Eliso - instructions for use, doses, side effects, contraindications

Active substanceTaliglucerase alphaTaliglucerase alpha

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Eliso

lyophilizate d / infusion

Pfizer Inc. USA

Dosage form: & nbsplyophilizate for the preparation of concentrate for the preparation of a solution for infusions

Composition:

Composition per one vial

active substance: taliglucerase alpha 200 units

Excipients: Mannitol 206.7 mg, polysorbate 80 0.56 mg, sodium citrate 30.4 mg, citric acid anhydrous q.s. up to pH 6.

Description:

Lyophilizate:

White or almost white powder or porous mass.

Reconstituted solution:

Transparent or slightly opalescent colorless or light yellow solution, free from visible particles.

Pharmacotherapeutic group:Enzyme agent

ATX: & nbsp

A.16.A.B.11 Taliglucerase alpha

Pharmacodynamics:

Taliglucerase alpha is a recombinant active form of human lysosomal enzyme, β-glucocerebrosidase, which is expressed in genetically modified carrot root cells grown in a disposable bioreactor. β-glucocerebrosidase (β-D-glucosyl-N-acylsphingosine glucohydrolase) is a lysosomal glycoprotein enzyme that catalyzes the hydrolysis of glycolipid glucocerebroside to glucose and ceramide.

Pharmacokinetics:

Adult patients

In patients with Gaucher disease taliglucerase alpha Quickly eliminated after intravenous infusion. After intravenous infusion for 60-120 minutes at doses of 30 and 60 U / kg, the median half-life range was 18.9-28.7 min, respectively. After a long dosing of the drug in a single infusion mode with a periodicity of two weeks, no clear indication of its accumulation was found. In the equilibrium state, the median AUCo-t (exposure) was 1989 ng-h / ml and 6751 ng-h / ml, respectively, after administration of the drug at doses of 30 and 60 U / kg to 38 weeks, indicating a more than proportionate dose increase AUCo-t. Exposure parameters did not differ depending on sex.

After a single administration of the median systemic clearance (CL) was about 30.5 l / h and 18.5 l / h when administered at doses of 30 and 60 units / kg, respectively. Median volume distribution in the elimination phase (V_z) varied in the range of 12.6 liters - 13.9 liters. The median of the volume of distribution in the equilibrium state (V_ss) ranged from 7.30 to 11.7 liters in both groups.

Children

The pharmacokinetics of allylglyceride was evaluated in children with Gaucher's disease. After multiple intravenous infusions of algal thaliglucerase 30 and 60 U / kg for a duration of about 100 minutes in children, the median half-life of thalidoglucerase alpha was 31.9 min (range: 12.9-56.8) and 32.5 min (range: 18 , 0 - 42.9), respectively. Median CL was 27.4 l / h (range: 10.9 - 37.8) when administered at a dose of 30 units / kg and 15.8 l / h (range: 11.7 to 24.9) at a dose of 60 units / kg . Median AUCo._t in the equilibrium state was 1491 ng-h / ml (range: 527 - 1932) when administered at a dose of 30 units / kg and 2969 ng-h / ml (range: 1593 to 4256) at a dose of 60 units / kg.

The observed mean values of the half-life of thaliglucerase alpha after repeated administration in children correspond to the values in adults (i.e., median 18.9 minutes at a range of 9.20 to 57.9 at 38 weeks with a dose of 30 units / kg and 28.7 min in the range from 11.3 to 104 at 38 weeks with a dose of 60 units / kg). The system's median CL after repeated administration in children, also matched the data obtained in adult patients (i.e., a median of 30.5 l / h in the range of 6.79 to 68.0 at 38 weeks when administered at a dose of 30 units / kg and 18, 5 l / h in the range from 6.25 to 37.9 at 38 weeks with a dose of 60 units / kg). Values AUCo._t were lower than in adult patients (ie, mean AUCo-t 1989 ng-h / ml with a range of 1002 to 9546 at week 38 with a dose of 30 units / kg and 6751 ng-h / ml with a range of 2545 to 20496 at week 38 at administration in a dose of 38 units / kg), taking into account the dosage of the drug per kg of body weight and the lower weight in children.

Elderly patients

In clinical studies of allylglycerase, no sufficient the number of patients aged 65 years and over to assess whether their response is different from the response in younger patients. Based on the previously obtained clinical experience, differences in the response between the elderly and young patients were not found.

