Description
Latin name
ACTEMRA
Release form
Concentrate for solution for infusions
Packing
Bottle 4 ml.
Indications
Medium or high activity rheumatoid arthritis in adults, both as monotherapy and in combination with methotrexate (MT) and / or other basic anti-inflammatory drugs (BPV).
Contraindications
Hypersensitivity to tocilizumab, any component of the drug
active infectious diseases (including tuberculosis)
pregnancy
lactation period.
With caution: a history of recurrent infections, concomitant diseases predisposing to the development of infections (diverticulitis, diabetes mellitus, etc.), active liver disease or liver failure of neutropenia.
Pregnancy and lactation
The safety and effectiveness of Actemra ® during pregnancy are not well understood. 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 / embryo-fetal death was found. The significance of this information to humans is unknown.
It is not known whether Actemra ® is excreted in human milk. Despite the release of endogenous IgG into breast milk, systemic absorption of the drug during breastfeeding is unlikely due to the rapid proteolytic degradation of such proteins in the digestive system.
Side effects
The following categories are used to describe the frequency of adverse reactions: very often – 1/10 often – 1/100 and <1/10 infrequently - 1/1000 and <1/100. Infections: very often – upper respiratory tract infections often – phlegmon, infections caused by Herpes simplex 1 and Herpes zoster infrequently – diverticulitis. From the digestive system: often – oral ulcers, gastritis infrequently – stomatitis. From the skin and its appendages: often – rash, itching infrequently – urticaria. From the nervous system: often – headache, dizziness. From the cardiovascular system: often – increased blood pressure. On the part of the body as a whole: infrequently – hypersensitivity reactions. On the part of laboratory indicators: often – leukopenia, neutropenia, hypercholesterolemia, increased activity of hepatic transaminases infrequently – hypertriglyceridemia, increased total bilirubin. The following is additional information on selected adverse reactions. Infections: According to controlled trials, the infection rate with the administration of tocilizumab at a dose of 8 mg / kg in combination with HDPE was 127 cases per 100 patient-years, compared with 112 cases per 100 patient-years in the group of patients receiving placebo in combination with BPVP. When conducting long-term open-label studies, the frequency of infections with Actemroy ® therapy in combination with HDL was 116 per 100 patient-years. According to controlled clinical trials, the incidence of serious infections in the group of patients receiving Actemra ® at a dose of 8 mg / kg in combination with NSAIDs was 5.3 cases per 100 patient-years, compared with 3.9 cases per 100 patient-years in a group of patients receiving placebo in combination with NSAIDs. With Actemroy ® monotherapy, the incidence of serious infections was 3.6 cases per 100 patient-years compared with methotrexate monotherapy (1.5 cases per 100 patient-years). In a long-term open-label study, the incidence of serious infections with Actemroy ® in combination with an NSAID was 3.9 per 100 patient-years The following serious infectious diseases were recorded: pneumonia, phlegmon, infections caused by Herpes zoster, gastroenteritis, diverticulitis, sepsis, bacterial arthritis. Serious infections were rarely fatal. There are reports of cases of opportunistic infections. Gastrointestinal perforation: during controlled studies lasting 6 months in the group of patients receiving Actemra ®, infrequently (in 0.1% of patients) there were cases of gastrointestinal perforation. Most cases of gastrointestinal perforation were identified as complications of diverticulitis, and included diffuse purulent peritonitis, perforation of the lower gastrointestinal tract, fistula, and abscess. Infusion reactions: adverse reactions associated with the administration of the drug (certain reactions that occur during administration of the drug or within 24 hours after administration) were detected in 6.9% of patients those who received 8 mg / kg Actemra ® in combination with NSAIDs, and in 5.1% of patients who received placebo in combination with NSAIDs. Adverse reactions that occurred during drug administration were mainly 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 (in 6 out of 3,778 patients) 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. In controlled and open clinical trials, clinically significant hypersensitivity reactions due to the introduction of Actemra and requiring the termination of treatment were observed in 13 of 3,778 patients (0.3%). Primarily, these reactions were observed between the 2nd and 5th infusions of Actemra ®. Immunogenicity: antibodies to tocilizumab were detected in 46 of 2876 examined patients (1.6%). In 5 of them, medically significant hypersensitivity reactions were noted, which led to the complete cancellation of treatment. In 30 patients (1.1%) who had neutralizing