Adzetris - instructions for use, dose, side effects, contraindications

Active substanceBrentuksimab vedotinBrentuksimab vedotin

Similar drugsTo uncover

lyophilizate d / infusion

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

Composition:

1 bottle contains:

Active substance.: brentuksimab vedotin (a conjugate consisting of CD30-directional monoclonal antibody (cAC10) covalently bound to monomethylauristatin E (MMAE) (SGD-1006)) 50 mg *.

Excipients: citric acid monohydrate 2.1 mg, sodium citrate dihydrate 56.1 mg, α, α-trehalose dihydrate 700 mg, polysorbate-80 2.0 mg.

* The amount of Brentuksimab vedotin, including an excess of 10%, is 55 mg.

After reconstitution, each ml of the solution contains 5 mg Brentuksimab vedotin.

Description:

The mass or powder is white or almost white.

The reconstituted solution - colorless, clear or slightly opalescent solution.

Pharmacotherapeutic group:Antitumor agent - antibodies monoclonal

ATX: & nbsp

L.01.X.C.12 Brentuksimab vedotin

Pharmacodynamics:

Brentuksimab vedotin is a conjugate of a monoclonal antibody and an antineoplastic agent that is delivered to tumor cells expressing an antigen Cd30, and causes their selective apoptosis. In preclinical studies, it was found that the biological activity of brutuksimab vedotin is the result of a multi-stage process.Binding of the conjugate of the antibody and the antitumor agent to the antigen Cd30 on the cell surface triggers the process of endocytosis, as a result of which the "conjugate-Cd30 "enters the cell and is transported to the lysosomes.Inside the cell, the active component of MMAE is released as a result of proteolytic cleavage.A binding of MMAE to tubulin leads to destruction of the microtubule network within the cell, inhibition of the cell cycle, and ultimately to the death of CD30-expressing tumor cell .

In patients with classical Hodgkin's lymphoma and systemic anaplastic large-cell lymphoma (systemic ACCL), the antigen Cd30 is expressed on the surface of tumor cells. This expression does not depend on the stage of the disease, previous therapy and transplantation. Thanks Cd30-directional mechanism of action, Brentuksimabudotin is able to overcome chemotherapeutic resistance, since in patients refractory to multicomponent chemotherapy, the antigen CD30 is invariably expressed, regardless of the previous status of transplantation.

Additional mechanisms of antibody exposure, due to their other properties, can not be excluded. Cd30-directional mechanism of action of Brentuksimab vedotin, stable expression Cd30 in patients with classical Hodgkin's lymphoma and systemic ACCL, as well as therapeutic application spectra and clinical evidence of the effectiveness of the drug for treating these two Cd30-positive tumors, even after several previous lines of therapy, are the biological rationale for using this drug in patients with recurrent or refractory Hodgkin's lymphoma and systemic ACCL with and without previous autologous stem cell transplantation.

Pharmacokinetics:

Suction

The maximum concentrations of brutuksimab vedotin were usually observed at the end of the infusion procedure or at the sampling point closest to the completion of the procedure. A multi-exponential decrease in serum concentrations of Brentuksimab vedotin was observed with a terminal half-life of approximately 4-6 days. Concentrations were approximately proportional to the administered doses.The minimum cumulation of brutuksimab vedotin or its absence, observed at multiple doses every 3 weeks, is consistent with an estimate of the duration of the final half-life.

Characteristic indices C_mOh and AUC for Brentuksimab vedotin after a single injection of the drug at a dose of 1.8 mg / kg, according to the Phase I study, were 31.98 μg / ml and 79.41 μg / ml per day, respectively.

The main metabolite of brutuksimab vedotin is MMAE. Medians C_max, AUC and T_mOhfor MMAE after a single injection of the drug at a dose of 1.8 mg / kg, according to the Phase I study, were 4.97 ng / ml, 37.03 ng / ml x day and 2.09 days, respectively. The level of MMAE decreased after multiple doses of Brentuksimab vedotin, and was approximately 50-80% of the level of the first dose.

MMAE is further metabolized predominantly to a metabolite exhibiting equivalent activity. However, the exposure of the metabolite is an order of magnitude lower than that of MMAE. Thus, the activity of this metabolite will not have any significant effect on the manifestation of systemic effects of MMAE.

In the first cycle, the increased level of MMAE correlated with an absolute decrease in the number of neutrophils.

Distribution

In studies in vitro the level of binding of MMAE to human plasma proteins ranged from 68 to 82%. It is not assumed that MMAE will displace other substances or will be replaced by drugs with a high degree of binding to plasma proteins. In studies in vitro MMAE was a substrate of P-glycoprotein and did not inhibit it in clinical concentrations.

