Arzerra

General characteristics. Structure:

Active ingredient: офатумумаб 20 mg

Excipients: acetate sodium trihydrate - 6.8 mg, dinatrium эдетат - 0.019 mg, polysorbate of 80 - 0.2 mg, arginine - 10 mg, sodium chloride - 2.98 mg, Acidum hydrochloricum - q.s. to pH 5.5, water for and - q.s. to 1 ml.

5 ml - bottles glass (3) complete with two infusional systems with the built-in filters with a diameter of time of 0.2 microns placed in a package - packs cardboard.
50 ml - bottles glass (1) complete with two infusional systems with the built-in filters with a diameter of time of 0.2 microns placed in a package - packs cardboard.

Pharmacological properties:

Antineoplastic drug. Ofatumumab represents the human monoclone (IgG1 isotype) which is specifically contacting an epitope which includes both small, and big extracellular loops of the molecule CD20. The molecule CD20 is transmembrane phosphoprotein which expresses on V-lymphocytes, since pre-V cells to mature V-lymphocytes, and also on cells of V-cellular tumors. V-cellular tumors include the chronic lymphocytic leukosis (CLL) (which is usually followed by lower degree of an expression of CD20) and nekhodzhkinsky lymphoma (in> 90% of tumors CD20 expression level high). At linkng with an antibody the molecule CD20 remains on a cell membrane, is not removed from its surface (shedding) and does not arrive in a cell (internalization).

Linkng of an ofatumumab with the specific epitope of the molecule CD20 located near a membrane causes binding and complement activation on a cell surface that the complement - to dependent cytotoxic reaction and a lysis of a tumor cell leads to development. It was shown what офатумумаб causes the expressed killing which is followed by the high level of an expression of protective proteins of a complement. Besides, binding of an ofatumumab causes death of cells and on the mechanism of antitelozavisimy cellular cytotoxicity. It was also shown what офатумумаб causes killing both with high, and with a low expression of CD20, and also the cells steady against a rituksimab.

At patients with hematologic tumoral diseases the maintenance of V-cells in blood decreased after the first introduction of an ofatumumab. At patients with HLL steady against earlier carried out treatment, average decrease in maintenance of V-cells in blood after the 1st introduction made 22%, and after the 8th introduction - 92%. At most of patients the maintenance of V-cells in blood remained low throughout all course of treatment, and then gradually increased (however and in 3 months after the termination of a course of treatment ofatumumaby the average content of V-cells was 69% lower than their concentration before treatment).

Proteinaceous drugs, similar to an ofatumumab, can cause an immune response, however antibody formation against an ofatumumab can be less intensive, than usually as офатумумаб is, first, a human antibody, and secondly, causes death of V-cells.

In the main clinical trial of an antibody to an ofatumumab were not revealed at 82 patients who in blood had very low concentration of an ofatumumab that did identification of such antibodies improbable (from them 81 patients received at least 8 infusions, and 61 patients of 12 infusions).

 

Pharmacokinetics. Absorption

The maximum concentration of an ofatumumab in serum were usually observed by the end of introduction or right after it. Data on pharmacokinetics of drug were obtained on 146 patients with HLL steady against earlier carried out treatment. The geometrical average for Cmax after the first introduction (300 mg) made 63 mkg/ml, after the eighth weekly introduction (the seventh introduction in a dose of 2000 mg) the geometrical average for Cmax was equal to 1482 mkg/ml, and the geometrical average for AUC(0-∞) (the area under a dependence curve "concentration time") made 674,463 мкг×ч/мл; after the twelfth introduction (the fourth monthly introduction) the geometrical average for Cmax was equal in a dose of 2000 mg to 881 mkg/ml, and the geometrical average for AUC(0-∞) made 265,707 мкг×ч/мл.

Distribution

Vd of an ofatumumab is small. Average Vd value in steady state depending on a dose, number of infusion and in different researches varied from 1.7 to 5.1 l.

