Tecentric® (Tecentriq®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceAtezolizumabAtezolizumab
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  • Tecentric®
    concentrate d / infusion 
    Hoffmann-La Roche Ltd.     Switzerland
    • Dosage form: & nbspconcentrate for solution for infusion
    Composition:

    1 bottle contains:

    active substance: atezolizumab - 1200 mg;

    Excipients: L- histidine - 62.0 mg, glacial acetic acid - 16.5 mg, sucrose - 821.6 mg, polysorbate 20 - 8.0 mg, water for injections up to 20 ml.

    Description:

    Transparent or slightly opalescent liquid from colorless to light yellow color.

    Pharmacotherapeutic group:Antitumor agent - antibodies monoclonal
    ATX: & nbsp

    L.01.X.C   Monoclonal antibodies

    Pharmacodynamics:

    Mechanism of action

    When binding a ligand PD-L1 (the ligand of the receptor for programmed cell death 1, also called PD-1) with receptors PD-1 and B7.1, located on T-lymphocytes, inhibition of cytotoxic activity of T-lymphocytes occurs. This inhibition occurs by inhibiting the proliferation of T lymphocytes and the production of cytokines. PD-L1 can be expressed on tumor cells and tumor-infecting immune cells and participate in suppressing the antitumor immune response in the tumor microenvironment.

    Atezolizumab is a humanized monoclonal antibody from the class of immunoglobulins G1 (IgG1) with a modified Fcfragment, which is directly associated with PD-L1 and blocks its interaction with receptors PD- 1 and B7.1. In this way, atezolizumab facilitates the cessation of the mediated PD- L1/PD-1 suppression of the immune response and causes reactivation of antitumor immunity. Atezolizumab does not affect the interaction of the receptor PD-1 with a ligand PD- L2.

    Blockade of the receptor PD-L1 in mice with genetically related tumor models leads to a decrease in tumor growth.

    Immunogenicity

    With the use of atezolizumab, the development of a reaction from the immune system is possible. Positive results of antibodies to atezolizumab antibodies at one or more time points after drug administration were noted in 43.9% of patients with locally advanced / metastatic urothelial cancer (MP / MHD). The incidence of antitherapeutic antibodies (ATA) in patients with locally advanced / metastatic non-small cell lung cancer (MR / MNRL) was 30.4%. The presence of ATA did not have a clinically significant effect on the pharmacokinetics, efficacy or safety of the preparation Tecentric®.

    The data on immunogenicity largely depend on various factors,such as the sensitivity and specificity of the method, the methodology of the analysis, as well as the handling of specimens and the time of their collection, the taking of concomitant medications and the nature of the underlying disease. Thus, a comparison of the incidence of antibodies to the preparation of Tetcentric® and the frequency of antibodies to other drugs may not be correct.

    Preclinical safety data

    Carcinogenicity: The carcinogenic potential of atezolizumab has not been investigated.

    Mutagenicity: the mutagenic potential of atezolizumab has not been studied.

    Impact on fertility: Studies of fertility with the use of atezolizumab were not conducted. Nevertheless, in a study of chronic toxicity in Javanese macaques, it was found that the preparation of Tecentric® influenced the menstrual cycle in all female monkeys who received the dose of 50 mg / kg, which was manifested by the irregularity of the cycle during the dosing phase and correlated with the absence of yellow body in the ovaries with terminal necrosis. This effect was reversible after drug withdrawal. Influence on male reproductive organs was not noted.

    Teratogenicity: studies of teratogenicity or toxicity in relation to the reproductive system with the use of the preparation of Tecentric® were not carried out. It is established that the signal transmission path PD-L1/PD-1 is key to establishing immunological tolerance of the maternal organism to the fetus, and hence for the survival of the fetus during pregnancy. It is expected that the use of the drug Tecentric® will have an adverse effect on the course of pregnancy, and also put the fruit at risk and potentially cause death of the embryo.

    Pharmacokinetics:

    The pharmacokinetics of atezolizumab was studied using doses of 0.01 mg / kg - 20 mg / kg every 3 weeks, including a fixed dose of 1200 mg in different patients. The exposure of atezolizumab was increased proportionally to the dose in the dose range from 1 mg / kg to 20 mg / kg. The pharmacokinetics of atezolizumab is described using a linear two-chamber distribution model with first-order elimination for the dose range of 1-20 mg / kg. At the same time, the equilibrium state was achieved after 6-9 weeks (2-3 cycles of therapy) with repeated administration. The average accumulation coefficient for the area under the "concentration-time" curve (AUC), maximum concentration (CmOh) and minimum concentration (Cmin) were 1.91, 1.46 and 2.75, respectively.

    The following factors did not exert a clinically significant influence on the systemic exposure of atezolizumab: age 21-89 years, body weight, sex, the presence of antitherapeutic antibodies (ATA), albumin level, tumor load, renal dysfunction, mild liver function disorder, expression level PD-L1 or status on a scale ECOG (the scale of the Eastern Cooperative Research Group for Cancer), as well as the region or ethnicity of the patient.

    Suction

    The drug is injected intravenously. Other ways of drug administration have not been studied.