In humans, the average volume of distribution at an equilibrium concentration of the drug conjugate is 6-10 liters. Based on the population pharmacokinetic analysis data, the characteristic apparent volume of distribution (the volume of distribution of the metabolite VM or volume of distribution in the peripheral compartment VMP) MMAE was 7.37 liters and 36.4 liters, respectively.

Metabolism

It is assumed that Brentuksimabudotin is catabolized as a protein with recycling or excretion of the amino acid component.

Research data in vivo, conducted on animals or with human participation, suggest that only a small fraction of MMAE released from brutuksimab vedotin is metabolized. The levels of MMAE metabolites in human plasma were not measured. At least one MMAE metabolite showed activity in vitro.

MMAE is a substrate CYP3A4 and, possibly, CYP2D6. Research data in vitro indicate that the metabolism of MMAE predominantly proceeds by oxidation via CYP3A4/5. In studies in vitro Using human liver microsomes, it was shown that MMAE has an inhibitory effect on CYP3A4/5 only in concentrations significantly exceeding the concentrations permitted for clinical use. MMAE does not inhibit other isoforms.

MMAE did not activate any of the major enzymes CYP450 in primary cultures of human hepatocytes.

Excretion

Brutuximab removal of vedotin occurs by catabolism with a characteristic clearance and half-life of 1.457 liters / day and a duration of 4-6 days, respectively.

The excretion of MMAE was limited by the rate of its release from the conjugate to the monoclonal antibody, the characteristic clearance and half-life of MMAE were 19.99 L / day and 3-4 days, respectively.

The excretion study was conducted with the participation of patients who received Brentuksimabudotin in a dose of 1.8 mg / kg. Approximately 24% of the total MMAE,introduced in a conjugate with a monoclonal antibody during the infusion of brutuksimab vedotin, was detected in urine and feces for 1 week. Of this amount, approximately 72% was found in the stool. A smaller amount of MMAE (28%) was excreted by the kidneys.

Special patient groups

Population pharmacokinetic analysis showed that the initial concentration of serum albumins significantly influences the clearance of MMAE. The analysis showed that in patients with low serum albumin concentrations (<3.0 g / dL), the MMAE clearance was lower by a factor of 2, compared to patients with normal serum albumin concentrations.

Liver failure

The pharmacokinetics of the drug and MMAE after administration of 1.2 mg / kg of the drug to patients with weak (Child-Pugh class A; n = 1), medium (Child-Pugh class B; n = 5) and severe (Child-Pugh class C; n = 1) the degree of hepatic insufficiency. In comparison with patients with normal hepatic function, in patients with hepatic insufficiency, the release of MMAE increased approximately 2.3-fold.

Renal insufficiency

The pharmacokinetics of the drug and MMAE after administration of 1.2 mg / kg of the drug to patients with mild (n = 4), moderate (n = 3) and severe (n = 3) degrees of renal failure were studied.In comparison with patients with normal renal function, in patients with severe renal failure, the release of MMAE increased approximately 1.9-fold.

Elderly patients

Clinical studies of brutuksimab vedotin did not include a sufficient number of patients older than 65 years. Thus, at the present time it is impossible to establish whether the response to treatment varies between elderly and young patients.

Children's population

Clinical studies of brutuksimab vedotin did not include sufficient numbers of patients younger than 18 years of age. Thus, at the present time it is impossible to establish whether the pharmacokinetics differ in these patients from adult patients.

Indications:

Treatment of patients with recurrent / refractory Cd30+ Hodgkin's lymphoma after autologous stem cell transplantation or after a minimum of two lines of previous therapy, when autologous stem cell transplantation or combined chemotherapy is not considered a treatment option.

Treatment of patients with Cd30+ Hodgkin's lymphoma with an increased risk of recurrence or progression of the disease * after autologous stem cell transplantation.

Treatment of patients with recurrent / refractory systemic anaplastic large-cell lymphoma.

* Factors of increased risk of recurrence or progression of the disease are:

Hodgkin's lymphoma, resistant to the first line of therapy;
relapse or progression of Hodgkin's lymphoma within 12 months after the end of the first line of therapy;
the presence of extranodal lesions, including the spread of nodal masses to vital organs, with relapse to autologous transplantation of hematopoietic stem cells.

Contraindications:

- Hypersensitivity to any of the components of the drug;

- joint use of brentuksimab vedotin with bleomycin due to the occurrence of pulmonary toxicity;

- pregnancy and the period of breastfeeding, children under 18 years of age (efficacy and safety not proven).

Pregnancy and lactation:

Women of reproductive age should be warned about the need to protect themselves from pregnancy while treating brethtuximab with vedotin, and should use two methods of effective contraception during the period of using brutuksimab vedotin, and also within 6 months after the end of treatment.In case of pregnancy during treatment with brutuksimab vedotin, the patient should be informed of the potential threat to the fetus.

