2010/09/17

Actemra

Composition, structure and packing

Concentrate for solution for infusion in the form of transparent or opalescent colorless or pale yellow liquid.

1 ml.totsilizumab 20 mg.

1 fl.totsilizumab 400 mg.

Excipients: polysorbate 80, sucrose, sodium hydrogen phosphate dodecahydrate, sodium dihydrogen phosphate dihydrate, water d / and.

Concentrate for solution for infusion in the form of transparent or opalescent colorless or pale yellow liquid.

1 ml. totsilizumab 20 mg.

1 vial. totsilizumab 200 mg.

Excipients: polysorbate 80, sucrose, sodium hydrogen phosphate dodecahydrate, sodium dihydrogen phosphate dihydrate, water d / and.

Concentrate for solution for infusion in the form of transparent or opalescent colorless or pale yellow liquid.

1 ml. totsilizumab 20 mg.

1 vial. totsilizumab 80 mg.

Excipients: polysorbate 80, sucrose, sodium hydrogen phosphate dodecahydrate, sodium dihydrogen phosphate dihydrate, water d / and.

Clinico-pharmacological group: Specific immunosuppressive drug. Receptor antagonist of interleukin-6.

Pharmacological action

Totsilizumab - recombinant humanised monoclonal antibody to the human receptor for interleukin-6 (IL-6) of the immunoglobulin subclass IgG1. Totsilizumab 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 involved in paracrine regulation, systemic physiological and pathological processes, such as stimulating the secretion of Ig, activation of T cells, stimulation of development of acute phase proteins in liver and stimulation of hematopoiesis. IL-6 is involved in the pathogenesis of various diseases, including inflammatory diseases, osteoporosis and tumors. Clinical efficacy in rheumatoid arthritis.

The clinical effect of 20%, 50% and 70% according to the criteria of the American College of Rheumatology (CAF) after 6 months was observed more frequently in the treatment of totsilizumabom than with placebo, regardless of the presence or absence of rheumatoid factor, age, gender, race, number of previous treatments or stage of disease. The response to therapy arose quickly (on the second week), was amplified for the entire course of treatment and persisted for more than 18 months.

In patients treated with totsilizumab, significant improvements were noted in respect of all of the AKP (the number of painful and swollen joints, improving the overall evaluation of the effectiveness of treatment in the opinion of the physician and the patient's degree of functional disorders according to the questionnaire HAQ, pain severity score, rates of C-reactive protein ) compared with patients receiving placebo + methotrexate (MT) / antiinflammatory drugs (BPVP). In patients treated totsilizumab significantly decreased disease activity index on a scale of DAS28 (Disease activity scale) compared with patients receiving placebo + BPVP. Good or moderate EULAR response criteria was found in significantly more patients treated totsilizumab than placebo + BPVP.

In patients treated with totsilizumab (monotherapy or combination with BPVP), compared with those who received MT / BPVP observed clinically significant improvement in the degree of functional disorders (HAQ-DI), fatigue (FACIT-F, Functional Assessment of fatigue in chronic diseases), as well as improving the performance of physical and mental health indicators on the questionnaire SF-36. By 24 weeks the proportion of patients who had clinically significant improvement with respect to HAQ-DI (defined as an individual decrease in the total score to> 0.25) during therapy totsilizumabom was significantly higher than during placebo therapy + MT / BPVP.

Totsilizumab both in monotherapy and in combination with BPVP / MT, statistically significant (p <0.0001), leads to an increase in hemoglobin to 24 weeks. The greatest increase was observed in patients with chronic anemia associated with rheumatoid arthritis. The average hemoglobin increased to 2 weeks and remained within normal limits during all 24 weeks.

After the introduction of a rapid decrease totsilizumaba averages acute phase indicators, C-reactive protein, ESR and serum amyloid A, and a decline in the number of platelets in the normal range.

Pharmacokinetics

Pharmacokinetic parameters totsilizumaba not change over time. The highest dose-dependent increase in AUC and Cmin observed for doses of 4 and 8 mg / kg every four weeks. Cmax increased in direct proportion to increasing the dose. In 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.

For totsilizumaba applying a dose of 8 mg / kg every 4 weeks, is characterized by the following indicators: the estimated average (± standard deviation) AUC in equilibrium - 35000 ± 15500 h x mg / mL, Cmin and Cmax - 9.74 ± 10.5 pg / ml and 183 ± 85.6 pg / ml, respectively. Cumulation ratios for AUC and Cmah low: 1.22 and 1.06, respectively. Cumulation rate was higher for Cmin (2.35), which was expected because of the nonlinear clearance at low concentrations. The equilibrium was reached after the first injection and after 8 and 20 weeks for Cmax, AUC and Cmin, respectively.

Distribution

After i / v administration totsilizumab undergoes biphasic elimination from the systemic krovotoka.U patients with rheumatoid arthritis central Vd is 3.5 l, peripheral - 2.91 l and Vd in the equilibrium state is 6.41 liters.