Table 3 Indications of pharmacokinetics of allyl thalliglycerase after taking a second dose in adults and children with Gaucher's disease type I

Children (N = 9)

Median (Range)

Adults at 38 weeks of age (N=29)

Median (Range)

30 units / kg n = 5

60 units / kg n = 4

30 units / kg n = 14

60 units / kg n = 15

Age

15(10, 17)

11 (4, 16)

35 (19, 74)

33 (19,58)

Weight, kg)

44,3 (22,8,

71,0)

28,6 (16.5,

50,4)

72,5 (51,5,

99,5)

73,5 (58,5,

87,0)^a

AUC_0-͚

(ng*h/ml)^b

1416 (535,

1969)

2984 (1606,

4273)

2007 (1007, 10092)

6459 (2548, 21020)^a

T1 / 2 (min)

37,1 (22,5,

56,8)

32,5(18,0,

42,9)

18,9 (9,20,

57,9)

28,7 (11,3,

104)^a

CL (l / h)

30,5 (17,4,

37,8)

15,8 (11,7,

24,9)

30,5 (6,79,

68,0)

18,5 (6,20,

37,9)^a

Vss (L)

14,9 (10,1,

35,6)

8,80 (3,75,

21,4)

11,7 (2,3,

22,7)

10,7 (1,4,

18,5)^a

^an = 14

^bValues are obtained from concentration data expressed in ng / ml.

Indications:

Taliglucerase alpha for intravenous administration is a glucocerebrosidase-specific hydrolytic lysosomal enzyme that is indicated for prolonged enzyme replacement therapy (FZT) in the following patients:

Adults and children with confirmed diagnosis of Gaucher disease type I. Manifestations of Gaucher disease may include one or more of the following symptoms: splenomegaly, hepatomegaly, anemia, thrombocytopenia, bone disease.

Children

Children aged 2 to 18 years with visceral or haematological manifestations of Gaucher disease.

Contraindications:

Allergic reactions expressed to a degree on thaliglycerase alpha or any auxiliary substances.

Use in patients with impaired renal or hepatic function was not performed (no studies were performed).

Use in children younger than 2 years.

Carefully:

Care should be taken when using the drug in patients with carrot allergy.

Pregnancy and the period of breastfeeding.

Pregnancy and lactation:

Pregnancy

Studies of the reproductive toxicity of thaliglucerase alpha have been conducted in rats and rabbits at doses up to 5 times the maximum dose in humans at recalculation on mg / m², and showed no signs of impaired fertility or adverse effects on the fetus associated with the administration of thaliglucerase alpha. However, well-planned controlled studies in pregnant women have not been conducted. Since studies of reproductive toxicity in animals do not always allow one to predict the response in humans, caution should be given to pregnant women.

Breast-feeding

It is not known whether taliglucerase alpha with breast milk.Because many medications are excreted in breast milk, caution should be exercised when using allylglyceride in lactating women.

Fertility

In animal studies taliglucerase alpha did not affect fertility, reproductive capacity and sperm characteristics.

Dosing and Administration:

Due to heterogeneity and polysystemic damage in case of Gauchers disease, dose adjustment should be carried out individually. Dose requirements may increase or decrease on the basis of achievement of the goals of therapy, which is assessed by a regular full analysis of the clinical manifestations of the disease in the patient.

Adult patients

Initial dose taliglyutserazy alpha in adult patients is in the range from 30 to 60 units / kg body weight, once per two weeks, depending on the clinical evaluation performed by the attending physician. AT the median of the estimated doses was 9 to 67 units / kg, once every two weeks.

Adult patients who are currently receiving imiglucerase therapy for Gaucher disease may switch to therapy with allyl thalliglycerase.Patients who previously received imiglucetase in a stable dose are advised to start therapy with algal glutamine in a dose equal to the dose of imiglucerase at the time of switching from this type of therapy to thalidiglycerase alpha.

Children

The initial dose of allyl in children ranges from 30 to 60 U / kg of body weight, once every 2 weeks, depending on the clinical evaluation conducted by the attending physician. In clinical studies, the median of the estimated doses was 26 to 69 units / kg, once every two weeks (see "Overdose").

Children who are currently receiving imiglucerase therapy for Gaucher disease may switch to algalysis therapy. In patients who have previously received imiglucetraz in a stable dose, it is recommended to begin therapy with algal glutamine in a dose equal to the dose of imiglucerase at the time of transition from this type of therapy to thalidiglycerase alpha.