Pregnancy

There are no data on the use of brutuksimab vedotin in pregnant women. The use of the drug during pregnancy is contraindicated.

Breast-feeding

There is no data on the excretion of the drug or its metabolites with breast milk. The risk to the baby can not be ruled out. The use of the drug in the period of breastfeeding is contraindicated.

Male fertility

It is not known whether the use of the drug has an effect on human spermatogenesis. Preclinical studies revealed testicular toxicity, which could lead to a change in male fertility. The presence of aneugenic effects in MMAE has been established. Men who plan treatment with brutuksimab vedotin are advised to donate sperm samples before starting therapy. Men undergoing treatment with brutuksimab vedotin, and also within 6 months after the last dose of the drug, are recommended to use a suitable method of barrier contraception,and it is not recommended to plan the conception of a child.

Dosing and Administration:

Intravenously, as infusions. The drug should be used under the supervision of a doctor who has experience in the use of antitumor drugs. Before each dose administration, a clinical blood test should be performed. Patients should be under strict supervision during and after infusion.

Dosage

The recommended dose is 1.8 mg / kg as an intravenous infusion for 30 minutes every 3 weeks.

If the patient's body weight exceeds 100 kg, a weight value of 100 kg should be used when calculating the dose.

The recommended initial dose for the re-treatment of patients with recurrent or Hodgkin's refractory lymphoma or systemic ACHL, with a previous response to therapy with Brentuksimab vedotin, is 1.8 mg / kg as an intravenous infusion for 30 minutes every 3 weeks. Treatment can also begin with the last tolerated dose.

Severe renal insufficiency

For patients with severe renal insufficiency, the recommended initial dose is 1.2 mg / kg, administered intravenously in the form of infusion for 30 minutes every 3 weeks.Patients with renal failure must be under strict supervision (see. The section "Pharmacological properties").

Liver failure

For patients with hepatic insufficiency recommended initial dose of 1.2 mg / kg, administered intravenously as an infusion over 30 minutes every 3 weeks. Patients with liver failure must be under strict supervision (see. The section "Pharmacological properties").

Duration of therapy

When a stable condition is reached or if the disease progresses, the patient with recurrent / refractory Hodgkin's lymphoma or systemic ACHL should pass, at least, 8, but no more than 16 cycles of treatment (approximately 1 year).

Have Patients with Hodgkin's lymphoma at an increased risk of recurrence or progression after autologous stem cell transplantation brentuximab vedotin application should be started after recovery from autologous stem cell transplantation is based on clinical evaluation. Such patients should undergo up to 16 courses of therapy.

Calculation of dose

Calculation of the total volume (ml) of the drug solution for further dilution:

Dose of the preparation (mg / kg) x body weight of the patient (kg) / Concentration of reconstituted solution (5 mg / ml) = Total dose of the preparation (ml) for further dilution

Calculation of the required number of vials of the drug:

Total dose of the preparation (ml) for administration / Total volume in one vial (10 ml / bottle) = Required number of vials of the preparation

Table. 1. Examples of calculations for patients with body weight from 60 kg to 120 kg. The recommended dose of the drug is 1.8 mg / kg.

Body weight of the patient (kg)	General information dose = body weight of the patient, multiplied by the recommended dose [1.8 mg / kg^a]	General information amount for breeding^b= total dose, divided on the concentration of the solution reconstituted in the vial [5 mg / ml]	Required number of vials = total volume for dilution, divided by total volume in one vial [10 ml / bottle]
60 kg	108 mg	21.6 ml	2,16 bottles
80 kg	144 mg	28.8 ml	2.88 bottles
100 kg	180 mg	36 ml	5.6 bottles
120 kg^at	180 mg^g	36 ml	3.6 bottles

^aIn the case of a reduced dose, a value of 1.2 mg / kg is used in the calculations.

^b For dilution in 150 ml of solution and administration by intravenous infusion for 30 minutes every 3 weeks.

^at If the patient's body weight exceeds 100 kg, a weight value of 100 kg should be used when calculating the dose.

^g The maximum recommended dose is 180 mg.

Dose adjustment

Neutropenia

If neutropenia is detected during treatment, interval between doses should be increased to control it. The corresponding recommendations for dosing are given in Table. 2 (see also section "Special instructions").

Table. 2. Recommendations for dosing with neutropenia

Severity of neutropenia (signs and symptoms [Abridged description of STAAE^a])

Changing the dosing regimen

Degree 1 (<the lower limit of the norm is 1500 / mm³<the lower limit of the norm is 1.5 x 10⁹/ l) or

Degree 2 (<1500-1000 / mm³<1.5-1.0 x 10⁹/ l)

Continue treatment with the same schedule and with the same dosage

Degree 3 (<1000-500 / mm³<1.0-0.5 x 10⁹/ l) or

Degree 4 (500 / mm)³<0.5 x 10⁹/ l)

Stop treatment until neutropenia severity returns to ≤ 2 or baseline, then continue treatment with the same schedule and with the same dosage^b.

