Actemra: side effects, instructions for use

Actemra is a drug used to treat advanced forms of rheumatoid arthritis. Available in the form of a solution, which is diluted with a 0.9% sodium chloride solution and administered intravenously (with a dropper). At the moment, it is difficult to find this medicine, and it costs about 15,000-20,000 rubles and more, which is associated with increased demand due to coronavirus infection.

Packaged in cardboard packs of 1 or 4 bottles each. The working solution is a colorless liquid with opalescence properties (scattering of light by large particles).

The drug is sold only with a prescription. It is stored in the refrigerator (dark place, temperature range from 2 to 8 degrees). Freezing is prohibited. Access by children should be excluded. The shelf life, provided the container remains intact, is 2.5 years from the date of production.

Indications and contraindications

The drug is used to treat rheumatoid arthritis in moderate and advanced stages. It is used as monotherapy, as well as in combination with a drug such as Methotrexate and other anti-inflammatory drugs.

There are several absolute contraindications in which the use of Actemra is excluded:

• active stage of development of infectious pathologies, including tuberculosis (you must first undergo fluorography to determine latent tuberculosis);
• hypersensitivity to the active substance of the drug or its additional components;
• immunization with a weakened vaccine (live viruses, bacteria, other infectious agents);
• period of pregnancy, breastfeeding (at any stage).

Use with caution is possible in the presence of the following pathologies:

• recurrent infection (chronic course);
• diabetes mellitus, diverticulitis and other pathologies that can provoke the development of infection;
• liver diseases;
• neutropenia.

Attention!

Overdose of the solution is not allowed. A violation was recorded in one case. The patient used a solution in an amount of 40 mg/kg body, and in his case there were no side effects. Healthy volunteers who received a solution in an amount of 28 mg/kg experienced symptoms of neutropenia (accompanied by an increased risk of developing infections).

Actemra (Tocilizumab) 400 mg for in. 20mg/ml 20ml No. 1 – Instructions

DOSAGE FORM AND PACKAGING

Concentrate for solution for infusion 400 mg/20 ml in bottle No. 1.

COMPOUND

1 vial contains 400 mg of tocilizumab.

PHARMACHOLOGIC EFFECT

Actemra is a specific immunosuppressive drug used in the treatment of rheumatoid arthritis with high/moderate activity. The drug is used both as a single agent and in combination with basic anti-inflammatory drugs. The active substance of Actemra, tocilizumab, is a recombinant humanized monoclonal antibody to the human interleukin-6 (IL-6) receptor from the IgG1 subclass of immunoglobulins.

Tocilizumab selectively binds to and inhibits both soluble and membrane IL-6 receptors (sIL-6R and mIL-6R). IL-6 is a multifunctional cytokine produced by various cell types 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.

INDICATIONS FOR USE

Rheumatoid arthritis with moderate or high activity in adults, both as monotherapy and in combination with methotrexate (MT) and/or with other disease-modifying anti-inflammatory drugs (DMARDs), including for the inhibition of radiologically proven joint destruction.

METHOD OF APPLICATION AND DOSES

Intravenous drip at a dose of 8 mg/kg for at least 1 hour once every 4 weeks. Actemra is diluted to 100 ml with a sterile 0.9% sodium chloride solution under aseptic conditions. Dose increases of more than 800 mg per infusion are not recommended for patients weighing more than 100 kg.

OVERDOSE

In case of overdose, neutropenia is possible, which may lead to dose reduction. Treatment is symptomatic.

USE IN PREGNANCY AND BREAST-FEEDING

Actemra should not be used during pregnancy and lactation, unless the expected benefit of therapy for the mother outweighs the potential risk to the fetus or child.

SIDE EFFECTS

Upper respiratory tract infections may occur when using Actemra; phlegmon, infections caused by Herpes simplex 1 and Herpes zoster; diverticulitis; oral ulcers, gastritis; stomatitis; rash, itching; hives; headache, dizziness; increased blood pressure; hypersensitivity reactions; leukopenia, neutropenia, hypercholesterolemia, increased activity of liver transaminases; hypertriglyceridemia, increased total bilirubin.

CONTRAINDICATIONS

Actemra is contraindicated if there is a history of hypersensitivity to tocilizumab or any component of the drug; active infectious diseases (including tuberculosis); in children under 2 years of age for patients with polyarticular juvenile idiopathic arthritis and systemic juvenile idiopathic arthritis; under the age of 18 for patients with rheumatoid arthritis; in combination with TNF-α inhibitors or use within 1 month after treatment with anti-TNF antibodies.

SPECIAL WARNINGS

Actemra should be used with caution if there is a history of recurrent infections, concomitant diseases that predispose to the development of infections (including diverticulitis, diabetes mellitus), active liver disease or liver failure, neutropenia, viral hepatitis, demyelinating diseases.

Patients with active infectious diseases should not begin treatment with Actemra.

If latent tuberculosis is detected, a standard course of antimycobacterial therapy should be administered before starting treatment with Actemra.

Immunization with live and live attenuated vaccines should not be administered concomitantly with Actemra therapy.

Lipid metabolism should be assessed 4–8 weeks after initiation of Actemra therapy.

SHELF LIFE AND STORAGE CONDITIONS

Store in a place protected from light at a temperature of 2° to 8°C. Shelf life: 2 years 6 months.

VACATION CATEGORY

On prescription.

