Actemra concentrate for infusion solution 20 mg / ml (200 mg / 10 ml) 10 ml (Totsylyzumab)

Dosage form

Concentrate for solution for infusion

Pharmacological action of

Mechanism of action of

Tocilizumab is a recombinant humanized monoclonal antibody to the human receptor for interleukin-6 (IL-6) from the IgG1 immunoglobulin subclass. Tocilizumab selectively binds and inhibits both soluble and membrane receptors of IL-6 (sIL-6R and mIL-6R). IL-6 is a multifunctional cytokine produced by various types of cells, and is involved in paracrine regulation, systemic physiological and pathological processes, such as stimulation of Ig secretion, activation of T cells, stimulation of the production of acute phase proteins in the liver and stimulation of hematopoiesis. IL-6 is involved in the pathogenesis of various diseases, including inflammatory diseases, osteoporosis and neoplasms.

It is impossible to exclude the possibility of a negative effect of tocilizumab on the antitumor and anti-infection protection of the body. The role of IL-6 receptor inhibition in tumor development is not known.

Clinical efficacy in rheumatoid arthritis (RA)

Drug efficacy in patients treated with tocilizumab as monotherapy, and in combination with methotrexate (MT) or basic anti-inflammatory drugs (BPV), it did not depend on the presence and absence of rheumatoid factor, age, gender, race, the number of previous treatment courses or the stage of the disease. The response to therapy arose quickly (already in the second week), further intensified and persisted for more than 3 years in ongoing open and extended studies.

In patients who received tocilizumab at a dose of 8 mg / kg, the disease activity index on the DAS28 scale decreased significantly compared with patients who received placebo + BPV. The number of patients who achieved clinical remission (DAS28 <2.6) at week 24 was significantly higher in the tocilizumab therapy group (28-34%) compared with the control group (1-12%). By week 52 of therapy, the number of patients reaching DAS28 <2.6, increases to 47% compared with 33% at week 24 of therapy.

A good or satisfactory EULAR response was observed more often in patients who received tocilizumab than did those who received placebo + BPV.

After 2 years of tocilizumab / MT therapy, a significant clinical response was observed in 14% of patients (AKP 70 persisted for 24 weeks or more).

X-ray assessment of

83% of patients treated with tocilizumab / MT therapy over the course of the year had no progression of joint destruction (the change in the total Sharpe index was zero or less) compared with 67% of patients receiving placebo / MT. This result was maintained for 2 years of therapy. In 93% of patients, there was no progression of joint destruction between 52 and 104 weeks of therapy.

Quality of life indicators

Patients treated with tocilizumab at a dose of 8 mg / kg (monotherapy or in combination with NSAIDs), compared with those who received MT / NSAIDs, there was a clinically significant improvement in functional activity (according to the HAQ-DI index), a decrease in fatigue (according to the functional rating scale of therapy chronic diseases in terms of fatigue FACIT-Fatigue), as well as improving both physical and mental health indicators according to the SF-36 questionnaire.

Laboratory parameters

After administration of tocilizumab, there is a rapid decrease in the average values ​​of acute phase, C-reactive protein, ESR and serum amyloid A, a decrease in platelet counts within normal values, as well as an increase in hemoglobin (Hb), which was observed most in patients with chronic anemia associated with RA.

Clinical efficacy in patients with early rheumatoid arthritis (pRA) who have not previously received MT therapy

When using tocilizumab monotherapy at a dose of 8 mg / kg and tocilizumab at a dose of 4 or 8 mg / kg every 4 weeks in combination with MT disease activity index according to the DAS28 scale, it is significantly reduced in the groups treated with tocilizumab at a dose of 8 mg / kg, compared with patients who received MT monotherapy. The number of patients who achieved clinical remission (DAS28 <2.6) at week 24 was significantly greater in the groups receiving tocilizumab (38.7-44.8%), compared with the MT monotherapy group (15%). By week 52, the number of patients reaching DAS28 <2.6 in the tocilizumab treatment groups increased to 39.4-49% compared to 19.5% in the MT monotherapy group. The number of patients who achieved an AKP response of 20, 50, 70, also significantly higher in the tocilizumab therapy groups (70.2-74.5% 47.6-56.9% 30.1-38.6% at 24 weeks and 63-67.2% 49.3-55.9% 36-43.1% at 52 weeks, respectively) compared with the MT monotherapy group (65.2 % 43.2% 25.4% at week 24 and 57.1% 40.8% 28.9% at week 52, respectively).

