Orencia 250 mg 1 pc. lyophilisate for the preparation of solution for infusion

Orencia®

Hypersensitivity reactions

Hypersensitivity reactions may occur during treatment with any injectable protein drug. Such reactions were observed with the use of Orencia® during clinical studies. After the first administration of the drug, there is a possibility of developing anaphylaxis or anaphylactoid reactions, including life-threatening ones. During post-marketing studies, a case of fatal anaphylaxis was reported after the first infusion of Orencia®. If an anaphylactic or other serious allergic reaction occurs, use of Orencia® (both lyophilisate for infusion and subcutaneous solution) should be discontinued without further resumption and appropriate treatment for the adverse reaction should be initiated immediately.

Infections

When using the drug, there have been cases of serious infections, including sepsis and pneumonia, including fatal ones, more often in patients using concomitant therapy with immunosuppressants. If during treatment a new infectious disease is identified in a patient, the patient should be closely monitored, and if a new serious infection develops, the drug should be discontinued. The safety of the drug in patients with latent tuberculosis has not been studied. Before prescribing abatacept, patients with latent tuberculosis should receive standard anti-tuberculosis therapy.

When prescribing antirheumatic drugs, reactivation of the hepatitis B virus may occur, therefore, before starting treatment with abatacept, carriage of this pathogen should be excluded. The use of the drug in patients with viral hepatitis has not been studied.

Influence or development of malignant neoplasms

The potential role of Orencia® in the development of malignant neoplasms has not been established. The incidence of malignancies during clinical trials of the infusion form of the drug was similar for patients receiving Orencia® and patients receiving placebo.

Effect on the immune system

Drugs that affect the immune response, including Orencia®. may affect the effectiveness of vaccinations, the body’s ability to resist infections and the development of malignant tumors.

Because medications that affect the immune system, including abatacept, may reduce the effectiveness of vaccinations, live vaccines should not be used during treatment with abatacept and for 3 months after its discontinuation. It is possible to use inactivated vaccines during treatment with the drug. When prescribed to children, it is recommended to complete the mandatory vaccination plan before starting to use the drug.

There was no significant effect of the drug on the effectiveness of vaccination using the 23-valent pneumococcal vaccine; most patients had an adequate immune response (increase in antibody titer) after this vaccination. Also, during treatment with Orencia®, vaccination with a trivalent vaccine against the seasonal influenza virus is possible - the immune reaction in most patients was expressed in at least a 4-fold increase in the level of antibodies.

Determination of blood glucose concentration

On the day of drug administration, it is possible to obtain false-positive results for determining blood glucose using tests due to a reaction with maltose contained in the drug. To determine glucose concentration, methods that exclude reaction with maltose should be used.

Orencia 250 mg 1 pc. lyophilisate for the preparation of solution for infusion

pharmachologic effect

Immunosuppressant.
Abatacept is a soluble protein consisting of the extracellular domain of cytotoxic T-lymphocyte antigen 4 (CTLA-4) linked to a modified Fc fragment of human immunoglobulin G1 (IgG1). Abatacept is a recombinant protein that is produced by genetic engineering in a mammalian cell system. Abatacept selectively modulates a key co-stimulatory signal required for full activation of cluster of differentiation 28 (CD28)-expressing T cells. In patients with rheumatoid arthritis, T lymphocytes are found in the synovial fluid. Activated T lymphocytes play an important role in the pathogenesis of rheumatoid arthritis and other autoimmune diseases. Full activation of T lymphocytes requires 2 signals from antigen-presenting cells: the first for recognition of a specific antigen by T-cell receptors (signal 1); the second (main, nonspecific) costimulatory signal involves the binding of CD80 and CD86 molecules on the surface of antigen-presenting cells to the CD28 receptor on the surface of T lymphocytes (signal 2). Abatacept specifically binds to CD80 and CD86, selectively inhibiting this pathway. It has been established that abatacept has a greater effect on the response of unactivated (naive) T-lymphocytes than memory T-lymphocytes.

Abatacept has been shown to reduce T cell-dependent antibody production and inflammation in in vitro studies and animal models. In vitro, abatacept reduces T-lymphocyte activation, as evidenced by a decrease in proliferation and cytokine production in human lymphocytes (TNF-α, interferon gamma and interleukin-2). In rats with collagen-induced arthritis, abatacept suppresses inflammation, reduces the formation of anti-collagen antibodies and antigen-specific production of interferon gamma.