With the development of grade 3 or 4 neutropenia, additional assignment of recombinant hematopoietic factors of G-CSF or GM-CSF is possible.

^a The classification is based on the "General terminology of the criteria undesirable Reactions "(STACEA) in. 3.0 National Cancer Institute (NCI)

^b With the development of lymphopenia of 3 and 4 degrees of severity, patients can continue treatment without changes.

Peripheral Neuropathy

If peripheral sensory or motor neuropathy occurs or aggravates during the treatment period, the following dosage recommendations should be followed (Table 3).

Table. 3. Recommendations for dosing with newly diagnosed or progressive sensory or motor neuropathy

Degree of severity of progressive sensory or motor neuropathy (signs and simpthen we [Abridged description of STAAE^a])	Changing the dosing regimen
Degree 1 (paresthesia and / or loss of reflexes, without loss of functionality)	Continue treatment with the same schedule and with the same dosage
Degree 2 (a violation of functionality, but without an obvious effect on daily activity) Degree 3 (difficulty daily activity)	Stop the treatment until the severity of neuropathy returns to ≤ Degree 1 or baseline, then re-start treatment, using a reduced dosage of 1.2 mg / kg every 3 weeks.
Degree 4 (sensory neuropathy leading to disability, or motor neuropathy, life-threatening or leading to paralysis)	Stop treatment

^a TOThe lassification is based on the "General terminology of the criteria for undesirable reactions" (CTCAE) c. 3.0 National Cancer Institute (NCI)

Elderly patients

The safety and efficacy of the drug in patients 65 years of age or older have not been established. No data available.

Children's population

The safety and efficacy of the drug in children younger than 18 years of age have not been established. No data available.

Preparation infusion solution

General Precautions

During the use of the drug, aseptic conditions must be observed.

Instructions for preparing a reconstituted solution

1. The contents of a single vial for single use must be dissolved in 10.5 ml of sterile water for injection to obtain a solution of 11 ml (including dissolved solids) with a final concentration of 5 mg / ml of Brentuksimab vedotin. Direct the jet along the wall of the vial. Do not direct the jet directly onto the lyophilized mass or powder.

2. Carefully turn the vial to facilitate dissolution. DO NOT BURST.

3. The solution reconstituted in the vial should be clear or slightly opalescent, colorless. The final pH should be 6.6.

4. The reconstituted solution must be inspected for any foreign mechanical inclusions and / or discoloration.In case of detection of foreign mechanical inclusions and / or discoloration, the solution must be destroyed.

Instructions for preparing a solution for administration

Required amount the reconstituted solution of the drug should be removed from the vial (s) and added to the infusion set with a minimum volume of 100 ml containing a solution of sodium chloride for injection of 9 mg / ml (0.9%) in order to obtain a final drug concentration of 0.4-1, 8 mg / ml.

The reconstituted solution can also be diluted with a 5% glucose solution for injection or Ringer's lactate injection.

Gently invert the bag to mix the drug solution.

DO NOT BURST.

Do not add other medications to the prepared infusion solution or intravenous infusion system. The infusion system must be washed with a solution of sodium chloride for injection 9 mg / ml (0.9%), or with a 5% glucose solution for injection or Ringer's lactate injection.

Infusion with the drug is carried out immediately after the preparation of the solution.

The total storage time of the solution from the moment of dissolution to the receipt of infusion by the patient should not exceed 24 hours at a temperature of 2 to 8 ° C. the preparation does not contain preservatives.

Mode of application

The recommended dose of the drug is administered as an infusion for 30 minutes.

Instructions on dissolution and dilution before the administration of the drug are given in the subsection "Preparation of an infusion solution."

Do not inject the drug solution with an intravenous bolus or bolus injection. The solution of the drug should be administered through a separate intravenous catheter, while it should not be mixed with other drugs.

Treatment should be discontinued in the event of progression of the disease or undesirable toxicity.

Side effects:

Unwanted reactions to the drug are ordered according to the system-organ class and are consistent with the terms of preferred use (in accordance with the Medical Dictionary for Regulatory Activities - MedDRA) (see Table 4). Within the category of the system-organ class, the reactions are distributed according to the frequency of occurrence according to the following scheme: very often (≥1 / 10), often (≥1 / 100 to <1/10), infrequently (≥1 / 1000 to <1/100) rarely (≥10,000 to <1/1000), very rarely (<1/10 000), the frequency is unknown (can not be calculated from available data).