X-ray assessment of

No progression of joint destruction (a change in the total Sharpe index is zero or less) is observed in 82-83% of patients receiving tocilizumab at a dose of 8 mg / kg as monotherapy or in combination with MT, compared with 73% of patients in MT monotherapy group.

Quality of Life Indicators

Clinically significant improvement in functional activity by the HAQ-DI index is observed in patients who received tocilizumab at a dose of 8 mg / kg as a monotherapy or combination with MT, compared with those who received MT monotherapy. With tocilizumab monotherapy (at a dose of 8 mg / kg iv every 4 weeks in patients with RA, with MT intolerance or with the inappropriateness of continuing MT therapy (including with an inadequate response to MT therapy)), a more pronounced statistically significant decrease disease activity according to the DAS28 scale compared with adalimumab monotherapy (at a dose of 40 mg sc every 2 weeks). The number of patients responding to therapy with DAS28 <2.6 and DAS28 3.2 was greater with tocilizumab therapy than with adalimumab therapy (39.9% versus 10.5% and 51.5% versus 19.8%, respectively). ACP responses of 20, 50, 70 were observed in 65%, 47.2%, 32.5% of patients receiving tocilizumab, compared with 49.4%, 27.8%, 17.9% of patients receiving adalimumab.

Clinical efficacy in polyarticular juvenile idiopathic arthritis (sJIA)

AKP responses of 30, 50, 70, 90 were obtained in 89.4%, 83.0%, 62.2% and 26.1% of patients, respectively. The proportion of patients with an AKP response of 30, 50, 70 at the 40th week of therapy relative to the indicators at the beginning of therapy was 74.4%, 73.2% and 64.6%, respectively.

Clinical efficacy in systemic juvenile idiopathic arthritis (sJIA)

The efficacy of tocilizumab for the treatment of active sJIA was studied in a 12-week, randomized, double-blind, placebo-controlled study period with 2 parallel groups. At week 12, the proportion of patients who achieved an AKP response of 30, 50, 70, 90 with JIA was also higher in the tocilizumab treatment group than in the placebo group: 90.7% versus 24.3%, 85.3% versus 10.8%, 70.7% versus 8.1%, 37.3% vs 5.4%, respectively (p <0.0001). The response to therapy remained in the open extended period of the study.

Systemic effects of

In 85% of patients who had initial fever, there was no fever after 12 weeks of tocilizumab therapy compared with 21% of patients receiving placebo (p <0.0001). In addition, in 64% of patients who had the rash at baseline, there was no rash after 12 weeks of tocilizumab therapy compared with 11% of patients receiving placebo (p = 0.0008). There was a significant decrease in pain intensity in the tocilizumab therapy group compared with placebo at week 12. The adjusted average change in pain score on the visual analogue scale (VAS) after 12 weeks of tocilizumab therapy corresponded to 41 points (from 0 to 100 points) compared to 1 point in patients receiving placebo (p <0.0001). Systemic effects persisted in the ongoing open extended study period.

Reducing the dose of corticosteroids

In 8 out of 31 patients in the placebo group and in 48 of 70 patients in the tocilizumab group receiving corticosteroids, an AKP 70 response was observed at JIA at 6 or 8 weeks, which reduced the dose of corticosteroids. At the same time, 24% of patients in the tocilizumab group and 3% of patients in the placebo group were able to reduce the dose of GCS by at least 20% without a subsequent decrease in the frequency of response according to the criteria of AKP 30 in JIA (according to the criteria of the American College of Rheumatologists, AKP) or the occurrence of systemic manifestations by 12 week (p = 0.028). The dose reduction of GCS continued, while 44 patients did not receive GCS at 44 weeks, and the AKP responses did not change.

Quality of life indicators

At week 12, the proportion of patients in the tocilizumab group, showing a minimal clinically significant improvement in the CHAQ-DI questionnaire (defined as a decrease in the individual total score of 0.13), was significantly higher than the proportion of patients in the placebo group - 77% versus 19%, respectively (p <0.0001). Responses persisted in the ongoing open extended study period.

