Aktempa: instructions for using the medicine, structure, Contraindications

Active material: tocilizumab
When ATH: L04AC07
CCF: Specific immunosuppressant drug. Receptor antagonist interleikina-6
ICD-10 codes (testimony): M05
When CSF: 05.02.01
Manufacturer: F.Hoffmann-La Roche Ltd. (Switzerland)

Aktempa: dosage form, composition and packaging

Concentrate for solution for infusion in the form of transparent or opalescirujushhej colourless or light yellow liquid.

1 ml1 fl.
tocilizumab20 mg80 mg

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

4 ml – colorless glass vials (1) – packs cardboard.
4 ml – colorless glass vials (4) – packs cardboard.

Concentrate for solution for infusion in the form of transparent or opalescirujushhej colourless or light yellow liquid.

1 ml1 fl.
tocilizumab20 mg200 mg

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

10 ml – colorless glass vials (1) – packs cardboard.
10 ml – colorless glass vials (4) – packs cardboard.

Concentrate for solution for infusion in the form of transparent or opalescirujushhej colourless or light yellow liquid.

1 ml1 fl.
tocilizumab20 mg400 mg

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

20 ml – colorless glass vials (1) – packs cardboard.
20 ml – colorless glass vials (4) – packs cardboard.

Aktempa: pharmachologic effect

Tocilizumab – recombinant humanized monoclonal antibody to human Interleukin-6 receptor (IL-6) from the subclass of immunoglobulins IgG1. Tocilizumab selectively binds and inhibits both soluble, and membrane receptors IL-6 (SIL-6R and mIL-6R). IL-6 is a multifunctional citokinom, generated by different types of cells, participating in paracrine regulation, system of physiological and pathological processes, such as the stimulation of the secretion of Ig, activation of t cells, stimulation of the formulation of the acute phase proteins in the liver and stimulation of Hematopoiesis. IL-6 is involved in the pathogenesis of various diseases, incl. inflammatory diseases, osteoporosis and cancer.

Clinical efficacy in rheumatoid arthritis

The clinical effect 20%, 50% and 70% According to the criteria of the American College of Rheumatology (ACRE) through 6 month was celebrated in therapy tocilizumabom, than placebo, regardless of the presence or absence of rheumatoid factor, age, gender, race, number of previous courses of treatment or disease stage. Response to therapy arose quickly (by the second week), intensified throughout the course of treatment and remained more 18 Months.

Patients, treated with tocilizumab, significant improvements were noted with regard to all criteria of ACRE (the number of painful and swollen joints, improvement of the overall assessment of the effectiveness of the treatment, according to the doctor and the patient, the degree of functional disorders according to the questionnaire HAQ, assessment of pain syndrome, rates of c-reactive protein) compared to patients, placebo + methotrexate (MT)/basic anti-inflammatory drugs (DMARDs).

Patients, treated with tocilizumab, significantly decreased disease activity index on the scale of DAS28 (Disease activity scale) compared to patients, placebo + DMARDs. Good or moderate response criteria have celebrated EULAR significantly greater numbers of patients, treated with tocilizumab, than receiving placebo + DMARDs.

Patients, treated with tocilizumab (monotherapy or combination with DMARDS), compared with those, who received MT/DMARDS, experienced clinically significant improvement in the degree of functional disorders (HAQ-DI), fatigue (FACIT-F, functional evaluation of fatigue in chronic diseases), as well as improved as indicators of physical, and indicators of mental health questionnaire SF-36.

K 24 week, the proportion of patients, had clinically significant improvement in HAQ-DI (defined as the decline in the overall individual points on the > 0.25), against the backdrop of tocilizumabom therapy was significantly higher, than placebo therapy + MT/DMARDS.

Tocilizumab as when alone, or in combination with DMARDS/MT, statistically significant (p<0.0001), leads to an increase in hemoglobin to 24 week. The greatest increase was observed in patients with chronic anemia, associated with rheumatoid arthritis. The average hemoglobin rose to 2 week and remained within the normal range for all 24 weeks.

After the introduction of the tocilizumaba occurred a rapid reduction in the average values of the acute-phase indicators, C-reactive protein, ESR and serum amyloid a, as well as a decrease in the number of platelets in the normal range.

Aktempa: pharmacokinetics

Pharmacokinetic parameters tocilizumaba does not change over time. The greatest increase in AUC and C sharpmin Notes for doses 4 and 8 mg/kg every four weeks. Cmax increases in direct proportion to the increases in dose. At equilibrium the estimated AUC and Cmin were in 2.7 and 6.5 times higher dose 8 mg/kg compared to the dose 4 mg / kg, respectively.

For tocilizumaba in the application of the dose of 8 mg / kg every 4 of the week, is characterized by the following indicators: the estimated average (± the standard deviation) AUC in equilibrium-35000 ± 15500 h x µg/ml, Cmin и Cmax -9.74 ± 10.5 µg/ml and 183 ± 85.6 µg/ml, respectively. Cumulation factors for AUC and Cmaх low: 1.22 and 1.06, respectively. Cumulation coefficient was higher for Cmin (2.35), that expected due to nonlinear clearance at low concentrations. The equilibrium was achieved after the first injection and through 8 and 20 weeks for Cmax, AUC и Cmin, respectively.