Mode of application

After reconstitution and dilution, the drug is administered intravenously in the form of infusions lasting from 60 to 120 minutes (see section "Special instructions"). The duration of the infusion can be varied depending on individual tolerability.The solution should be injected through a filter built in the infusion system with a pore size of 0.2 μm and with a low ability to bind proteins. The entire volume of the infusion solution should be administered for at least 60 minutes.

Each vial with allylglycerase is intended for single administration in one patient.

Impaired liver or kidney function

Studies of allyl taliglucerase in patients with Gaucher disease and impaired renal or hepatic function were not performed.

Elderly patients (> 65 years)

During clinical trials, 8 patients aged 65 years and older received thalliglycerase alpha. The available data do not indicate the need for dose adjustment in this age group.

Recovery and breeding instructions

For accurate measurement of the required amount of the drug, each the vial contains an excess volume of 6% (12 units).

Liofilizate for the preparation of concentrate for the preparation of a solution for infusions should be restored with the help of sterile water for injection, immediately diluted 9 mg / ml (0.9%) with sodium chloride solution for infusion and enter as an intravenous infusion.

The number of vials that need to be restored must be determined based on the patient's body weight and dosage regimen. Vials should be removed from the refrigerator 1 hour before the planned dilution.

Use aseptic technique.

Store the vial with lyophilizate until reconstituted / diluted at room temperature for a maximum of 24 hours.

Recovery

Each vial is reconstituted with 5.1 ml of sterile water for injection. The reconstituted volume is 5.3 ml. Water for injection should be added slowly to reduce the formation of air bubbles and ensure uniform mixing of the drug. Carefully turn the vial. DO NOT BURST.

After reduction the solution is clear or slightly opalescent colorless or light yellow solution, containing no visible particles. Then the reconstituted solution should be diluted. Before breeding it is necessary to visually check the reconstituted solution in each vial for the content of foreign particles and discoloration. Do not use vials that indicate discoloration or the presence of foreign particles.

After reconstitution, immediately dilute the solution with the drug and dispose of the vial. Do not store unused solution in a vial for subsequent administration.

Breeding

The reconstituted solution contains taliglucerase alpha at a dose of 40 units per ml. The volume of the reconstituted solution allows to accurately collect 5.0 ml (200 units) from each vial. Take 5.0 ml of reconstituted solution from each vial and add the withdrawn volume to a sterile infusion bag.

Then, the introduced volume of 9 mg / ml (0.9%) is diluted with sodium chloride solution for infusions to a total volume of 100 ml-200 ml. Carefully mix the solution for infusion. Since the solution is protein, sometimes after dilution there is a slight flocculation (described as the appearance of translucent side particles or fibers). The diluted solution should be injected through a filter built in the infusion system with a pore size of 0.2 μm and with a low ability to bind proteins.

Side effects:

The most serious adverse reactions in the participants of clinical trials were immune reactions of type 1 hypersensitivity.

The most frequent adverse reactions were infusion mediated reactions that occurred within 24 hours after its onset.

The most common symptoms of infusion reactions included arthralgia, headache, vomiting, hypersensitivity, hot flashes, itching, pain in the extremities, and pulmonary hypertension. Other infusion reactions were diarrhea, chest discomfort, fever, muscle spasms, tremor, throat irritation, erythema and skin rash.

The safety of thaliglucerase alpha has been established in children between 2 and 16 years old. In clinical trials involving children, there was one serious adverse event associated with therapy: a patient at the age of 8 had a serious undesirable reaction (gastroenteritis). The incidence of adverse reactions in children and adults does not appear to be significantly different, with the exception of vomiting and abdominal pain, which are more frequent in children.

Table 1. Undesirable reactions^a (all patients) *

System-Organic grade	Unwanted reaction
Immune system disorders	Anaphylactic reaction **, hypersensitivity
Disturbances from the nervous system	Dizziness, headache
Vascular disorders	Tides
Disturbances from the respiratory system, chest and mediastinal organs	Throat irritation
Infringements from gastrointestinal tract	Vomiting, abdominal pain^a, nausea
Disturbances from the skin and subcutaneous tissues	Angioedema^at, skin rash, hives , itchy skin^b, erythema
Disturbances from musculoskeletal and connective tissue	Bone pain, back pain, arthralgia, pain in the extremities
General disorders and disorders at the site of administration	Pain in place of infusion, fatigue, peripheral edema
Injuries, intoxication and complications of manipulation	Infusion reaction
Laboratory and instrumental data	Weight gain
^a Abdominal pain includes pain in the upper abdomen and pain in the lower abdomen. ^b Skin itching involves generalized itching. ^atAngioedema includes edema of the eyelids, swelling of the lips, swelling of the face, swelling of the conjunctiva, swelling of the eyes, swelling of the lips, swelling of the mouth, swelling of the tongue and swelling of the larynx. * The frequency of unwanted reactions to the drug was calculated on the basis of data on adverse events, regardless of the cause-effect relationship. ** The undesirable reaction was registered in the post-marketing period.