Laboratory values ​​

Initially, in 67% of the tocilizumab patients, the Hb content was below the normal range. 80% of these patients had an increase in Hb within the normal range at week 12 compared with 7% of patients in the placebo group (p <0.0001). In 88% of the patients from the tocilizumab group who had an initially reduced Hb content, its level increased by 10 g / l by the 6th week, in the placebo group the frequency of increase was 3% (p <0.0001).

Percentage of patients having initial thrombocytosis and having a normal platelet count at week 12, was higher in the tocilizumab group compared with the placebo group - 90% versus 4% (p <0.0001).

After administration of tocilizumab, there was a rapid decrease in the mean values ​​of acute phase indicators: C-reactive protein, ESR, and serum amyloid A.

Preclinical safety data

Carcinogenicity: no studies on the carcinogenicity of tocilizumab have been performed. Available preclinical data demonstrate the contribution of pleiotropic IL-6 to the progression of malignant neoplasms and resistance to apoptosis in various forms of cancer. These data do not suggest that treatment with tocilizumab leads to a significant risk of cancer development and progression.

Mutagenicity: standard genotoxic tests as in prokaryotic, so in eukaryotic cells were negative.

Impact on fertility: Available preclinical data do not suggest the effect of tocilizumab analogues on fertility. In studies on the study of chronic toxicity in cynomolgus monkeys and in female or male mice with IL-6 deficiency, no negative effect of tocilizumab on endocrine or reproductive organs was found.

Teratogenicity: there was no direct or indirect adverse effect on pregnancy or prenatal development with iv administration of tocilizumab to cynomolgus monkeys in the early stages of the gestational period.

Other: there was a slight increase in cases of spontaneous miscarriage / fetal death with a high level of systemic cumulative exposure (more than 100 times greater than that in humans) with a dose of 50 mg / kg / day compared with placebo or a lower level of doses. The frequency of miscarriage was within the historical control for cynomolgus monkeys, in captivity isolated cases of miscarriage / fetal death did not show any correlation between these phenomena and the dose or duration of tocilizumab administration. Despite the fact that IL-6 does not seem to play a decisive role in the development of the fetus or the immunological regulation of the mother-fetus system, the relationship of these phenomena with the administration of tocilizumab cannot be ruled out.

Excretion of the mouse analog of tocilizumab in milk of lactating mice was observed. The use of the mouse analog of tocilizumab did not have a toxic effect on juvenile mice. In particular, there was no violation of skeletal growth, immune function and sexual development.

Pharmacokinetics

Rheumatoid Arthritis

The pharmacokinetic parameters of tocilizumab do not change over time. A more than dose-dependent increase in AUC and Cmin is noted for doses of 4 and 8 mg / kg every four weeks. Cmax increases in direct proportion to the increase in dose. At equilibrium, the calculated AUC and Cmin were 2.7 and 6.5 times higher at a dose of 8 mg / kg compared with a dose of 4 mg / kg, respectively.

AUC, Cmin and Cmax increase with increasing body weight. With a body weight of 100 kg, the calculated average (± standard deviation) AUC in equilibrium was 55 500 ± 14 100 μg H / ml, Cmin and Cmax 19.0 ± 12.0 μg / ml and 269 ± 57 μg / ml, respectively. Since these indicators exceed the average exposure values ​​in the patient population, it is not recommended to increase the dose of the drug above 800 mg per infusion in patients with a body weight of 100 kg.

Polyarticular juvenile idiopathic arthritis (sJIA)

For patients with a body weight of 30 kg receiving tocilizumab at a dose of 8 mg / kg every 4 weeks, the following indicators are characteristic: estimated mean (± standard deviation)

AUC4weed, Cmax and Cmin 29 500 ± 8 660 μg H / ml, 182 ± 37 μg / ml and 7.49 ± 8.2 μg / ml, respectively.

For patients with body weight <30 kg receiving tocilizumab at a dose of 10 mg / kg every 4 weeks, the following indicators are characteristic: calculated average (± standard deviation) AUC4weed, Cmax and Cmin tocilizumab was 23,200 ± 6,100 μg h / ml , 175 ± 32 μg / ml and 2.35 ± 3.59 μg / ml, respectively.