Metabolism

Ofatumumab is a protein for which the usual way of metabolism consists in destruction by proteolytic enzymes to peptides and separate amino acids. Therefore the researches of biotransformation of drug accepted usually were not conducted.

Removal

Ofatumumab leaves from an organism in two ways: the interaction which is not connected with a target, as well as all other molecules IgG, and caused with a target, namely linkng with V-cells. After the first introduction of an ofatumumab bystry and permanent decrease in number of CD20+ of V-cells therefore at further administrations of drug it will contact already considerably smaller quantity of CD20+ of cells is observed. As a result at the subsequent introductions of an ofatumumab value of its clearance (C) will be below, and the size T1/2 — is significantly higher, than at his first introduction; at repeated weekly introductions of AUC and Cmax value increased in much bigger degree, than it was expected for alleged accumulation of the ofatumumab calculated on the basis of the data obtained at its first introduction.

In the researches conducted at patients with HLL, the C average values and T1/2 made 64 ml/h (range: 4,3-1122 ml/h) and 1,3 days (range: 0,2-6,0 days) after the first introduction, 8,5 ml/h (range: 1,3-41,5 ml/h) and 11,5 days (range: 2,3-30,6 days) after the fourth introduction, 9,5 ml/h (range: 2,2-23,7 ml/h) and 15,8 days (range: 8,8-61,5 days) after the eighth introduction and 10,1 ml/h (range: 3,3-23,6 ml/h) and 13,9 days (range: 9,0-29,2 days) after the twelfth introduction.

Separate groups of patients

Elderly (65 years are also more senior): as it was shown in the cross population analysis of pharmacokinetics at patients aged from 21 up to 86 years in different researches, the age had no significant effect on pharmacokinetics of an ofatumumab.

Children and teenagers (up to 18 years inclusive): data on pharmacokinetics of an ofatumumab in this age group are absent.

Floor: in the cross analysis it was shown that a floor exerted moderate impact (14-25%) on pharmacokinetics of an ofatumumab - at women of Cmax and AUC were slightly higher (in the analyzed group of 41% of patients there were men and 59% — women). These distinctions were considered not having clinical value therefore it is not recommended to adjust a dose depending on a sex of the patient.

Renal failure: in the cross population analysis at patients with the indicators of clearance of creatinine varying in the range from 33 ml/min. up to 287 ml/min. it was shown that clinically significant interrelation between the value of clearance of creatinine defined before introduction of an ofatumumab, and pharmacokinetics of the last was absent. To somehow adjust a drug dose for patients with a renal failure of weak or moderate severity (clearance of creatinine> of 30 ml/min.) it is not recommended. For patients with a heavy renal failure (clearance of creatinine <30 ml/min.) data on pharmacokinetics of an ofatumumab are absent.

Abnormal liver function: data on drug pharmacokinetics at patients with an abnormal liver function are absent. Nevertheless, as офатумумаб, as well as all other molecules IgG1, catabolizes by means of the most usual proteolytic enzymes which prevalence is not limited to tissues of a liver at all, abnormal liver functions can hardly exert any impact on the speed of removal of an ofatumumab from an organism.

Indications to use:

— treatment of the chronic lymphocytic leukosis (CLL) at inefficiency of earlier carried out therapy with inclusion of a fludarabin and/or alemtuzumab.

Route of administration and doses:

Ofatumumab it is necessary to enter under observation of the doctor having experience of use of antineoplastic drugs. Due to a possibility of development of anaphylactoid reactions, infusion of an ofatumumab should be carried out in the conditions of the immediate availability of the equipment and medicines necessary for rendering the emergency help in such situations.

The drug is administered in a look in/in infusions. Before use drug should be dissolved. Strong solution should be mixed only from 0.9% chloride sodium solution for in/in introductions. It is not recommended to mix офатумумаб in capacity for introduction with other drugs.