Withdrawal

The total clearance totsilizumaba depends on the concentration and represents the sum of linear and nonlinear clearance. Line clearance is 12.5 ml / h. Non-linear clearance, depending on the concentration, has a maximum value at low concentrations totsilizumaba. At higher concentrations totsilizumaba dominant linear clearance in connection with the saturation of the nonlinear path clearance. T1 / 2 depends on the concentration.

In equilibrium, the effective T1 / 2 for tolitsizumaba applying a dose of 8 mg / kg every 4 weeks decreased at lower concentrations in the intervals between the introduction of 14 to 8 days.

Pharmacokinetics in special clinical situations

Totsilizumaba pharmacokinetics in patients with hepatic insufficiency has not been studied.

Totsilizumaba pharmacokinetics in patients with renal insufficiency has not been studied. The majority of patients recorded in a population pharmacokinetic analysis was normal renal function or renal dysfunction mild (CC by Cockcroft-Gault <80 ml / min and ≥ 50 ml / min), which had no effect on the pharmacokinetics totsilizumaba.

No dose adjustment totsilizumaba elderly patients, as well as by gender and race.

Statement
rheumatoid arthritis with moderate or high degree of activity in adults as monotherapy and in combination with methotrexate and / or other antiinflammatory drugs.

Dosage regimen

In / to drip at a dose of 8 mg / kg for at least 1 h, once every four weeks.

Actemra is diluted to 100 ml of sterile 0.9% sodium chloride solution under aseptic conditions.

Safety and effectiveness in totsilizumaba children have not been established.

Dosage adjustment in elderly patients is not required.

Dosage adjustment in patients with renal insufficiency is not required.

Safety and efficacy totsilizumaba in patients with hepatic insufficiency has not been studied.

Terms of cooking and storage solution

The necessary amount of drug at the rate of 0.4 ml per 1 kg body weight (0.4 ml / kg) gain in aseptic conditions and are bred to the estimated concentration in infusion bottles (package) with 0.9% sodium chloride solution for injection (a solution must be sterile and apyrogenic). To mix gently invert the vial (package) to avoid foaming. Before the introduction of the solution must be inspected for absence of impurities or discoloration.

The prepared infusion solution Actemra physically and chemically stable in 0.9% sodium chloride solution for 24 h at 30 ° C.

From microbiological point of view of the prepared solution should be used immediately.

If the drug is not used immediately, the time and storage conditions of the prepared solution are the responsibility of the user and should not exceed 24 hours at 2 ° C to 8 ° C, and only if the preparation of the solution was carried out under controlled and validiruemyh aseptic conditions.

Side effect

The following categories are used to describe the frequency of adverse reactions: very common (≥ 1 / 10), frequently (≥ 1 / 100 and <1 / 10), rare (≥ 1 / 1000 and <1 / 100).

Infections: very often - upper respiratory tract infections; often - abscess, infections caused by Herpes simplex type 1 and Herpes zoster; rarely - diverticulitis. With long-term observation of recorded serious infectious diseases, including pneumonia, abscess, infection caused by Herpes zoster, gastroenteritis, diverticulitis, sepsis, bacterial arthritis, reactivation of latent infections, including mycobacterial.

On the part of the digestive system: often - oral ulcers, gastritis, rarely - stomatitis.

On the part of the skin and its appendages: frequent - rash, itching, rarely - urticaria.

On the part of the nervous system: frequent - headache, dizziness.

Since the cardiovascular system: often - increase blood pressure.

On the part of the body as a whole: rarely - hypersensitivity reactions, including anaphylactic reactions (from 0.3% of patients).

Changes of laboratory parameters: often - leukopenia, neutropenia, hypercholesterolemia, increase in liver transaminases; rarely - hypertriglyceridemia, increased total bilirubin.

Contraindications
Hypersensitivity to totsilizumabu, any component of the drug;
active infections (including tuberculosis);
pregnancy and lactation (breastfeeding).

With caution is prescribed for recurrent infections in history; concomitant diseases predisposing to the development of infections (diverticulitis, diabetes, etc.) for liver diseases in the active phase or hepatic failure, neutropenia.

Pregnancy and lactation

Safety and efficacy of Actemra in pregnancy are not well understood. The animals use Actemra in high doses increases the risk of spontaneous abortion / embryo-fetal death.

The potential risk for humans is unknown.

It is not known whether derived Actemra with breast milk in humans. Despite the release of endogenous IgG in breast milk, and systemic absorption of the drug while breastfeeding is unlikely due to rapid proteolytic degradation of proteins in the digestive system

Application for violations of liver function

With caution is prescribed for liver disease in the active phase or hepatic failure.

Application for violations of renal function

Dosage adjustment in patients with renal failure required

Cautions

Do not start treatment Actemra patients with active infectious diseases. With the development of serious infections treatment Actemra should be interrupted until the elimination of infection. Caution must be exercised when using Actemra patients with recurrent infectious diseases in history, as well as concomitant diseases predisposing to the development of infections (eg, diverticulitis, diabetes).