Distribution

After the on/in the introduction of tocilizumaba excretion of systemic blood flow has two-phase nature. In patients with rheumatoid arthritis Central Vd is 3.5 l, peripheral- 2.91 l, and (V)d at steady state 6.41 l.

Deduction

The total klirens tocilizumaba depends on the concentration and represents the sum of linear and nonlinear ground clearance. Line clearance is 12.5 ml / h. Nonlinear clearance, concentration-dependent, has the greatest value at low concentrations tocilizumaba. At higher concentrations the predominant tocilizumaba line clearance in connection with the clearance of a nonlinear path congestion. T1/2 depends on the concentration of. In equilibrium effective T1/2 for tolicizumaba in the application of the dose of 8 mg/kg once per 4 week decreased with decreasing concentration in the intervals between the introduction of 14 to 8 days.

Pharmacokinetics in special clinical situations

Pharmacokinetics of tocilizumaba in patients with hepatic insufficiency have not studied.

Pharmacokinetics of tocilizumaba in patients with renal insufficiency was not studied. In most patients, posted in population pharmacokinetic analysis, had a normal kidney function or kidney function light gravity (QC formula CW Galt < 80 mL/min. and ≥ 50 ml / min), that does not affect the farmakokinetiku tocilizumaba.

Is not required correction doses of tocilizumaba in elderly patients, and also depending on the sex and race.

Aktempa: testimony

  • rheumatoid arthritis with moderate or severe activity in adults as monotherapy, or in combination with methotrexate and/or other basic anti-inflammatory drugs.

Aktempa: dosing regimen

The drug is injected in/drip in the dose 8 mg/kg for at least 1 no, 1 once every 4 of the week.

Aktemru® bred to 100 ml sterile 0.9 % solution of sodium chloride in aseptic conditions.

Safety and efficacy of tocilizumaba u children not set.

Dose adjustment at the elderly not required.

Dose adjustment at patients renal failure not required.

The safety and efficacy of tocilizumaba u Patients with liver failure I have not been studied.

Rules of preparation and storage solution

The required quantity of the drug at the rate of 0.4 ml 1 kg body weight (0.4 ml / kg) gaining in aseptic conditions and bred to the estimated concentration in infuzionnom vial (package) from 0.9 % solution of sodium chloride for injection (the solution should be sterile and non-pyrogenic). For stirring gently invert the vial (package) to avoid foaming. Before the introduction of the solution should be inspected for extraneous matter or discoloration.

Cooked recovery solution Aktemry® physically and chemically stable in 0.9 % solution of sodium chloride for 24 h at 30° c.

From a microbiological point of view cooked solution should be used immediately.

If the drug is not used immediately, the time and conditions of storage of prepared solution are the responsibility of the user and shall not exceed 24 h at a temperature from 2° c to 8° c and only, If the solution preparation was carried out in a controlled and validated aseptic conditions.

Aktempa: side effects

Determination of the frequency of adverse reactions: Often (≥ 1/10), often (≥ 1/100 and < 1/10), rarely (≥ 1/1000 and < 1/100).

Infection: Often upper respiratory tract infection; often flegmona, infection, caused by Herpes simplex type 1 and Herpes zoster; rarely diverticulitis. With long-term observation recorded serious infectious diseases, incl. pneumonia, flegmona, infection, caused by Herpes zoster, gastroenteritis, diverticulitis, sepsis, bacterial arthritis, reactivation of latent infections, incl. Mycobacterial.

On the part of the digestive system: often mouth ulcers, gastritis; rarely stomatitis.

CNS: often headache, dizziness.

Cardio-vascular system: often increased blood pressure.

Dermatological reactions: often rash, itch; rarely hives.

Allergic reactions: rarely - hypersensitivity reactions, incl. anaphylactic reactions (in 0.3 % patients).

From the laboratory parameters: often - leukopenia, neutropenia, hypercholesterolemia, increase in liver transaminases; rarely – hypertriglyceridemia, increase in total bilirubin.

Aktempa: Contraindications

  • active infectious diseases (incl. tuberculosis);
  • pregnancy;
  • lactation (breast-feeding);
  • hypersensitivity to tocilizumab or other components of the drug.

FROM caution You should use the drug in children with recurrent infections in history, related diseases, predisposing to the development of infections (incl. diverticulitis, diabetes), liver diseases in the active phase or when liver failure, If neutropenia.

Aktempa: Pregnancy and lactation

Safety and efficacy of Aktemry® when pregnancy is not sufficiently studied.

IN experimental studies Introduction to animal Aktemry® in high doses increases the risk of spontaneous miscarriage/embryo-fetal death. The potential risk to humans is unknown.

Unknown, whether tocilizumab in breast milk in humans. Despite the allocation of endogenous IgG with breast milk, systemic absorption of the drug if breastfeeding is unlikely owing to the rapid proteolytic degradation of these proteins in the digestive system.