Premedication

In 30 min. - 2 h before introduction of an ofatumumab by the patient need to be spent premedication according to the following scheme.

Number of introduction      GKS Dose in/in      an analgetic Dose      the Dose of antihistaminic
(dose)                                                                                               of drug
 1 (300 mg)           Equivalent       Equivalent           Equivalent 10 mg
                              100                      mg 1000 mg                       of a tsetirizin
                                       paracetamol Prednisolonum
                                                                (acetaminophen)
2 (2000 mg)           Equivalent       Equivalent           Equivalent
                              100                                             mg 1000 mg 10 mg of a tsetirizin
                                        paracetamol Prednisolonum
                                                                (acetaminophen) 
3-8 (2000 mg)        Equivalent       Equivalent          Equivalent
                               0-100                                          mg 1000 mg 10 mg of a tsetirizin
                              prednizolonaa)       paracetamol
                                                                (acetaminophen) 
9 (2000 mg)           Equivalent      Equivalent           Equivalent
                              100                                            mg 1000 mg 10 mg of a tsetirizin
                                     paracetamol Prednisolonum
                                                              (acetaminophen) 
10-12 (2000 mg)    Equivalent      Equivalent         Equivalent
                               50-100                                     mg 1000 mg 10 mg of a tsetirizin
                                 преднизолонаб)   paracetamol
                                                               (acetaminophen) 

a) If the second introduction comes to the end without development of serious undesirable reactions, the dose at the discretion of the doctor, can be lowered.

b) If the ninth introduction comes to the end without development of serious undesirable reactions, the dose, at the discretion of the doctor can be lowered to equivalent 50 mg of Prednisolonum.

Doses

The recommended dose makes 300 mg of an ofatumumab for the first introduction and 2000 mg of an ofatumumab — for all subsequent introductions. The scheme of introduction provides 8 consecutive weekly introductions, and 4-5 weeks later — 4 consecutive monthly (i.e. every 4 week) introductions.

First and second introductions

Initial rate of administering of drug at the first and second introduction has to make 12 ml/h. During introduction its speed should be increased gradually so that each 30 min. it doubled and increased up to the maximum, equal 200 ml/h.

Subsequent introductions

If the second introduction comes to the end without development of the serious undesirable reactions connected with introduction, all other introductions can be carried out with an initial speed of 25 ml/h which has to increase gradually, doubling each 30 min. to the maximum, equal 400 ml/h.

Change of a dose and resuming of treatment

Development of the undesirable reactions connected with introduction of an ofatumumab can cause the necessity of reduction in the rate of introduction.

In case of development poorly or moderately expressed undesirable reactions introduction should be stopped and if the condition of the patient needs stable to be renewed again with a speed equal to a half of at what introduction was interrupted. If by the time of the termination of introduction of an ofatumumab because of development of undesirable reactions speed did not manage to increase from initial, equal 12 ml/h, then when resuming introduction it should be seen off with the standard initial speed equal of 12 ml/h. Further rate of administering, taking into account portability of drug the patient and at the discretion of the doctor, it is possible to increase according to the standard scheme (so that speed doubled not quicker, than every 30 min.).

In case of development of serious undesirable reactions introduction should be stopped and if the condition of the patient remains stable, again to renew with a speed of 12 ml/h. Further rate of administering, taking into account portability of drug the patient and at the discretion of the doctor, it is possible to increase according to the standard scheme (so that speed doubled not quicker, than every 30 min.).

Special groups of patients

Safety and efficiency of an ofatumumab at children and teenagers are younger than 18 years it was not investigated.

Any noticeable influence of age on efficiency and safety of drug is noted. Considering the available data on efficiency and safety of drug at patients of advanced age, dose adjustment in this group is not required.

Any special researches of pharmacokinetics of an ofatumumab at patients with a renal failure were not conducted. Nevertheless, it is improbable that patients with a renal failure will require drug dose adjustment.