The cumulation coefficient was 1.05 and 1.16 for AUC4weed and 1.43 and 2.22 for Cmin at a dose of 10 mg / kg (for patients weighing <30 kg) and 8 mg / kg (for patients weighing 30 kg), respectively. No cumulation for Cmax was observed.

Systemic juvenile idiopathic arthritis (sJIA)

The following indicators are characteristic: estimated mean (± standard deviation) AUC2 wk - 32,200 ± 9,960 μg h / ml, Cmax and Cmin - 245 ± 57.2 μg / ml and 57.2 ± 23.3 μg / ml, respectively. The cumulation coefficient for Cmin (12 weeks / 2 weeks) is 3.2 ± 1.3. Cminthocilizumab stabilized after 12 weeks. The calculated mean exposure indices of tocilizumab did not differ in the group of patients weighing 30 kg and in the group of patients weighing <30 kg.

Distribution of

After iv administration, tocilizumab undergoes biphasic elimination from the systemic circulation. In patients with RA, Vd in the central chamber is 3.5 L, in the peripheral chamber - 2.9 L, and Vd in the equilibrium state is 6.4 L.

In children with PUIA, Vd in the central chamber is 1.98 L, in the peripheral chamber it is 2.1 L, and Vd in equilibrium is 4.08 L.

In children with SJIA, Vd in the central chamber is 0.94 L, in the peripheral chamber it is 1.6 L, and Vd in the equilibrium state is 2.54 L.

Excretion

The total clearance of tocilizumab depends on the concentration and is the sum of the linear and non-linear clearance. The linear clearance is 12.5 ml / h in patients with rheumatoid arthritis, 5.8 ml / h in children with PUIA and 7.1 ml / h in children with SIIA. Non-linear clearance, depending on the concentration, is most important at low concentrations of tocilizumab. At higher tocilizumab concentrations, linear clearance predominates due to the saturation of the non-linear clearance path.

T1 / 2 is concentration dependent for rheumatoid arthritis. In rheumatoid arthritis, the apparent concentration-dependent apparent T1 / 2 for tocilizumab at a dose of 4 mg / kg once every 4 weeks is up to 11 days, and for tocilizumab at a dose of 8 mg / kg once every 4 weeks - up to 13 days.

With PUIA T1 / 2 for tocilizumab (at a dose of 8 mg / kg for children with body weight 30 kg and at a dose of 10 mg / kg for children with body weight <30 kg in equilibrium) up to 16 days.

With sJIA T1 / 2 for tocilizumab (at a dose of 8 mg / kg for children with a body weight of 30 kg and at a dose of 12 mg / kg for children with a body weight of <30 kg) at week 12 it is up to 23 days.

Pharmacokinetics in special clinical cases

The pharmacokinetics of tocilizumab in patients with liver failure has not been studied.

No specific studies have been conducted to study the pharmacokinetics of tocilizumab in patients with renal failure. Most patients with rheumatoid arthritis, taken into account in a population pharmacokinetic analysis, had normal renal function or impaired renal function of mild severity (CC according to the Cockcroft-Gault formula <80 ml / min and 50 ml / min), which did not affect the pharmacokinetics of tocilizumab . Dose adjustment of tocilizumab in patients with impaired renal function of mild severity is not required.

Population pharmacokinetic analysis in adult patients with rheumatoid arthritis showed that age, gender and race do not affect the pharmacokinetics of tocilizumab. Appropriate dose adjustment of tocilizumab is not required.

Indications

rheumatoid arthritis with moderate or high activity in adults, both as monotherapy and in combination with methotrexate and / or other basic anti-inflammatory drugs, incl. for inhibition of radiologically proven destruction of

joints, active polyarticular juvenile idiopathic arthritis in patients aged 2 years and older, both as monotherapy and in combination with

methotrexate, active systemic juvenile idiopathic arthritis in patients aged 2 years and older as monotherapy, and in combination with methotrexate.

Contraindications

hypersensitivity to tocilizumab, any component of the drug in the history of

active infectious diseases (including tuberculosis)

children under 2 years of age for patients with polyarticular juvenile idiopathic arthritis and systemic juvenile idiopathic arthritis

age under 18 for patients with rheumatoid arthritis

combination with TNF-α inhibitors or use within 1 month after treatment with anti-TNF antibodies.