Table. 4. Undesirable reactions recorded after application of the drug

Frequency	Undesirable reactions
Infectious and parasitic diseases
Often:	Infection^a, upper respiratory tract infection
Often:	Sepsis / septic shock, shingles, pneumonia, herpes simplex
Infrequently:	Candidiasis stomatitis, pneumocystis pneumonia, staphylococcal bacteremia
Frequency unknown:	Progressive multifocal leukoencephalopathy
Violations of the blood and lymphatic system
Often:	Neutropenia
Often:	Anemia, thrombocytopenia
Frequency unknown:	Febrile neutropenia
Immune system disorders
Frequency unknown:	Anaphylactic reaction
Disorders from the metabolism and nutrition
Often:	Hyperglycaemia
Infrequently:	Tumor lysis syndrome
Disturbances from the nervous system
Often:	Peripheral sensory neuropathy, peripheral motor neuropathy
Often:	Dizziness, demyelinating polyneuropathy
Disturbances from the respiratory system, chest and mediastinal organs
Highly often:	Cough, shortness of breath
Frequency unknown:	Pneumonitis, interstitial lung disease, acute adult respiratory distress syndrome (ARDS)^b
Disorders from the gastrointestinal tract
Often:	Diarrhea, nausea, vomiting, constipation, abdominal pain
Infrequently:	Acute pancreatitis
Frequency unknown:	Intestinal obstruction, enterocolitis, neutropenic colitis, erosion, ulcer, perforation and bleeding^b
Violations from cmliver and bile ducts ways
Often:	An increase in the level of alanine aminotransferase / aspartate aminotransferase (ALT / AST)
Frequency unknown:	Hepatotoxicity^b
Disturbances from the skin and subcutaneous tissues
Often:	Alopecia, itching
Often:	Rash
Infrequently:	Stevens-Johnson syndrome, toxic epidermal necrolysis
Disturbances from musculoskeletal and connective tissue
Often:	Myalgia, arthralgia
Often:	Backache
General disorders and disorders at the site of administration
Often:	Fatigue, chills, fever, infusion reactions^at
Laboratory and instrumental data
Often:	Decreased body weight

^aThe terms of preferred use, registered in the class "Infectious and parasitic diseases", include sepsis / septic shock, upper respiratory tract infection, shingles and pneumonia.

^bSome of these unwanted reactions led to a fatal outcome.

^at The terms of preferred use associated with the class "Infusion reactions" are headache, skin rash, back pain, vomiting, chills, nausea, shortness of breath, itching and coughing.

Selective description of undesirable reactions

Neutropenia delayed the following infusions in 14% and 22% of patients participating in Phase II and III studies, respectively.

In the treatment of brutuksimab vedotin, severe and prolonged (≥ 1 week) neutropenia can develop, and this can increase the risk of severe infections.

In Phase II studies the average duration of neutropenia of grade 3 or 4 was limited (1 week), 2% of patients had grade 4 neutropenia, lasting ≥ 7 days. In less than half of Phase II patients, grade 3 or 4 neutropenia was the cause of the temporary development of the infection, most patients with associated infections had neutropenia of 1 or 2 severity.

In patients who participated in Phase III studies, grade 3 neutropenia was noted in 22% of patients receiving treatment with Brentuksimab vedotin, and grade 4 neutropenia was seen in 7% of patients in the same group.None of the patients required a dose reduction or discontinuation of treatment.

In patients who participated in Phase III studies, serious infections were noted in 9% of patients treated with ventotin. In this group there were no cases of bacteremia, sepsis or septic shock.

Peripheral sensory neuropathy delayed the next infusion in 13% and 16% of Phase II and Phase III patients, respectively. In addition, peripheral motor neuropathy and upper respiratory tract infection delayed the next infusion in 6% of patients in the Phase III study.

Peripheral sensory neuropathy resulted in a dose reduction in 9% and 22% of Phase II and Phase III patients, respectively. In addition, peripheral motor neuropathy also resulted in a lower dose in 6% of patients in the Phase III study. 90% and 68% of Phase II and Phase III patients, respectively, continued to receive the recommended dose of 1.8 mg / kg.

In Phase II studies among patients with peripheral neuropathy, the average follow-up from the end of treatment until the last evaluation was approximately 48.9 weeks. At the time of the last evaluation, 83% of 89 patients with peripheral neuropathy, the disappearance or alleviation of peripheral neuropathy symptoms was noted. Average the duration of the period from the beginning to the resolution or alleviation of the symptoms for all undesirable reactions 16 weeks (range 0.3 weeks - 106.6 weeks). Among the patients of the Phase III study, who noted the development of peripheral neuropathy, the median follow-up after the end of treatment and up to the latest assessment of the condition was about 98 weeks. During the last evaluation, 85% of patients who noted the development of peripheral neuropathy in the group of brentuksimab vedotin, the disappearance or improvement of symptoms of peripheral neuropathy. In general, the median time to resolution or improvement of peripheral neuropathy in the group of brutuksimab vedotin was 23.4 weeks (0.1 to 138.3 weeks).