Any special researches of pharmacokinetics of an ofatumumab at patients with an abnormal liver function were not conducted. It is improbable that patients with an abnormal liver function will require drug dose adjustment.

Rules of preparation of solutions and administration of drug

1) Before cultivation of an ofatumumab

Before cultivation it is necessary to check a concentrate of an ofatumumab regarding existence in it of particles and discoloration. Not to use офатумумаб if its color is changed. The concentrate may contain a small amount of visible particles. These particles will be removed with the filters which are included in the package for introduction.

Not to stir up a bottle with ofatumumaby before conducting the described check.

2) How to prepare solution for in/in introductions

Before introduction the concentrate of an ofatumumab needs to be parted in 0.9% chloride sodium solution for in/in introductions in aseptic conditions.

Dose of 300 mg

It is necessary to use 3 bottles (totally - 15 ml, on 5 ml in a bottle):

- from 0.9% chloride sodium solution for in/in introductions of 1000 ml to select and remove 15 ml from capacity;

- from each of 3 bottles with ofatumumaby to select 5 ml of a concentrate (only 15 ml) and to enter them into capacity from 985 ml of 0,9% of solution of sodium of chloride for in/in introductions;

- not to stir up capacity - to mix contents by a careful turning.

Dose of 2000 mg

      Dose of 2000 mg from bottles on 5 ml                       the Dose of 2000 mg from bottles on 50 ml
For receiving a dose of 2000 mg to use          2000 mg For receiving a dose to use 2
20 bottles (totally - 100 ml,                           a bottle (totally - 100 ml, on 50 ml in
on 5 ml in a bottle):                                                     bottle):
- from capacity from 0.9% sodium solution                  - from capacity from 0.9% chloride sodium solution
chloride for in/in introductions of 1000 ml        for in/in introductions of 1000 ml to select and
to select and remove 100 ml;                                              to remove 100 ml;
- from each of 20 bottles with ofatumumaby     - from each of 2 bottles with ofatumumaby
to select 5 ml of a concentrate (all - 100 ml)  to select 50 ml of a concentrate (all - 100 ml)
 and to enter them into capacity of 1000 ml;           and to enter them into capacity of 1000 ml;
- not to stir up capacity - to mix              - not to stir up capacity - to mix
contents by careful                             contents by careful
turning.                                                             turning.

3) Introduction

Ofatumumab it is not necessary to enter in/in quickly or bolyusno. For in/in introductions the infusional systems attached to drug with the built-in filters are used.

The concentrate of an ofatumumab for preparation of solution for infusions does not contain preservatives therefore its cultivation should be carried out in aseptic conditions. The prepared solution for infusions needs to be stored at a temperature not above 25 °C and to use during 24 h after preparation. After this term the remains of solution should be destroyed.

Ofatumumab it is not necessary to mix or enter along with other drugs or solutions for into introductions. That to avoid it, before and after introduction of an ofatumumab it is necessary to wash out system for introduction of 0.9% chloride sodium solution.

At the first and second introduction the drug should be administered during 6.5 h through infusional system or through a constant catheter according to the following scheme.

The scheme of introduction for 1 and 2 introductions of an ofatumumab
Time (min.)              Speed of infusion (ml/h)
                                      0-30 12
                                    31-60 25
                                    61-90 50
                                  91-120 100
                              More than 121 200

If the second introduction took place without development of serious undesirable reactions, other introductions (3-12) should be carried out during 4 h through infusional system or through a constant catheter according to the following scheme.