Table 2. Undesirable reactions (adult patients) *

System-Organic grade	Unwanted reaction
Immune system disorders	Anaphylactic reaction **, hypersensitivity
Disturbances from the nervous system	Dizziness, headache
Vascular disorders	Tides
Disturbances from the respiratory system, chest and mediastinal organs	Throat irritation
Infringements from gastrointestinal tract	Vomiting, abdominal pain^a, nausea
Disturbances from the skin and subcutaneous tissues	Angioedema^at, skin rash, hives , itchy skin^b, erythema
Disturbances from musculoskeletal and connective tissue	Bone pain, back pain, arthralgia, pain in the extremities
General disorders and disorders at the site of administration	Pain in place of infusion, fatigue, peripheral edema
Trauma, intoxication and complications of manipulation	Infusion reaction
Laboratory and instrumental data	Weight gain
^a Abdominal pain includes pain in the upper abdomen and pain in the lower abdomen. ^b Skin itching involves generalized itching. ^atAngioedema includes edema of the eyelids, swelling of the lips, swelling of the face, swelling of the conjunctiva, swelling of the eyes, swelling of the lips, swelling of the mouth, swelling of the tongue and swelling of the larynx. * The incidence of adverse drug reactions was calculated on the basis of data on undesirable phenomena, regardless of the cause-effect relationship. ** The undesirable reaction was registered in the post-marketing period.

In clinical trials, hypersensitivity reactions were recorded already with the first infusion (see section "Special instructions").

Immunogenicity

As in the case of all medicinal protein preparations, patients were noted antibody formation IgG to allylglyceride. In a study in adult patients who had not previously received FZT, 17 out of 32 (53%) patients who received taiglucetraz alfa once every two weeks had antibodies to allylglycerase alpha (a positive test for antibodies to allylglycerase alpha was obtained after the therapy at one or more time points after therapy). Two patients had antibodies to allylglycerase alpha at the initial evaluation; one patient was excluded from the study after developing an allergic reaction to thalidiglycerase alpha when the first dose was administered,in another patient, while continuing therapy, stably low tigers of antibodies to allylglycerase remained. Among children who had not previously received FZT, 2 of 11 (18%) patients observed the formation of antibodies to allylglyceride. In one child who had not previously received FZT, the result of an analysis of the presence of antibodies to allylglycerase was positive in the initial evaluation, but became negative during therapy with alginum thalliglycerase. In a study in adults and children receiving FZT (N=31; 26 adults and 5 children), 5 adult patients (16% of all patients) who switched from imiglucerase therapy to thalidoglycerase alpha once every two weeks, after the change of therapy, the formation of antibodies to allylglycerase was noted. None of the children who had previously received FZT had antibodies to allylglycerase after switching from therapy with imiglucerase to therapy with allyl thalliglycerase. In the population receiving FZT, one adult patient and two children who switched from imiglucerase therapy had a positive test for antibodies to allyl thalloglycerase at the initial evaluation, but the result became negative after treatment with allyl thalliglycerase.The role of antibodies to allylglucose in the development of adverse events is currently unknown (also see the section "Pharmacological properties" subsection "Pharmacodynamics").

Neutralizing antibodies with limited sensitivity were tested in two adult patients who had not previously received such therapy (after 24 months with allyl thalliglucerase) and one adult who switched from therapy with imiglucerase (after 9 months of therapy with taliglucerase) was registered positive neutralizing activity in the enzyme inhibition assay in vitro and negative when analyzed on cells.

The significance of this data is currently unknown.

The results of the immunogenicity assay largely depend on the sensitivity and specificity of the analysis, the results can be influenced by many factors, for example, analytical technique, sample handling, sampling time, concomitant therapy and underlying disease. For these reasons, a comparison of the frequency of antibody formation with allylglycerase alpha with the frequency of antibodies to other drugs may lead to incorrect conclusions.

