tel: + 43 1 4073919 |
United Kingdom Chiesi Ltd Tel: + 44 (0)161 488 5555 |
This leaflet was last revised in {MM/YYYY}.
This medicine has been authorised under ‘exceptional circumstances’. This means that because of the rarity of this disease it has been impossible to get complete information on this medicine.
The European Medicines Agency will review any new information on this medicine every year and this leaflet will be updated as necessary.
Other sources of information
Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu. There are also links to other websites about rare diseases and treatments.
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The following information is intended for healthcare professionals only.
Lamzede requires reconstitution and is intended for intravenous infusion only. Each vial is for single use only.
Instructions for reconstitution and administration
Lamzede should be reconstituted and administrated by a healthcare professional.
Aseptic technique is to be used during preparation. Filter needles must not be used during preparation.
a) The number of vials to be used should be calculated based on the individual patient’s weight. The recommended dose of 1 mg/kg is determined using the following calculation:
- Patient’s weight (kg) × dose (mg/kg) = Patient dose (in mg)
- Patient dose (in mg) divided by 10 mg/vial (content of one vial) = number of vials to reconstitute. If the number of calculated vials includes a fraction, it should be rounded up to the next whole number.
- Approximately 30 minutes prior to reconstitution, the required number of vials should be removed from the refrigerator. The vials should reach ambient temperature (between 15°C and 25°C) prior to reconstitution.
Each vial is reconstituted by slowly injecting 5 mL of water for injections to the inside of the wall of each vial. Each mL of reconstituted solution contains 2 mg of velmanase alfa. Only the volume corresponding to the recommended dose should be administered.
Example:
- Patient’s weight (44 kg) × dose (1 mg/kg) = Patient dose (44 mg)
- 44 mg divided by 10 mg/vial = 4.4 vials, therefore, 5 vials should be reconstituted.
- From the total reconstituted volume, only 22 mL (corresponding to 44 mg) should be administered.
b) The powder should be reconstituted in the vial by a slow drop-wise addition of the water for injections down the inside of the vial and not directly onto the lyophilised powder. Forcefully ejecting the water for injections from the syringe onto the powder should be avoided to minimise foaming. The reconstituted vials should stand on the table for about 5-10 minutes. Thereafter each vial should be tilted and rolled gently for 15-20 seconds to enhance the dissolution process. The vial should not be inverted, swirled, or shaken.
c) An immediate visual inspection of the solution for particulate matter and discoloration should be performed after reconstitution. The solution should be clear and not used if opaque particles are observed or if the solution is discoloured. Due to the nature of the medicinal product, the reconstituted solution may occasionally contain some proteinaceous particles in form of thin white strands or translucent fibers which will be removed by the in-line filter during infusion (see point e).
d) The reconstituted solution is to be slowly withdrawn from each vial with caution to avoid foaming in the syringe. If the volume of the solution exceeds one syringe capacity, the required number of syringes should be prepared in order to replace the syringe quickly during the infusion.
e) The reconstituted solution should be administered using an infusion set equipped with a pump and an in-line low protein-binding 0.22 μm filter.