Pregnancy and lactation

The safety and effectiveness of Actemra during pregnancy have not been adequately studied. Studies in monkeys did not reveal the dysmorphogenetic potential of Actemra. However, with the introduction of the drug in high doses, an increased risk of spontaneous miscarriage / fetal death was found. The significance of this information to humans is not known.

Tocilizumab should not be used during pregnancy, unless there is a clear clinical need.

It is not known whether Actemra is excreted in human milk. Despite the release of endogenous IgG with breast milk, systemic absorption of the drug during breastfeeding is unlikely due to the rapid proteolytic degradation of such proteins in the digestive system.

When deciding whether to continue / discontinue breastfeeding or to continue / discontinue tocilizumab therapy, the benefits of breastfeeding for the baby and the benefits of continuing therapy for the mother should be taken into account.

Dosing and dose

Standard dosing

Actemra should divorce doctor or nurse sterile 0.9% sodium chloride solution under aseptic conditions. It is recommended to administer iv drip for at least 1 hour.

Rheumatoid arthritis

The drug is administered iv drip at a dose of 8 mg / kg once every 4 weeks.

Actemra can be used both in monotherapy and in combination with methotrexate and / or BPV.

A dose increase of more than 800 mg per infusion is not recommended for patients weighing> 100 kg.

Preparation of

solution Calculate the amount of drug required for administration to the patient (based on 0.4 ml per 1 kg of body weight (0.4 ml / kg)).

Under aseptic conditions, from an infusion vial (package) containing 100 ml of 0.9% sodium chloride solution (the solution must be sterile and pyrogen-free), take a single sterile syringe with the amount of 0.9% sodium chloride solution equal to the amount of Actemra calculated for administration.

Using another disposable sterile syringe under aseptic conditions, take the calculated amount of the drug from the bottle with Actemra and put it into the infusion bottle (bag) with 0.9% sodium chloride solution, as a result, the volume of the prepared solution should be equal to 100 ml.

To mix, gently flip the bottle (bag) to prevent foaming.

Side effects

Infections: The following serious infectious diseases were recorded: pneumonia, phlegmon, infections caused by Herpes zoster, gastroenteritis, diverticulitis, sepsis, bacterial arthritis, some of them were fatal. Cases of opportunistic infections have been reported.

Gastrointestinal Perforation: mainly cases of gastrointestinal perforation were recorded as complications of diverticulitis and included diffuse purulent peritonitis, perforation of the lower gastrointestinal tract, fistula, and abscess.

Infusion reactions: The adverse reactions that were most commonly observed during drug administration were episodes of increased blood pressure. Adverse reactions that were noted within 24 hours after the end of the drug were headache and reactions from the skin (rash, urticaria). These reactions did not limit therapy.

The frequency of anaphylaxis was several times higher in patients receiving the drug at a dose of 4 mg / kg than in patients receiving the drug at a dose of 8 mg / kg. Clinically significant hypersensitivity reactions due to the administration of Actemra and requiring the cessation of treatment were observed in 0.3% of patients. These reactions were observed, as a rule, between the 2nd and 5th infusion of Actemra.

Immunogenicity: antibodies to tocilizumab were detected in 1.6% of the examined patients. In 5 of them, clinically significant hypersensitivity reactions were noted, which led to the complete cancellation of treatment. In 1.1% of patients, neutralizing antibodies were detected.

Polyarticular juvenile idiopathic arthritis

Infections: The most common infections were nasopharyngitis and upper respiratory tract infections. The incidence of severe infections, as well as infections leading to the temporary cessation of the use of tocilizumab, is significantly higher in patients with body weight <30 kg who received tocilizumab at a dose of 10 mg / kg, compared with patients whose body weight was 30 kg who received tocilizumab at a dose of 8 mg / kg.

Infusion reactions: reactions, associated with infusion, in patients with PUIA, was defined as any phenomenon that occurs during or within 24 hours after infusion. In 5.9% of patients receiving tocilizumab, infusion reactions were observed directly during infusion, in 20.2% of patients, infusion reactions were observed within 24 hours after the infusion. Adverse reactions in patients with PUIA observed during infusion or within 24 hours after infusion did not differ in nature from those observed in patients with RA and SUIA.