antibodies, there was no apparent correlation between the formation of these antibodies and the response to treatment. Changes in laboratory parameters Hematologic abnormalities: a decrease in the number of neutrophils below 1 · 109 / l was observed in 3.4% of patients who were administered Actemru ® at a dose of 8 mg / kg in combination with BPVP, compared with less than 0, 1% of patients who received a placebo in combination with an NSAID. In approximately half the cases, a decrease in the absolute number of neutrophils (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 observed in 0.3% of patients receiving Actemra ® at a dose of 8 mg / kg in combination with BPVP. There was no clear connection between a decrease in the number of neutrophils below 1 · 109 / L and the development of serious infectious diseases. A decrease in platelet count below 100 · 103 / μl was observed in 1.7% of patients receiving Actemra ® at a dose of 8 mg / kg in combination with NSAIDs, compared with less than 1% of patients receiving placebo in combination with NSAIDs. These changes were not accompanied by the development of episodes of bleeding. Increased activity of hepatic transaminases: a transient increase in ALT / AST activity (more than 3 times the upper normal limit – VGN) was observed in 2, 1% of patients receiving Actemra ® at a dose of 8 mg / kg, and 4.9% of patients receiving MT. These changes occurred in 6.5% of patients receiving Actemra ® at a dose of 8 mg / kg in combination with NSAIDs, and in 1.5% of patients receiving placebo in combination with NSAIDs. The addition of drugs with potential hepatotoxicity (e.g. MT) to tocilizumab monotherapy led to an increase in the incidence of transaminase activity. An increase in ALT / AST activity, more than 5 times higher than VGN, was observed at 0 having a potential hepatotoxic effect (for example, MT), led to an increase in the frequency of cases of increased transaminase activity. An increase in ALT / AST activity, more than 5 times higher than VGN, was observed at 0 having a potential hepatotoxic effect (for example, MT), led to an increase in the frequency of cases of increased transaminase activity. An increase in ALT / AST activity, more than 5 times higher than VGN, was observed at 0, 7% of patients receiving Actemra ® monotherapy, and in 1.4% of patients receiving Actemra ® in combination with BPVP. However, most patients discontinued Actemroy ® therapy. The increased activity of hepatic transaminases was not accompanied by a clinically significant increase in direct bilirubin levels, as well as clinical manifestations of hepatitis or liver failure. Change in lipid metabolism: during controlled trials lasting 6 months with Actemroy ® therapy, 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 in 15% of patients. In most patients, the atherogenic index did not increase, and an increase in total cholesterol was effectively corrected by lipid-lowering drugs.
Drug Interaction
Population pharmacokinetic analysis of clinical studies did not reveal any effect of MT, NSAIDs or corticosteroids on the clearance of tocilizumab.
Co-administration of tocilizumab at 10 mg / kg and MT at 10 25 mg once weekly did not have a clinically relevant effect on MT exposure.
No studies have been conducted to investigate the combined use of tocilizumab with other biological BPVs.
Because the formation of CYP450 hepatic isoenzymes is suppressed by cytokines (eg, IL-6, which stimulates chronic inflammation), CYP450 isoenzyme expression may be impaired when treated with cytokine inhibiting agents (eg tocilizumab).
In vitro studies, conducted on human hepatocyte culture, it has been shown that IL-6 causes a decrease in the expression of CYP1A2, CYP2C9, CYP2C19, and CYP3A4 isoenzymes. The use of tocilizumab normalizes the expression of these isoenzymes.
The effect of Actemra ® on CYP isoenzymes (except CYP2C19 and CYP2D6) is of clinical relevance for drugs that are CYP450 substrates with a narrow therapeutic index for which doses are selected individually.
Simvastatin concentration (CYP3A4 substrate) decreased by 57% 1 week after single administration of tocilizumab to similar or slightly increased simvastatin concentrations in healthy volunteers.
Patients receiving medicinal products that are metabolised by CYP450 3A4 isoenzymes should be carefully monitored at the beginning or at the end of therapy with Actemroy ®, 1A2 or 2C9 (for example, atorvastatin, CCB, theophylline, warfarin, phenytoin, cyclosporin or benzodiazepines). To ensure the therapeutic effect of these drugs, it may be necessary to increase their dose. Given the prolonged 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 Actemru ® at a single dose up to 28 mg / kg once, although neutropenia was observed, which reduced the dose.
Storage conditions
In a dark place at a temperature of 2 8 ° C (do not freeze).
Keep out of the reach of children.
The Expiration of
is 2.5 years.
Pharmacy leave conditions
Prescription
Dosage Form A dosage form
infusion solution
F. Hoffmann-La Roche Ltd., Switzerland