Composition and release form Orencia 250 mg 1 pc. lyophilisate for the preparation of solution for infusion

Lyophilisate – 1 vial:

• Active substance: abatacept 250 mg*.
• Excipients: maltose monohydrate, sodium dihydrogen phosphate monohydrate, sodium chloride, hydrochloric acid, sodium hydroxide.
• Glass bottles (1) complete with a silicone-free sterile syringe (1 pc.) - plastic trays (1) - cardboard boxes.

* - packaging is carried out taking into account the refill rate of 5% - 262.5 mg

Description of the dosage form

Lyophilisate for the preparation of a solution for infusion in the form of a porous mass or powder of white or pale yellow color.

Directions for use and doses

Abatacept can be used as monotherapy or in combination with disease-modifying anti-inflammatory drugs (for example, methotrexate).

The drug Orencia® is administered intravenously as an infusion over 30 minutes in the doses indicated in the table.

For adults, after the first dose, subsequent doses are recommended at 2 and 4 weeks and then every 4 weeks.

For children aged 6 to 17 years weighing less than 75 kg, the dose of the drug is 10 mg/kg body weight. The dose should be calculated individually immediately before each administration of the drug. For children weighing 75 kg or more, the dosage regimen is the same as for adults. The maximum dose is 1000 mg.

Rules for preparing the infusion solution and administering the drug

Abatacept solution cannot be used with equipment containing silicone.

After removing the protective plastic cover, wipe the stopper with sterile cotton wool soaked in alcohol. The contents of one bottle are dissolved in 10 ml of water for injection using a disposable silicone-free syringe included with the drug (the stream of water when dissolving the drug should be directed towards the wall of the bottle). To reduce the formation of foam, the bottle should be carefully turned until the powder is completely dissolved. Do not shake! After the powder has dissolved, air should be released from the bottle through the needle to remove any bubbles that may have formed. The resulting concentrate should be colorless or pale yellow. Do not use a solution that is cloudy, has a different color, or contains foreign particles.

The resulting concentrate is immediately diluted to 100 ml with 0.9% sodium chloride solution for injection to obtain an infusion solution as follows: from a 100 ml bottle of sodium chloride, take 10 ml of solution for each added bottle of abatacept. Then the previously obtained concentrate is slowly added to the remaining solution using a disposable silicone-free syringe included in the drug kit. The concentration of abatacept in the resulting solution is approximately 5, 7.5 or 10 mg/ml, respectively, when using 2, 3 or 4 vials of the drug.

The prepared solution can be stored for 24 hours in the refrigerator at a temperature of 2° to 8°C. If foreign particles or discoloration are observed in the solution before administration, the solution must be discarded. The prepared solution must be administered within 24 hours after opening the bottle.

The prepared infusion solution is administered over 30 minutes through an infusion system with a sterile pyrogen-free filter with a low ability to bind proteins (pore size from 0.2 to 1.2 µm). Abatacept should not be administered simultaneously with other drugs through the same infusion system.

Pharmacokinetics

The values ​​of pharmacokinetic parameters are given in Table 1.

Table 1. Pharmacokinetic parameters (mean and confidence intervals) in healthy people and patients with RA when abatacept was administered intravenously at a dose of 10 mg/kg.

*IV infusions were carried out on days 1, 15, 30, and then monthly.

The pharmacokinetics of abatacept in patients with rheumatoid arthritis and healthy volunteers were comparable.

Distribution

With repeated intravenous administration, a proportional increase in Cmax and AUC values ​​was observed in the dose range from 2 mg/kg to 10 mg/kg. When administered at a dose of 10 mg/kg, Css in plasma is achieved by day 60, with the average value (interval) Cmax being 24 (from 1 to 66) μg/ml. Systemic accumulation of abatacept in the body was not observed in patients with rheumatoid arthritis with prolonged repeated administration of the drug at a dose of 10 mg/kg at intervals of 1 month.

Metabolism and excretion

Studies have not been conducted to evaluate the metabolism and elimination of abatacept in humans. Due to its spatial structure and hydrophilicity, abatacept is not metabolized in the liver by isoenzymes of the cytochrome P450 system. Given the large molecular weight of abatacept, it is expected that abatacept is not excreted in the urine.