Side effects

In most cases, taking the drug does not cause side effects. But sometimes the following manifestations are observed:

• infection of the upper respiratory tract;
• itching, rash, less often urticaria;
• headaches;
• dizziness;
• increased blood pressure;
• hypersensitivity reactions.

If side effects occur, you must stop taking the drug and undergo treatment. If the condition worsens, seek emergency medical attention.

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Instructions for use "Actemra"

The solution is given as an intravenous injection or as a dropper for 60 minutes, maximum once a month. The drug is diluted to a total volume of 100 ml using saline solution of 0.9% sodium chloride. To do this, it is necessary to treat the surface of the skin with alcohol or another antiseptic.

When preparing the solution, follow the following instructions:

1. Measure out the required amount of the drug in the amount of 0.4 ml per 1 kg of body weight.
2. Take a disposable syringe and withdraw 100 ml of 0.9% sodium chloride solution.
3. Another disposable syringe is used to measure the Actemra solution.
4. After this, mix the working solution with a sodium chloride solution.
5. Mix thoroughly, carefully turning the bag up and down. In this case, it is important to avoid foaming and check the contents of the package (visually) for the absence of any particles or suspension.
6. You also need to make sure that the solution is colorless or has a faint light yellow color.
7. Turn the bag over and insert an IV.

Research results

The patients of all three groups included in the analysis were comparable in age and gender. There were no statistically significant differences in the average time of drug administration from the onset of the disease, the volume of damage to the lung parenchyma, according to CT data, and the content of C-reactive protein before and 24 hours after drug administration (Table 1).

Table 1. Main characteristics of patients in the compared groups

Table 1. The main characteristics of patients in the compared group

* The result is presented as: mean value ± standard deviation.

** The result is presented as the median of the interquartile range.

When analyzing the “Lethal outcome” indicator depending on the drug administered (tocilizumab, olokizumab, levilimab), we were unable to identify significant differences (p = 0.259, Fisher’s exact test for multifield tables) (Table 2). Comparisons of percentages in the analysis of multifield contingency tables were performed using Fisher's exact test. Post hoc comparisons were performed using Pearson's χ2 test with Holm's correction.

Table 2. Analysis of the “Lethal outcome” indicator depending on the administered drug

Table 2. Analysis of the “Lethal outcome” indicator depending on the injected drug

* The percentage is given in parentheses.

When assessing the outcome “Sepsis” depending on the drug administered, we were unable to establish statistically significant differences (p = 0.587, Fisher’s exact test for multi-field tables) (Table 3). As a quantitative measure of the effect when comparing relative indicators, we used the OR indicator with a 95% confidence interval (95% CI).

Table 3. Analysis of the “Sepsis” indicator depending on the drug administered

Table 3. Analysis of the “Sepsis” indicator depending on the injected drug

An analysis of the Sepsis indicator was carried out depending on the subcutaneous or intravenous administration of tocilizumab (Table 4). When assessing the Sepsis indicator depending on the route of administration of tocilizumab, it was not possible to detect statistically significant differences (p = 0.293, Fisher's exact test). The odds of sepsis in the subcutaneous tocilizumab group were 2.28 times lower compared with the intravenous tocilizumab group, and the odds difference was not statistically significant (OR = 0.44; 95% CI 0.1–1.88). When assessing the “Lethal outcome” indicator depending on the route of administration, it was not possible to identify statistically significant differences (p = 0.279, Fisher’s exact test). The odds of dying in the subcutaneous group were 1.85 times lower compared to the intravenous group, and the difference in odds was not statistically significant (OR = 0.54; 95% CI 0.18–1.62) (Table 5).

Table 4. Analysis of the Sepsis indicator depending on the route of administration of tocilizumab

Table 4. Analysis of the “Sepsis” indicator depending on the way of injected drug tocilizumab

Table 5. Analysis of the “Lethal outcome” indicator depending on the route of administration of tocilizumab

Table 5. Analysis of the indicator “Lethal outcome” depending on way of injection tocilizumab

Drug interactions and special instructions

Actemra should be used with caution in combination with drugs that are labeled CYP. Also, the use of Actemra requires careful monitoring of patients who use or have previously used the following drugs:

• "Atorvastatin";
• "Warfarin";
• "Fenitonn";
• "BKK";
• "Cyclosporine";
• "Theophylline";
• benzodiazepine-based drugs.

Since Actemra weakens the therapeutic effect of these drugs, you may need to increase the dosage (in consultation with your doctor). It is also important to understand that the active ingredient in Actemra (tocilizumab) is eliminated slowly, so its indirect effects on the body may persist for several weeks after complete withdrawal.

Taking the drug during pregnancy and lactation is undesirable, since it can affect the child’s immune system and the characteristics of intrauterine development.

conclusions

The use of different drugs of monoclonal antibodies against IL-6 in patients with severe COVID-19 did not reveal significant differences in lethal outcomes between tocilizumab, levilimab and olokizumab. The identified differences between drugs in the incidence of sepsis and death require further randomized controlled trials.

Conflict of interest. The authors declare no conflict of interest.

Authors' contributions. Bobkova S.S., Zhukov A.A., Protsenko D.N., Samoilenko V.V., Tyurin I.N. — development of the concept of the article, obtaining and analyzing factual data, writing and editing the text of the article, checking and approving the text of the article.

ORCID of authors

Bobkova S.S.

Zhukov A.A.

Protsenko D.N.

Samoilenko V.V.

Tyurin I.N.