Immunogenicity: antibodies to tocilizumab without developing a hypersensitivity reaction were detected in one patient weighing <30 kg who received 10 mg / kg of tocilizumab and subsequently discontinued treatment.

Systemic juvenile idiopathic arthritis

Basically, adverse reactions in patients with SIA did not differ in nature from those observed in patients with rheumatoid arthritis.

Infections: Severe infections reported did not differ from those in patients with RA, with the exception of chickenpox and otitis media.

Infusion reactions: infusion-related reactions in patients with sJIA have been defined as any phenomenon that occurs during or within 24 hours after the infusion. In patients receiving tocilizumab, adverse events were: rash, urticaria (severe), diarrhea, epigastric discomfort, arthralgia, headache, etc. In <1% of patients receiving tocilizumab, a clinically significant hypersensitivity reaction associated with therapy was recorded and demanding its cancellation.

Immunogenicity: antibodies to tocilizumab were detected in 2 of 112 examined patients. One of them developed a hypersensitivity reaction, which led to the cancellation of treatment.

Changes in laboratory parameters (hematologic abnormalities)

Neutrophils

Rheumatoid arthritis

A decrease in the number of neutrophils below 1 × 109 / L was observed in 3.4% of patients treated with Actemra at a dose of 8 mg / kg in combination with BPV, compared to less than with 0.1% of patients who received placebo in combination with NSAIDs. In approximately half the cases, a decrease in ACN below 1 × 109 / L occurred within 8 weeks after the start of treatment. A decrease in the number of neutrophils below 0.5 × 109 / L was reported in 0.3% of patients receiving Actemra at a dose of 8 mg / kg in combination with BPV.

There was no clear link between a decrease in the number of neutrophils below 1 × 109 / L and the development of serious infectious diseases.

Polyarticular juvenile idiopathic arthritis

During routine monitoring of laboratory parameters, a decrease in the number of neutrophils below 1 × 109 / L was observed in 3.7% of patients receiving Actemra. There was no association between a decrease in the number of neutrophils below 1 × 109 / L and the development of serious infectious diseases.

Systemic juvenile idiopathic arthritis

When routine monitoring of laboratory parameters during 12 weeks of therapy, a decrease in the number of neutrophils below 1 × 109 / L occurred in 7% of patients receiving Actemra, and was absent in patients receiving placebo.

In the subsequent observation period, a decrease in the number of neutrophils below 1 × 109 / L was recorded in 15% of patients receiving Actemra.

There was no clear link between a decrease in the number of neutrophils below 1 × 109 / L and the development of serious infectious diseases.

Platelets

Rheumatoid arthritis

A decrease in platelet count below 100–103 / μl was observed in 1.7% of patients treated with Actemra at a dose of 8 mg / kg in combination with BPD and was not accompanied by the development of bleeding episodes.

Polyarticular juvenile idiopathic arthritis

During routine monitoring of laboratory parameters, a decrease in platelet count of 50 × 103 / μl occurred in 1% of patients treated with Actemra. These changes were not accompanied by the development of episodes of bleeding.

Systemic juvenile idiopathic arthritis

When routine monitoring of laboratory parameters within 12 weeks of therapy, a decrease in platelet count of 100 × 103 / μl occurred in 1% of patients, in the subsequent follow-up period a decrease in platelet count below 100 103 / μl was recorded in 3% of patients receiving Actemra. These changes were not accompanied by the development of episodes of bleeding.

Increased activity of hepatic transaminases

Rheumatoid arthritis

Adding drugs with potential hepatotoxicity (for example, methotrexate) to tocilizumab monotherapy led to an increase in the incidence of increased transaminases. An increase in hepatic transaminase activity was not accompanied by a clinically significant increase in direct bilirubin, as well as clinical manifestations of hepatitis or liver failure. In patients who received tocilizumab at a dose of 8 mg / kg in combination with HDL, the incidence of indirect bilirubin VHF was 6.2%. A transient increase in ALT activity (more than 3 times higher than VGN) observed in adult patients with medium or high activity PPA (mean disease duration 6 months) who have not previously received methotrexate therapy, had a more pronounced tendency to return to normal values compared with the rheumatoid arthritis patient population.