Aktempa: Special instructions

Should not begin treatment Aktemroj® patients with active infectious diseases. When developing serious infections therapy Aktemroj® should be interrupted until the infection. Be careful when using Aktemry® in patients with recurrent infectious diseases in history, as well as in related diseases, predisposing to the development of infections (eg, When diverticuli, diabetes).

Aktemroj therapy® increases the risk of serious infectious diseases (pneumonia, flegmona, Herpes zoster, gastroenteritis, diverticulitis, sepsis, bacterial arthritis). In rare cases, serious infections result in death. Recorded sporadic development of conditionally pathogenic infections, sensitive to therapy (pneumonia, caused by Pneumocystis jirovecii and Mycobacterium avium).

Care must be taken with a view to early detection of serious infectious diseases in patients with rheumatoid arthritis, receiving Biologicals, because the signs or symptoms of acute inflammation can be erased, in connection with the Suppression of acute phase reaction. Patients should be instructed to immediately appeal to the doctor if any symptoms, evidence of infection appears, with a view to the timely diagnosis and treatment assignment.

Immunization should not be alive and living weakened vaccines concurrently with Aktemroj therapy®, because the safety of such combinations is not installed. No data on the secondary transmission from patients, receiving live vaccines, to patients, receiving tocilizumab.

With the introduction of the drug in some cases observed infusion reactions (separate phenomenon, occur during infusion or within 24 hours after). During the infusion were observed mainly episodes raise HELL, and for 24 h skin reactions (rash, hives). These effects do not lead to a restriction of the possibility of holding therapy.

During the second-fifth infusion Aktemry® anaphylactic reactions have been observed and serious hypersensitivity reactions (in 0.3% patients). Necessary for the treatment of anaphylactic reactions drugs should be available for immediate use during application of Aktemry®.

Caution should be exercised in patients with active liver disease or liver failure, Since therapy Aktemroj®, especially with methotrexate simultaneously, can be associated with an increase in liver transaminaz.

Tranzithornoe increase in ALT/AST more than 3 times concerning the VGN observed in 2.1% patients, treated with tocilizumab 8 mg / kg, and 6.5 % patients, treated with tocilizumab 8 mg/kg in combination with DMARDS. Adding a potentially gepatotoksicnah drugs (methotrexate) the tocilizumabu led to an increase in frequency increase the enzyme activity. Increased activity ALT/AST more than 5 times concerning the VGN observed in 0.7% patients, received tocilizumab as monotherapy, and 1.4% patients, received tocilizumab in combination with DMARDS, While most patients stopped treatment course. These changes were not associated with clinically significant increased levels of direct bilirubin, clinical signs of hepatitis or liver failure.

Should be cautious appoint Aktemru® patients with neutropenia. The decline in the number of Klebsiella below 1.0 x 109/ml indicated in 3.4%, and below 0.5 x 109/ml- 0.3 % patients, receiving Aktemru® dose 8 mg/kg in combination with DMARDS, without an explicit connection with the development of serious infections. While the absolute number of neutrophils < 0.5 x 109/l treatment Aktemroj® not recommended.

There has been improvement in lipid metabolism (total cholesterol, HDL, LDL, triglycerides). Most patients have no haemoglobin index rose, (a) increased levels of total cholesterol effectively korrigirovalos lipid drugs.

In 1.4% patients identified antibodies to tocilizumabu, 0.2% of whom have allergic reactions. In 1% patients, which appeared neutralizing antibodies, the effectiveness of the therapy Aktemroj® throughout the 96-week course was not observed.

Effects on ability to drive vehicles and management mechanisms

Studies on the effect of the drug on the ability to drive and use machines have not been conducted. Based on the mechanism of action and safety profile, Aktempa® has no such action.

Aktempa: overdose

Available data on overdose Aktemry® limited. In one case of unintentional drug overdose at a dose 40 mg/kg in a patient with multiple myeloma unwanted reactions not observed. There have been no serious adverse reactions in healthy volunteers, who were once Aktemru® at a dose of 28 mg / kg, Although neutropenia was observed, affecting the lower doses.

Aktempa: drug interaction

Simultaneous application of drugs for the treatment of rheumatoid arthritis, such as methotrexate, chloroquine and its derivatives, immunosuppressants (azathioprine, leflunomide), GCS (prednisone 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 farmakokinetiku tocilizumaba.

Study on combined use of tocilizumaba with other biological DMARDS have been conducted.

Education system is suppressed by CYP450 enzymes, cytokines, challenging chronic inflammation. Therefore, it is expected, that any drug, with pronounced anti-inflammatory effect, such as tocilizumab, can normalize CYP450 enzyme activity. This has clinical significance for CYP450 substrates with a narrow therapeutic index, for which doses selected individually. At the beginning of therapy Aktemroj® patients, receiving such medicines, should carry out careful monitoring of therapeutic action (eg, for warfarin) or drug concentration (eg, for Cyclosporine) and, if necessary, pick up the dose individually.

Aktempa: terms of dispensing from pharmacies

The drug is released under the prescription.

Aktempa: terms and conditions of storage

The drug should be stored out of reach of children, dark place at a temperature of 2 ° to 8 ° C; Do not freeze. Shelf life – 2 year 6 months.

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