In 11% and 15% of patients in phase II and III studies, respectively, infusion reactions were recorded. In both phase and phase studies, adverse events most commonly associated with infusion reactions were mild to moderate (grade 1 or 2).They included headache, skin rash, back pain, vomiting, chills, nausea, shortness of breath, itching and coughing.

Were registered cases of development of anaphylaxis (section "Special instructions"). Symptoms of anaphylaxis, among others, may include: urticaria, angioedema, hypotension and bronchospasm.

There have been reported cases of febrile neutropenia (see section "Method of administration and dose"). Febrile neutropenia of the 5th degree of severity was observed in the patient included in the first phase of the study with increasing dose, after a single dose of 3.6 mg / kg of brentuksimab vedotin.

Immunogenicity

In two Phase II studies, patients with recurrent or refractory Hodgkin's lymphoma or systemic ACC were assessed for antibodies to Brentuksimab Vedotin every three weeks using sensitive electrochemiluminescent immunoassays. also in Phase III trials involved patients with Hodgkin's lymphoma and an increased risk of recurrence or progression after autologous stem cell transplantation. Approximately 7% of patients who participated in Phase II studies and 6% patients who participated in Phase III studies, the availability of sustainable antibodies to brentuksimabu vedotinu (ATA). Have 2 patients participating in the studies II phase, and 2 patients participating in the studies II phase, undesirable reaction, related to the infusion, which caused discontinuation of treatment.

The appearance of antibodies to brentuksimabu vedotin did not correlate with a clinically significant decrease in serum levels of Brentuksimab vedotin, and did not lead to a decrease in the efficacy of Brentuksimab vedotin. The appearance of antibodies to brentuksimabu vedotin did not necessarily lead to the development of infusion reactions. The incidence of infusion reactions was higher in the group of permanently ATA-positive patients (30%), compared to the group of temporarily ATA-positive patients (12%) and the group of patients in whom ATA was never detected (7%).

Repeated treatment

Repeated treatment 21 patients with recurrent or refractory Hodgkin's lymphoma and 8 patients from recurrent systemic ACC. The average number of courses was 7 (from 2 to 37 courses).

The types and severity of adverse reactions were consistent with those observed in combined Phase II trials with the exception of peripheral motor neuropathy,the frequency of which was higher (28% compared with 9% in phase II studies), often 1 or 2 degrees. Also, patients were more likely to have arthralgia, grade 2 anemia and back pain compared to Phase II patients.

The patient should be informed of the need inform the doctor about all cases undesirable reactions, including those not listed in this manual for medical use.

Overdose:

There is no known antidote to neutralize the effects of an overdose of Brentuksimab vedotin. In case of an overdose, the patient should be placed under strict supervision to detect undesirable reactions, in particular neutropenia, along with this, symptomatic treatment should be carried out.

Interaction:

Interaction with medicinal products metabolized through CYP3A4 (inhibitors / inducers CYP3A4)

As a result of the joint use of Brentuksimab vedotin and ketoconazole, a potent inhibitor CYP3A4 and P-glycoprotein, an increase in the concentration of the anti-microtubulein agent MMAE was approximately 73%, while the level of vinutin in plasma remained unchanged.Thus, the use of brentuksimab vedotin along with potent inhibitors of CYP3A4 and P-glycoprotein may lead to an increase in the incidence of neutropenia. In case of development of neutropenia, see Table. 2 (Recommendations for dosing for neutropenia, section "Method of administration and dose").

As a result of the joint use of Brentuksimab vedotin and rifampicin, a powerful inducer CYP3A4, the level of Brentuksimab vedotin in plasma did not change. Although the amount of pharmacokinetic data is limited, co-administration of rifampicin appears to reduce the plasma concentrations of those MMAE metabolites whose content can be determined.

Combined application midazolam, which is a substrate CYP3A4, and brutuksimaba vedotina did not change the metabolism of midazolam. Thus, it is not assumed that Brentuksimabudotin will change the concentration medicinal substances, metabolized by enzymes CYP3A4.

Special instructions:

Progressive multifocal leukoencephalopathy

Patients undergoing treatment with brutuksimab vedotin may undergo a reactivation of the John Cunningham virus (JC-Virus), leading to the development of progressive multifocal leukoencephalopathy (PML) and death. Cases of PML development have been reported in patients undergoing this treatment after several previous chemotherapeutic regimens.

PML syndrome is a rare demyelinating disease of the central nervous system, resulting from the reactivation of a latent JC-Virus, often ends in a lethal outcome.