Polyarticular juvenile idiopathic arthritis

During routine monitoring of laboratory parameters, an increase in ALT or ACT activity 3 times higher than VGN was recorded in 3.7% and <1% of patients, respectively.

Systemic juvenile idiopathic arthritis

During routine monitoring of laboratory parameters in the 12-week treatment period, an increase in ALT or AST activity 3 times greater than VGN was recorded in 5% and 3% of patients receiving tocilizumab, respectively. In the subsequent follow-up period, an increase in ALT or ACT activity, which is 3 times higher than VGN, was registered in 12% and 4% of patients receiving tocilizumab, respectively.

Change in lipid metabolism

Rheumatoid arthritis

During therapy with Actemra, an increase in lipid metabolism (total cholesterol, triglycerides, HDL, LDL) was observed. A persistent increase in total cholesterol> 6.2 mmol / L (240 mg / dl) was observed in 24% of patients, and a persistent increase in LDL 4.1 mmol / L (160 mg / dl) in 15% of patients. In most patients, the atherogenic index did not increase, and the increase in total cholesterol was effectively corrected by lipid-lowering drugs.

Polyarticular juvenile idiopathic arthritis

During routine monitoring of laboratory parameters, an increase in total cholesterol> 1.5 VGN-2 VGN was observed in one patient (0.5%) treated with Actemra. An increase in LDL> 1.5 VGN-2 VGN was observed in only one patient (0.5%) treated with Actemra.

Systemic juvenile idiopathic arthritis

An increase in total cholesterol> 1.5 VGN-2 VGN occurred in 1.5% of patients treated with Actemra. An increase in LDL> 1.5 VGN-2 VGN occurred in 1.9% of patients receiving Actemra.

Post-marketing observation

The safety profile of the drug for post-marketing use is consistent with clinical studies, with the exception of cases of fatal anaphylaxis recorded with Actemra.

Drug Interaction

Polyvinyl alcohol undergoes esterification reactions characteristic of compounds with secondary hydroxy groups. It breaks down in strong acids and softens or dissolves in weak acids and alkalis. At high concentrations, the substance is incompatible with inorganic salts, especially phosphates and sulfates. Sludge formation of 5% polyvinyl alcohol can be caused by reaction with phosphates.

The pharmacokinetic parameters of tocilizumab remain unchanged with the use of other drugs for the treatment of rheumatoid arthritis (such as antimalarial drugs (chlorchinin and its derivatives), immunosuppressants (azathioprine, leflunomide), foliogetic acid and folic acid paracetamol, tramadol, codeine and their derivatives)).

Concurrent administration of tocilizumab at 10 mg / kg and methotrexate at 10-25 mg once weekly did not have a clinically relevant effect on methotrexate exposure.

No studies have been conducted to investigate the combined use of tocilizumab with other biological BPVs.

Because the expression of CYP450 hepatic isozymes is inhibited by cytokines (eg, IL-6, which stimulates chronic inflammation), was slightly elevated or similar to that of healthy volunteers.

At the beginning or at the end of therapy, Aktemra should be closely monitored for patients receiving the medicines at individually selected doses and which are metabolized by CYP450 3A4, 1A2 or 2C9 isoenzymes (eg, atorvastatin, slow calcium channelin blockers, vartofenin, , cyclosporine or benzodiazepines). To ensure the therapeutic effect of these drugs may need to increase their dose. Given the long-term T1 / 2 of Actemra, its effect on CYP450 isoenzyme activity may persist for several weeks after discontinuation of therapy.

Overdose

Available data on overdose on Actemra is limited. In one case of unintentional overdose of the drug at a dose of 40 mg / kg in a patient with multiple myeloma, no adverse reactions were noted. There were also no serious adverse reactions in healthy volunteers who received a single dose of Actemra at a dose of up to 28 mg / kg, although neutropenia requiring a dose reduction was observed.

Storage conditions

The drug should not be frozen, out of the reach of children, protected from light at a temperature of 2 ° to 8 ° C.

Expiration

2.5 years

dosage form

dosage form srd lkp infusion solution



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