The total volume of infusion is determined by the patient’s weight and should be administrated over a minimum of 50 minutes. For patients weighing less than 18 kg, and receiving less than 9 mL reconstituted solution, the infusion rate should be calculated so that the infusion time is
≥50 minutes. The maximum infusion rate is 25 mL/hour. The infusion time can be calculated from the following table:
Patient weight (kg) |
Dose (mL) |
Maximum infusion rate (mL/h) |
Minimum infusion time (min) |
|
Patient weight (kg) |
Dose (mL) |
Maximum infusion rate (mL/h) |
Minimum infusion time (min) |
5 |
2.5 |
3 |
50 |
53 |
26.5 |
25 |
64 |
|
6 |
3 |
3.6 |
50 |
54 |
27 |
25 |
65 |
|
7 |
3.5 |
4.2 |
50 |
55 |
27.5 |
25 |
67 |
|
8 |
4 |
4.8 |
50 |
56 |
28 |
25 |
67 |
|
9 |
4.5 |
5.4 |
50 |
57 |
28.5 |
25 |
68 |
|
10 |
5 |
6 |
50 |
58 |
29 |
25 |
70 |
|
11 |
5.5 |
6.6 |
50 |
59 |
29.5 |
25 |
71 |
|
12 |
6 |
7.2 |
50 |
60 |
30 |
25 |
72 |
|
13 |
6.5 |
7.8 |
50 |
61 |
30.5 |
25 |
73 |
|
14 |
7 |
8.4 |
50 |
62 |
31 |
25 |
74 |
|
15 |
7.5 |
9 |
50 |
63 |
31.5 |
25 |
76 |
|
16 |
8 |
9.6 |
50 |
64 |
32 |
25 |
77 |
|
17 |
8.5 |
10.2 |
50 |
65 |
32.5 |
25 |
78 |
|
18 |
9 |
10.8 |
50 |
66 |
33 |
25 |
79 |
|
19 |
9.5 |
11.4 |
50 |
67 |
33.5 |
25 |
80 |
|
20 |
10 |
12 |
50 |
68 |
34 |
25 |
82 |
|
21 |
10.5 |
12.6 |
50 |
69 |
34.5 |
25 |
83 |
|
22 |
11 |
13.2 |
50 |
70 |
35 |
25 |
84 |
|
23 |
11.5 |
13.8 |
50 |
71 |
35.5 |
25 |
85 |
|
24 |
12 |
14.4 |
50 |
72 |
36 |
25 |
86 |
|
25 |
12.5 |
15 |
50 |
73 |
36.5 |
25 |
88 |
|
26 |
13 |
15.6 |
50 |
74 |
37 |
25 |
89 |
|
27 |
13.5 |
16.2 |
50 |
75 |
37.5 |
25 |
90 |
|
28 |
14 |
16.8 |
50 |
76 |
38 |
25 |
91 |
|
29 |
14.5 |
17.4 |
50 |
77 |
38.5 |
25 |
92 |
|
30 |
15 |
18 |
50 |
78 |
39 |
25 |
94 |
|
31 |
15.5 |
18.6 |
50 |
79 |
39.5 |
25 |
95 |
|
32 |
16 |
19.2 |
50 |
80 |
40 |
25 |
96 |
|
33 |
16.5 |
19.8 |
50 |
81 |
40.5 |
25 |
97 |
|
34 |
17 |
20.4 |
50 |
82 |
41 |
25 |
98 |
|
35 |
17.5 |
21 |
50 |
83 |
41.5 |
25 |
100 |
|
36 |
18 |
21.6 |
50 |
84 |
42 |
25 |
101 |
|
37 |
18.5 |
22.2 |
50 |
85 |
42.5 |
25 |
102 |
|
38 |
19 |
22.8 |
50 |
86 |
43 |
25 |
103 |
|
39 |
19.5 |
23.4 |
50 |
87 |
43.5 |
25 |
104 |
|
40 |
20 |
24 |
50 |
88 |
44 |
25 |
106 |
|
41 |
20.5 |
24.6 |
50 |
89 |
44.5 |
25 |
107 |
|
42 |
21 |
25 |
50 |
90 |
45 |
25 |
108 |
|
43 |
21.5 |
25 |
52 |
91 |
45.5 |
25 |
109 |
|
44 |
22 |
25 |
53 |
92 |
46 |
25 |
110 |
|
45 |
22.5 |
25 |
54 |
93 |
46.5 |
25 |
112 |
|
46 |
23 |
25 |
55 |
94 |
47 |
25 |
113 |
|
47 |
23.5 |
25 |
56 |
95 |
47.5 |
25 |
114 |
|
48 |
24 |
25 |
58 |
96 |
48 |
25 |
115 |
|
49 |
24.5 |
25 |
59 |
97 |
48.5 |
25 |
116 |
|
50 |
25 |
25 |
60 |
98 |
49 |
25 |
118 |
Patient weight (kg) |
Dose (mL) |
Maximum infusion rate (mL/h) |
Minimum infusion time (min) |
|
Patient weight (kg) |
Dose (mL) |
Maximum infusion rate (mL/h) |
Minimum infusion time (min) |
51 |
25.5 |
25 |
61 |
99 |
49.5 |
25 |
119 |
|
52 |
26 |
25 |
62 |
|
f) When the last syringe is empty, the dosage syringe is replaced with a 20 mL syringe filled with sodium chloride 9 mg/mL (0.9%) solution for injection. A volume of 10 mL sodium chloride solution should be administered through the infusion system to infuse the remaining fraction of Lamzede in the line to the patient.
Disposal
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
ANNEX IV
CONCLUSIONS ON THE GRANTING OF THE MARKETING AUTHORISATION UNDER EXCEPTIONAL CIRCUMSTANCES PRESENTED BY THE EUROPEAN MEDICINES AGENCY
Conclusions presented by the European Medicines Agency on:
· Marketing authorisation under exceptional circumstances
The CHMP having considered the application is of the opinion that the risk-benefit balance is favourable to recommend the granting of the marketing authorisation under exceptional circumstances as further explained in the European Public Assessment Report.