Patients should be under strict supervision to identify the occurrence or aggravation of neurological, cognitive or behavioral signs or symptoms that may be harbingers of PML. In case of suspicion of PML, the appointment of vetotinum should be suspended. The recommended scheme for determining PML includes neurologic consultation, magnetic resonance imaging of the brain with gadolinium-based contrast and analysis of cerebrospinal fluid for the presence of DNA JC-Virus by polymerase chain reaction (PCR) or brain biopsy with symptoms of presence JC-virus. Negative PCR result does not exclude PML.Further monitoring and evaluation are reasonable if an alternative diagnosis has not been established. Treatment with brutuksimab vedotin should be completely discontinued if the diagnosis of PML is confirmed.

The physician should be especially attentive to the symptoms suggesting the development of PML, which the patient may not notice (eg, cognitive, neurological or psychiatric symptoms).

Pancreatitis

In patients undergoing treatment with brentuksimab vedotin, cases of acute pancreatitis, including those with fatal outcomes, were reported.

Patients should be under strict supervision to detect first-appearing or worse pain in the abdominal region, which may be a sign of acute pancreatitis. The examination of a patient may include a physical examination, a laboratory test for serum amylase and serum lipase, and visualization of the abdominal cavity with ultrasound or other suitable diagnostic methods. In the case of suspicion of acute pancreatitis, the appointment of brutuksimab vedotin should be suspended.Treatment with brutuksimab vedotin should be completely discontinued if the diagnosis of acute pancreatitis is confirmed.

Pulmonary Toxicity

In patients undergoing treatment with brutuksimab vedotin, cases of pulmonary toxicity were observed, including pneumonitis, interstitial lung disease, and acute adult respiratory distress syndrome (ARDS), in some cases fatal. Although there was no relationship between pulmonary toxicity and brutuksimab, Vedotin, the risk of developing this undesirable The reaction due to the use of brentuksimab vedotin can not be excluded. In detecting or exacerbating pulmonary symptoms (eg, cough, dyspnea), appropriate diagnostic assessment and treatment of patients should be carried out. It is necessary to decide whether to continue therapy Brentuksimab vedotin from the moment of examination of the patient to symptomatic improvement of the condition.

Severe and opportunistic infections

Severe and opportunistic infections such as pneumonia, staphylococcal bacteremia, shingles, candidiasis stomatitis, sepsis / septic shock (including fatal outcomes) have been reported in patients undergoing treatment with brentuksimab vedotin.To identify possible severe and opportunistic infections, patients should be under strict supervision during the treatment period.

Infusion reactions

In patients undergoing treatment with brentuksimab vedotin, infusion reactions, including anaphylactic ones, were recorded.

Patients should be under strict supervision during and after infusion.

With the development of an anaphylactic reaction, the administration of vinutinum should be stopped immediately, and further treatment with this drug is discontinued. Appropriate therapeutic measures should be taken to stop the reaction.

With the development of infusion reactions, the drug should be discontinued immediately, and the necessary therapeutic measures must be taken to stop the reactions. After resolving the symptoms, the infusion can be continued at a slower rate.

Patients who have previously had infusion reactions are advised to take precautionary measures before administering the drug.

Premedication may include paracetamol, an antihistamine or a corticosteroid.

Infusion reactions are more frequent and most pronounced in patients with antibodies to Brentuksimab vedotin (see section "Side effect").

Tumor lysis syndrome

Patients undergoing treatment with brutuksimab vedotin had a tumor lysis syndrome. Patients with a rapidly proliferating tumor and a large tumor mass have an increased risk of developing tumor lysis syndrome. These patients should be under strict control, their treatment should be carried out in accordance with the best methods of medical practice. Treatment of tumor lysis syndrome includes active fluid replenishment in the body, control of kidney function, correction of electrolyte balance disorders, antihyperuricemic therapy, as well as symptomatic therapy.

Peripheral Neuropathy

Treatment with brutuksimab with vedotin can cause the development of peripheral neuropathy, sensory and motor.

Peripheral neuropathy, caused by the introduction of brutuksimab vedotin, is usually the effect of the cumulative effect of this drug, and in most cases reversible.In clinical trials, in most patients, the symptoms of peripheral neuropathy were alleviated.

In patients who participated in the baseline phase II study (SG035-0003 and SG035-0004), the incidence of previous peripheral neuropathy was 24%.

56% of patients received treatment for developing neuropathy. At the time of the last evaluation, the majority of patients (83%) experienced relief of peripheral neuropathy symptoms.

Among patients who had peripheral neuropathy, treatment was stopped in 17%, the dose was reduced to 13%, the administration of the next dose was delayed 21% of patients.