The scheme of introduction for introductions of an ofatumumab with 3 on 12

Time (min.)             Speed of infusion (ml/h)
                                    0-30 25
                                  31-60 50
                                  61-90 100
                                 91-120 200
                            More than 121 400

Features of use:

Reactions to introduction

At use of an ofatumumab the reactions to introduction demanding the temporary termination of treatment or its cancellation can be observed. Premedication can weaken reactions to introduction, however even in this case reactions can develop, generally during the first introduction. Reactions to introduction can include: anaphylactic reactions, the undesirable phenomena from cardiovascular system, a fever, cough, a syndrome of emission of cytokines, diarrhea, short wind, fatigue, inflows, increase or decrease in the ABP, nausea, pain, temperature increase, rash and urticaria. Cases of development of serious reactions to introduction of an ofatumumab, including a syndrome of emission of cytokines, were described even when carrying out premedication. In case of development of serious reactions to introduction it is necessary to suspend immediately administration of drug and to carry out a symptomatic treatment.

Most often reactions to introduction develop in day of the first introduction, and at the subsequent introductions their expressiveness decreases. At patients with dysfunction of lungs in the anamnesis the risk of development of the complications from respiratory system caused by development of serious reactions to introduction therefore during introduction of an ofatumumab it is necessary to monitor function of breath carefully can be increased.

Syndrome of a lysis of a tumor

At patients with HLL at introduction of an ofatumumab the syndrome of a lysis of a tumor can develop. Medical actions in such cases include correction of electrolytic balance, control of function of kidneys, podderzhrezultata of clinical tests do not contain any data on cases of overdose of an ofatumumab.

aniye of a water balance and symptomatic treatment.

The progressing multifocal leukoencephalopathy

At patients from HLL receiving treatment by cytotoxic drugs the progressing multifocal leukoencephalopathy (PMOLEP) including leading to a lethal outcome can develop. The diagnosis of PMOLEP should be excluded at all patients who report about development in them of neurologic symptomatology or about change of character of the neurologic symptoms existing earlier. At suspicion on PMOLEP treatment ofatumumaby it is necessary to stop and address for consultation the neurologist.

Vaccination

Safety of vaccination the live weakened or inactivated vaccines and developmental potency of primary or secondary immune response on them during treatment ofatumumaby did not investigate. As the quantitative maintenance of V-cells decreases, the response to vaccination can be weakened. Before vaccination of the patients who are receiving medical treatment ofatumumaby it is necessary to estimate a ratio of risks and advantage of vaccination of these patients. Due to the existence of risk of development of an infection it is necessary to avoid administration of live attenuated vaccines on an extent or upon termination of therapy ofatumumaby before normalization of quantity of V-lymphocytes.

Hepatitis B

The patients receiving офатумумаб owing to immunosuppressive effect of therapy have an increased risk of infection with a virus of hepatitis B (HBV) and its reactivation which can, including, lead to a lethal outcome. Before an initiation of treatment ofatumumaby it is necessary to reveal patients with high risk of development of the disease caused by HBV. At HBV carriers during treatment ofatutumaby and within 6-12 months after its termination it is necessary to watch laboratory and clinical signs of development of an active infection of HBV carefully. Treatment ofatumumaby those patients at whom the viral hepatitis develops should be stopped and carried out by him the corresponding antiviral therapy. Data on safety of use of an ofatumumab for patients with active hepatitis are not enough to draw a certain conclusion.

Cardiovascular diseases

With heart diseases in the anamnesis it is necessary to watch a condition of patients carefully. If at patients serious or life-threatening violations of a heart rhythm, treatment ofatumumaby develop it is necessary to stop.

Impassability of intestines

At the patients receiving treatment anti-СD20 monoclones, in particular ofatumumaby development of impassability of intestines was sometimes noted. Patients with complaints to the abdominal pains in particular developing at the beginning of a course of treatment ofatumumaby they need to inspect and appoint the corresponding therapy.

Laboratory inspection

As офатумумаб contacts all CD20-positive lymphocytes (both tumoral, and normal), during treatment ofatumumaby it is necessary to carry out control of a gemogramma through regular periods; if at patients the cytopenia develops, the research should be done to a thicket. At development of a cytopenia it is necessary to carry out the corresponding therapy.