Overdose:

There is no information about an overdose of thaliglucerase alpha. The maximum dose of allyl thalliglycerase in clinical trials was 69 units / kg body weight.

Interaction:

No interaction studies were conducted.

In the absence of compatibility studies, this medication should not be mixed with other medicines, except as indicated in the section "Dosing and Administration".

Special instructions:

Thaliglucerase alpha therapy should be performed under the supervision of a physician experienced in treating patients with Gaucher disease. The introduction of the drug at home under the supervision of a medical worker can only be considered in patients who had previously tolerated infusions (see section "Side effect").

The formation of antibodies

In patients, the formation of antibodies - immunoglobulins G (IgG) to allyl thalliglycerase. The role of antibodies to allylglycerase in the occurrence of adverse events is currently unknown, given the small number of patients who have been evaluated to date under the clinical research program.However, an analysis of the relationship between the presence of antibodies to taliglucerase and the occurrence of undesirable phenomena that may be associated with hypersensitivity demonstrated that patients with a positive antibody test IgG to allylglyceride alpha, a greater number of adverse events were noted than in patients with a negative test result for the presence of such antibodies. Two patients who had not previously received similar therapy and one patient who switched from therapy with imiglucerase registered a positive result of neutralizing activity in the inhibition assay enzyme in vitro; In all three patients, a negative result was obtained in the cell analysis.

In patients who have experienced the development of infusion or immune responses to therapy with allylglyceride, the presence of antibodies to allylglyceride should be evaluated. In addition, the presence of antibodies to allylglycerase should be evaluated in patients who had immune responses to other means of FZT, which switched to therapy with allyl thalliglucose.

Infusion reactions and hypersensitivity

Possible occurrence of hypersensitivity reactions, including anaphylaxis; in this regard, when introducing allylglycerase, appropriate medical care should be available. When allylglyceride was given, infusion reactions (reactions that occurred within 24 hours after infusion) and allergic hypersensitivity reactions were noted. If a severe allergic reaction occurs, it is recommended to immediately stop the infusion of taliglucerase alpha. If an infusion reaction or a hypersensitivity reaction occurs, it is usually possible to stop these manifestations and continue therapy by lowering the infusion rate by treating with drugs such as antihistamines, antipyretics and / or corticosteroids and / or by stopping therapy and then restarting at a reduced rate. Preliminary therapy with antihistamines and / or corticosteroids can prevent subsequent reactions.

It is necessary to assess the benefit and risk of resuming the use of Eliso in patients who undergo severe hypersensitivity reactions. Repeated administration of the drug and its administration to such patients should be done with caution in conditionsdepartment, equipped with the necessary equipment for emergency medical care (see section "Side effect").

Allergy to carrots

The occurrence of allergic reactions to thalidiglycerase alpha in patients with a known carrot allergy is currently unknown and has not been studied in clinical trials; Therefore, care must be taken when treating such patients. If infusion or hypersensitivity occurs, therapy should be performed as described above.

A ready-made solution of the drug should be used immediately.

Any unused product should be disposed of in accordance with local requirements.

The vials should be stored together with the outer packaging for protection from the light.

Effect on the ability to drive transp. cf. and fur:

Since dizziness has been noted in the clinical studies of thaliglucerase alpha, patients should evaluate their response to the administration of allyl allyl before administering vehicles or working with mechanisms.

Form release / dosage:

Liofilizate for the preparation of concentrate for the preparation of a solution for infusion 200 units.

Packaging:

Lyophilizate in a vial of colorless borosilicate glass (type I), capped with a rubber cap of red-brown color and sealed with an aluminum cap with a liner in the form of a plastic disc.

1 bottle with instructions for use in a cardboard box.

Storage conditions:

Store at 2 - 8 ° C. Keep out of the reach of children.

Shelf life:

2 years.

The reconstituted solution

Since taliglucerase alpha does not contain preservatives, the drug should be used immediately after reconstitution.

Do not use the drug after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-004410

Date of registration:15.08.2017

Expiration Date:15.08.2022

The owner of the registration certificate: Pfizer Inc. Pfizer Inc. USA

Manufacturer: & nbsp

PHARMACIA & UPJOHN COMPANY USA

Representation: & nbspPfizer LtdPfizer LtdUSA

Information update date: & nbsp31.08.2017

Illustrated instructions

Instructions

Eliso (Eliso)