When treatment Actemra increases the risk of serious infectious diseases (pneumonia, abscess, Herpes zoster, gastroenteritis, diverticulitis, sepsis, bacterial arthritis). In rare cases, severe infection led to death. Registered individual cases of opportunistic infections, sensitive to therapy (pneumonia caused by Pneumocystis jirovecii and Mycobacterium avium).

It should be particularly careful to ensure early detection of serious infections in patients with rheumatoid arthritis receiving biological agents, as signs or symptoms of acute inflammation can be erased, in connection with the suppression of the acute-phase reaction. Patients should be instructed to immediately by a doctor for any symptoms, indicating the emergence of infection, with a view to timely diagnosis and appropriate treatment purposes.

You should not immunize alive and living attenuated vaccines concurrently with treatment Actemra, since the security of this sochetaniyane installed. There is no evidence of secondary transmission of infection from patients receiving live vaccines to patients receiving totsilizumab.

With the introduction of the drug in some cases there are infusion reactions (some phenomena occurring during infusion or within 24 hours after). During the infusion were observed mainly episodes of blood pressure increase, and within 24 hours - skin reactions (rash, urticaria). These effects do not lead to restriction of the possibility of therapy

During the second to fifth infusion Actemra ® observed anaphylactic reaction and severe hypersensitivity reactions (from 0.3% of patients). Necessary for the treatment of anaphylactic reactions drugs should be available for immediate use during the application of Actemra.

Care should be exercised in patients with active liver disease or liver failure, since Actemra therapy, especially in conjunction with methotrexate, may be associated with increased activity of hepatic transaminases.

Transient increase in activity of ALT / AST greater than 3 times on FHG was observed in 2.1% of patients treated totsilizumab 8 mg / kg, and at 6.5% of patients treated totsilizumab 8 mg / kg in combination with preparations of basic therapy (BPVP). Adding a potentially hepatotoxic drugs (methotrexate) to totsilizumabu led to an increase in the frequency of increased activity of enzymes. Increased activity of ALT / AST greater than 5 times on FHG was observed in 0.7% of patients treated totsilizumab as monotherapy and in 1.4% of patients treated in combination with totsilizumab BPVP, with the majority of patients discontinued treatment. These changes were not associated with clinically significant increase in the level of direct bilirubin, clinical signs of hepatitis or liver failure.

Care should be exercised in the appointment of Actemra patients with neutropenia. Reducing the number of neutrophils below 1.0 x 109/ml was observed in 3.4% and below 0.5 x 109/ml - at 0.3% of patients treated with Actemra 8 mg / kg in combination with BPVP, with no apparent connection with the development of serious infections. If the absolute neutrophil count <0.5 x 109 / l treatment Actemra is not recommended.

There has been improvement in lipid metabolism (total cholesterol, HDL, LDL, triglycerides). In most patients, atherogenicity index does not rise, and rising levels of total cholesterol effectively corrected with lipid-lowering drugs.

At 1.4% of patients identified antibodies to totsilizumabu, 0.2% of whom had an allergic reaction. In 1% of patients who appeared neutralizing antibodies, reducing the effectiveness of treatment Actemra for the entire 96-week course was not observed.

Effects on ability to drive vehicles and management mechanisms

Studies on the effect of the drug on driving ability and work with the arrangements were not made. Based on the mechanism of action and safety profile, Actemra has no such action.

Overdose

Available data on Actemra overdose is limited. In one case of unintentional overdose of the drug in a dose of 40 mg / kg in patients with multiple myeloma adverse reactions were observed. Not noted as serious adverse reactions in healthy volunteers who received Actemra in single dose to 28 mg / kg, although there was neutropenia, affecting the decrease in dose.

Drug Interactions

The simultaneous use of drugs for the treatment of rheumatoid arthritis such as methotrexate, chloroquine and its derivatives, immunosuppressants (azathioprine, leflunomide), GCS (prednisolone and derivatives), folic acid and its derivatives, NSAIDs (diclofenac, ibuprofen, naproxen, meloxicam, celecoxib, and other Cox-2 inhibitors), analgesics (paracetamol, codeine and its derivatives, tramadol), does not affect the pharmacokinetics totsilizumaba.

Studies on the combined use with other biological totsilizumaba BPVP, drugs antiinflammatory therapy have been conducted.

Education CYP450 enzymes is suppressed cytokines that stimulate chronic inflammation.

It is therefore expected that any drug with pronounced anti-inflammatory effect, such as totsilizumab can normalize the activity of enzymes CYP450. This has clinical significance for CYP450 substrates with a narrow therapeutic index, for which doses are selected individually. At the beginning of therapy Actemra patients receiving these drugs should be careful monitoring of therapeutic effects (eg, warfarin) or the concentration of the drug (eg, cyclosporine) and, if necessary, to select a dose individually.

Terms and Conditions of storage

The drug should be stored at 2-8 ° C protected from light, away from children, do not freeze.

Shelf life - 2 years 6 months.