Pharmacokinetics in special clinical situations

It was found that higher clearance of abatacept is observed in patients with high body weight.

The age and gender of patients (when adjusted for body weight) did not affect the clearance of abatacept.

The simultaneous administration of methotrexate, anti-inflammatory drugs, corticosteroids and tumor necrosis factor blockers did not affect the clearance of abatacept.

Studies have not been conducted to evaluate the effect of renal and hepatic dysfunction on the pharmacokinetics of abatacept.

Indications for use Orencia 250 mg 1 pc. lyophilisate for the preparation of solution for infusion

• To reduce symptoms, enhance clinical response, suppress the progression of structural damage, and improve functional activity in adult patients with moderately to severely active rheumatoid arthritis who have had an insufficient response to one or more disease-modifying anti-inflammatory drugs (such as methotrexate) or biologic antirheumatic drugs;
• to reduce the manifestations and symptoms in children aged 6 years and older with moderate to severe active juvenile idiopathic arthritis with multiple joint damage.

Contraindications

• Combined use with TNF blockers;
• severe uncontrolled infections (sepsis, opportunistic infections), active infections (including tuberculosis) until control is established;
• pregnancy;
• lactation period (breastfeeding);
• children under 6 years of age;
• hypersensitivity to the components of the drug.

Use with caution in patients with recurrent infections; conditions predisposing to infections (diabetes mellitus), hepatitis; in elderly patients. Abatacept should be discontinued if an infectious disease develops.

Application of Orencia 250 mg 1 pc. lyophilisate for the preparation of solution for infusion during pregnancy and lactation

Contraindicated for use during pregnancy and lactation (breastfeeding).

Use in children

Use is contraindicated in children under 6 years of age.

special instructions

When prescribing immunomodulatory drugs, it is necessary to perform a tuberculin skin test to detect the presence of tuberculosis infection. Abatacept has not been used in patients with a positive tuberculin test, so the safety of the drug in patients with latent tuberculosis is unknown. If the reaction is positive, standard anti-tuberculosis therapy must be administered before prescribing abatacept.

Live vaccines should not be used during treatment with abatacept and for 3 months after its discontinuation. Medicines that affect the immune system, including abatacept, may reduce the effectiveness of vaccinations.

It is possible to obtain false-positive results when determining blood glucose levels on the day of drug administration using tests based on glucose dehydrogenase-pyrroloquinoline quinone due to a reaction with maltose contained in the drug. If glucose determination is required, methods that do not react with maltose should be used.

Overdose

Orencia® is administered as an intravenous infusion under medical supervision. At doses up to 50 mg/kg, no obvious toxic effects were observed. Overdose symptoms are not described.

Treatment: in case of overdose, medical supervision and, if necessary, symptomatic therapy are recommended.

Side effects Orencia 250 mg 1 pc. lyophilisate for the preparation of solution for infusion

Adverse reactions that were observed in clinical studies when using abatacept or placebo with other treatments for rheumatoid arthritis. Determination of the frequency of adverse reactions: very often (>10%), often (>1% and 0.1% and 0.01% and

Infections and infestations: often - lower respiratory tract infections (including bronchitis), urinary tract infections, herpes simplex and herpes zoster, upper respiratory tract infections (including tracheitis, nasopharyngitis), rhinitis; sometimes - dental infections, infected skin ulcers, onychomycosis.

Benign and malignant tumors: rarely - basal cell skin cancer, lung cancer, lymphoma, myelodysplastic syndrome.

From the hematopoietic system: sometimes - thrombocytopenia, leukopenia.

From the central nervous system and peripheral nervous system: very often - headache; often - vertigo; sometimes - depression, anxiety, paresthesia.

From the organ of vision: sometimes - conjunctivitis, decreased visual acuity, dry eyes.

From the cardiovascular system: often - arterial hypertension, hot flashes; sometimes - tachycardia, bradycardia, palpitations, feeling of heat, decreased blood pressure.

From the respiratory system: often - cough, exacerbation of COPD, shortness of breath; sometimes - bronchospasm, sore throat.