The prevalence of pre-existing peripheral neuropathy in patients with recurrent / refractory Hodgkin's lymphoma or systemic ACHL treated with brutuksimab vedotin was 48%. 69% of patients received treatment for developing neuropathy. At the time of the last evaluation, the majority of patients (80%) experienced relief of peripheral neuropathy symptoms. Among patients who had peripheral neuropathy, treatment was stopped in 21%, the dose was reduced in 34% of patients.

In the study III phase at the time of the last evaluation, the improvement or disappearance of the symptoms of peripheral neuropathy was noted in the majority of patients treated with Brentuksimab Vedotin (85%). In patients who noted the development of peripheral neuropathy, the cessation of therapy with brutuksimab vedotin took place in 23% of patients, a dose reduction was reported in 29% of patients, and a delay in regular infusion occurred in 22% of patients.

Patients should be monitored for signs of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, burning sensation, neuropathic pain, or weakness. If the symptoms of peripheral neuropathy develop or worsen, it may be necessary to delay or adjust the dose of the drug until the treatment is discontinued (see "Dosage and Administration").

Hematological toxicity

In the treatment of brentuksimab vedotin, anemia of grade 3 or 4, thrombocytopenia and prolonged (≥ 1 week) neutropenia of grade 3 or 4 may develop. In patients undergoing treatment with brentuksimab vedotin, febrile neutropenia was recorded.A clinical blood test should be performed before each injection. Patients should be monitored to identify signs of fever. In the case of development of grade 3 or 4 neutropenia, it is necessary to change the dose of the drug until the treatment is discontinued (see section "Method of administration and dose").

Stevens-Johnson syndrome and toxic epidermal necrolysis

In patients undergoing treatment with brutuksimab vedotin, cases of Stevens-Johnson syndrome and toxic epidermal necrolysis, including those with lethal outcomes, were reported. In the event of the development of Stevens-Johnson syndrome or toxic epidermal necrolysis, treatment with brutuksimab vedotin should be stopped, and appropriate therapeutic measures should be taken.

Complications with hand gastrointestinal tract (GIT)

Have patients receiving treatment with brutuksimab vedotin, complications from the gastrointestinal tract, such as intestinal obstruction, enterocolitis, neutropenic colitis, erosion, ulceration, perforation and bleeding, in some cases fatal, have been reported.When new or worsening of previously observed symptoms from the gastrointestinal tract, an immediate diagnostic examination should be performed and adequate therapy started.

Hepatotoxicity

Have of patients receiving treatment with brentuksimab vedotin, manifestations of hepatotoxicity as an isolated increase in alanine aminotransferase (ALT) and aspartate aminotransferase (ACT). Serious cases of development of hepatotoxicity, including those with a fatal outcome, have also been registered.

The presence of liver diseases in history, concomitant diseases and joint intake of drugs may increase the risk of hepatotoxicity.

The liver function should be evaluated in patients before starting therapy and be monitored regularly during the entire time of therapy with brutuksimab vedotin (see section "Side effect"). If the patient has signs of hepatotoxicity, it is necessary to postpone therapy with Brentuksimab vedotin, change the dose of the drug or stop therapy.

Hyperglycaemia

Hyperglycemia has been documented in clinical studies in patients with an increased body mass index, both with and without history of diabetes mellitus.Regardless of the history, the level of serum glucose should be monitored in all patients with a reported case of hyperglycemia. Such patients should be prescribed an appropriate antidiabetic agent.

Renal and hepatic failure

The experience of using the drug in patients with renal or hepatic insufficiency is limited. The available data showed that the clearance of MMAE can be disturbed in cases of severe renal insufficiency, liver failure, and also at low serum albumin concentrations (see section "Pharmacological properties").

The sodium content as an auxiliary substance

The drug contains no more than 2.1 mmol (or 47 mg) of sodium in a single dose. Patients who follow a controlled sodium diet should take this into account.

For single use. Before use, read the instructions for use.

Unused drug residues and medical waste must be disposed of in accordance with national requirements.

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

The drug may have little effect on the ability to drive vehicles and the use of various mechanisms due to the potential for the development of adverse reactions described in these instructions for use.

Form release / dosage:

Lyophilizate for the preparation of concentrate for the preparation of a solution for infusions, 50 mg.

Packaging:

50 mg Brentuksimaba vedotina in a bottle of transparent glass type I, corked with a rubber stopper, crimped aluminum cap with a cap made of polypropylene.

One bottle is placed in a cardboard box with instructions for use. Protective stickers are applied to the pack to control the first opening of the package.

Storage conditions:

Store at a temperature of 2 to 8 ° C, in a consumer package to protect from light.

The reconstituted / infusion solution should be stored at a temperature of 2 to 8 ° C not more than 24 hours. Do not freeze.

Keep out of the reach of children.

Transportation conditions

At a temperature of 2 to 8 ° C, in a dark place.

Do not freeze.

Shelf life:

4 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-003476