Influence on ability to driving of motor transport and to control of mechanisms

Researches of influence of an ofatumumab on ability to drive the car or to work at the automatic equipment were not conducted. Proceeding from pharmacological properties of an ofatumumab, the bases to suspect adverse effect of drug on these types of activity is not present. By consideration of a possibility of the patient to perform the operations demanding the increased concentration of attention and speed of psychomotor reactions it is necessary to consider a clinical condition and a profile of side reactions of an ofatumumab.

Side effects:

Determination of frequency of side reactions: very often (≥1/10), it is frequent (≥1/100 and <1/10), infrequently (≥1/1000 and <1/100), is rare (≥1/10 000 and <1/1 000), is very rare (<1/10 000, including separate cases), it is unknown (frequency cannot be determined on the basis of the available data). Categories of frequency were created on the basis of clinical trials of drug.

From bodies of a hemopoiesis: very often - a neutropenia, anemia; often - a febrile neutropenia, thrombocytopenia, a leukopenia; infrequently - an agranulocytosis, a coagulopathy, a lymphopenia, an aplasia of an erythrocyte sprout.

From immune system: often - hypersensitivity; infrequently - anaphylactic reactions, including an acute anaphylaxis.

From a metabolism: infrequently - a syndrome of a lysis of a tumor.

From cardiovascular system: often - tachycardia, arterial hypertension, arterial hypotension.

From respiratory system: often - pains in laryngopharyngeal area, short wind, cough, a bronchospasm, discomfort in a thorax, a nose congestion, a hypoxia.

From the alimentary system: often - nausea, impassability of thin department of intestines, diarrhea.

From skin and a hypodermic fatty tissue: very often - rash; often - an itch, urticaria, inflows.

Consecutive infections: very often - bronchitis, pneumonia; often - sepsis, septic shock, the infection caused by the Varicella zoster virus, infections of urinary tract; it is unknown - the progressing multifocal leukoencephalopathy, hepatitis B.

General reactions: often - fatigue, a fever, a hyperhidrosis, a syndrome of emission of cytokines, a hyperthermia, dorsodynias.

Interaction with other medicines:

Any researches of medicinal interaction between ofatumumaby and other drugs were not conducted.

At combined use of an ofatumumab with the drugs having immunosuppressive activity increase in risk of development of infectious diseases is possible.

Contraindications:

— heavy renal failures (KK <30 ml/min.);

— pregnancy;

— breastfeeding period;

— children's and teenage age up to 18 years;

— hypersensitivity to drug components.

With care: hepatitis B in the anamnesis, dysfunction of lungs and a heart disease in the anamnesis.

Use of the drug ARZERRA® at pregnancy and feeding by a breast
The drug Arzerra® is contraindicated at pregnancy and in the period of a lactation (breastfeeding).

Use at abnormal liver functions
Any special researches of pharmacokinetics of an ofatumumab at patients with an abnormal liver function were not conducted. Nevertheless, it is improbable that for patients with an abnormal liver function it will be required to adjust a drug dose.

Use at renal failures
Any special researches of pharmacokinetics of an ofatumumab at patients with a renal failure were not conducted. Nevertheless, it is improbable that for patients with a renal failure it will be required to adjust a drug dose.

Use for elderly patients
Any noticeable influence of age on efficiency and safety of drug was not noted. Considering the available data on efficiency and safety of drug at elderly people, dose adjustment in this group is not required.

Use for children
Safety and efficiency of an ofatumumab at children and teenagers are younger than 18 years it was not investigated.

Overdose:

Results of clinical tests do not contain any data on cases of overdose of an ofatumumab.

Storage conditions:

Drug should be stored in the unavailable to children, protected from light place, at a temperature from 2 °C to 8 °C. Not to freeze. A period of validity - 3 years.

Issue conditions:

According to the recipe

Packaging:

• a concentrate for пригот. solution for инф. 20 mg / 1 ml: фл. 5 ml 3, фл. 50 ml 1 in set. with 2 infusional systems with the built-in filters - LP-001550, 01.03.12. Acting.