From the digestive system: often - abdominal pain, diarrhea, nausea, dyspepsia, abnormalities in laboratory tests of liver function (including increased transaminase activity); sometimes - gastritis, ulceration of the oral mucosa, aphthous stomatitis.

Dermatological reactions: often - rash (including dermatitis); sometimes - bruising, alopecia, dry skin, psoriasis.

From the musculoskeletal system: sometimes - arthralgia, pain in the extremities.

From the reproductive system: sometimes - amenorrhea.

Other: often - fatigue, asthenia; sometimes - flu-like syndrome, weight gain.

In clinical placebo-controlled studies, the following serious infections were observed in 0.05% of patients, the relationship of which was at least possible with the drug: bronchitis, pneumonia, acute pyelonephritis, diverticulitis, intestinal abscess, local infections, skin abscess, muscle and bone infections, sepsis, bacteremia, empyema, hepatitis E, tuberculosis.

Drug interactions

Serious infections occurred more frequently in patients receiving abatacept with TNF blockers than in patients receiving TNF blockers alone. The combination of abatacept with TNF blockers is not recommended.

There is insufficient information about the safety and effectiveness of the combination of abatacept with anakinra or rituximab, and such combinations are not recommended.

Abatacept has not been studied in combination with drugs that cause a decrease in lymphocyte counts. With this combination, it is possible to potentiate the effect of abatacept on the immune system.

Description of the drug RENEURO

Use with caution in case of renal failure or heart failure. Due to isolated isolated cases of uncontrolled use of pregabalin, it should be used with caution in patients with a history of drug dependence (strict medical supervision is required during treatment in such cases).

In patients with diabetes mellitus, in case of weight gain during treatment with pregabalin, dosage adjustment of hypoglycemic drugs may be required.

Pregabalin should be discontinued if symptoms of angioedema (such as facial swelling, perioral edema or upper respiratory tract swelling) develop.

Pregabalin, like other anticonvulsants, may increase the risk of suicidal thoughts or behavior. Therefore, during the treatment period, patients require careful medical monitoring for the emergence or worsening of depression, the emergence of suicidal thoughts or behavior.

Pregabalin treatment has been associated with dizziness and drowsiness, which increase the risk of accidental injury (falls) in older adults. Cases of loss of consciousness, confusion and cognitive impairment have also been reported during post-marketing use. Therefore, until patients appreciate the possible effects of pregabalin, they should exercise caution.

Data on the possibility of discontinuing other anticonvulsants when seizures are suppressed with pregabalin and the advisability of pregabalin monotherapy are insufficient. There are reports of the development of seizures, incl. status epilepticus and minor seizures, during the use of pregabalin or immediately after the end of therapy.

There have also been cases of renal failure; in some cases, renal function was restored after discontinuation of pregabalin.

The following adverse events have been observed following discontinuation of pregabalin following long-term or short-term therapy:

• insomnia, headache, nausea, diarrhea, flu-like syndrome, depression, sweating, dizziness, cramps and anxiety. There is no information on the frequency and severity of manifestations of pregabalin withdrawal syndrome depending on the duration of therapy with the latter and its dose.

During post-marketing use of pregabalin, the development of chronic heart failure during pregabalin therapy has been reported, primarily in elderly patients with impaired cardiac function and receiving the drug for neuropathy. Therefore, pregabalin should be used with caution in this category of patients. After discontinuation of pregabalin, the manifestations of such reactions may disappear.

The incidence of central nervous system adverse reactions, especially drowsiness, increases with the treatment of central neuropathic pain due to spinal cord lesions, which, however, may be due to the additive effects of pregabalin and other concomitantly administered drugs (eg, antispastic agents). This circumstance should be taken into account when prescribing pregabalin for this indication.

There are reports of cases of dependence developing with the use of pregabalin. Patients with a history of drug dependence require close medical monitoring for symptoms of pregabalin dependence.

Cases of encephalopathy have been reported, especially in patients with concomitant diseases that may lead to the development of encephalopathy.

Impact on the ability to drive vehicles and operate machinery

Pregabalin may cause dizziness and drowsiness and, accordingly, affect the ability to drive vehicles and use complex equipment. Patients should not drive vehicles, use complex machinery, or engage in other potentially hazardous activities until their individual response to pregabalin has been established.