    Distribution

    According to the results of the analysis of population pharmacokinetics, the volume of distribution in the central chamber (V1) is 3.28 liters, and the volume of distribution in the equilibrium state (Vss) - 6.91 l of the average patient.

    Metabolism

    No studies of atezolizumab metabolism have been conducted. Like other antibodies, atezolizumab predominantly subjected to catabolism.

    Excretion

    The clearance of atezolizumab is 0.200 l / day, and the average half-life (t1/2) - 27 days (according to the results of the analysis of population pharmacokinetics).

    Pharmacokinetics in specific patient groups

    Children

    Studies of the pharmacokinetics of atezolizumab in children have not been conducted.

    Elderly patients

    In elderly patients, no separate studies of the pharmacokinetics of atezolizumab have been conducted.

    According to the results of the analysis of population pharmacokinetics in patients aged 21 to 89 years, age does not have a significant effect on the pharmacokinetics of atezolizumab. Clinically significant differences in the pharmacokinetics of atezolizumab in patients younger than 65 years of age, aged 65-75 years and patients older than 75 years were not observed (see section "Special instructions for dosing" in the section "Dosing and Administration").

    Patients with impaired renal function

    In patients with impaired renal function, no studies of the pharmacokinetics of atezolizumab have been performed.

    According to the results of the analysis of population pharmacokinetics, there were no clinically significant differences in the clearance of atezolizumab in patients with impaired renal function (60/89 mL / min / 1.73 m2) or medium (rSFP 30-59 ml / min / 1.73 m2) degrees of severity in comparison with patients with normal renal function (rSFR more than 90 ml / min / 1.73 m2). Violation renal function of severe degree (rSKF 15-29 ml / min / 1.73 m2) has been reported in a small number of patients in clinical trials, and therefore it is not known whether severe renal failure affects the pharmacokinetics of atezolizumab (see the section on "Specific dosage instructions" in the "Application and dosage" section).

    Patients with impaired hepatic function

    Separate studies of the pharmacokinetics of atezolizumab in patients with impaired liver function were not performed. There were no clinically significant differences in clearance of atezolizumab in patients with mild liver function disorder (bilirubin concentration ≤ upper limit of norm (UGN) and activity of aspartate aminotransferase (ACT) > VGN or bilirubin concentration <1.0-1.5 x VGN and any activity ACT) and normal liver function (bilirubin concentration and level ACT ≤ VLN).

    Data for patients with impaired liver function average (bilirubin concentration> 1.5-3.0 x VGN and any activity ACT) or severe (bilirubin concentration> 3.0 x VGN and any activity ACT) degrees of gravity are absent. The violation of liver function was determined in accordance with the criteria of the National Cancer Institute (NCI) (cm.subsection "Special instructions for dosing" in the section "Method of administration and dose").

    Indications:

    Monotherapy of locally advanced or metastatic urothelial cancer in adults

    Locally or metastatic urothelial cancer after previous chemotherapy or when cisplatin is not available.

    Monotherapy of locally advanced or metastatic non-small cell lung cancer in adults

    Locally or metastatic non-small cell lung cancer after previous chemotherapy.

    Contraindications:

    Hypersensitivity to atezolizumab or any component of the drug in history.

    Pregnancy and the period of breastfeeding.

    Children under 18 years of age (efficacy and safety of the use of the drug Tecentric in children and adolescents <18 years have not been studied).

    Carefully:

    Violation of the liver function of the average (bilirubin concentration> 1.5-3.0 x VGN and any activity ACT) or severe (bilirubin concentration> 3.0 x VGN and any activity ACT) degrees of severity (efficacy and safety of the use of the drug Tecentric® have not been studied).

    Autoimmune diseases (efficacy and safety of the use of the drug Tecentric® have not been studied).

    Violation of the function of the kidneys of severe severity.

    Pregnancy and lactation:

    Pregnancy

    The use of the drug Tecentric® can have a negative effect on the fetus due to the mechanism of action. Animal studies have shown that inhibition of the pathway PD-L1/PD-1 may lead to an increased risk of immuno-mediated rejection of the developing fetus and its death. It is necessary to inform the pregnant woman about the risk to the fetus.

    Clinical studies of the drug Tecentric ® in pregnant women have not been conducted. The preparation of Tecentric® should not be used during pregnancy (see the section "Teratogenicity" in the section "Pharmacological properties").

    Contraception

    Women with a safe reproductive function should use effective methods of contraception and take proactive measures to prevent pregnancy during the treatment with the drug Tecentric® and for a minimum of 5 months after the last infusion of the drug (see section "Specific guidance" and the section "Teratogenicity" in the section "Pharmacological properties ").

    Breastfeeding period

    It is not known whether atezolizumab with breast milk. The effect of the drug on the formation of breast milk or the presence of the drug Tecentric® in breast milk has not been investigated. Since the possibility of a negative impact on a child who is breastfed is unknown, either breastfeeding or the use of the drug Tecentric® should be discontinued.

    Dosing and Administration:

    General recommendations

    Replacement of the drug with any other biological medicinal product requires agreement with the attending physician.

    The drug Tecentric® should be administered only as an intravenous (IV) infusion under the close supervision of an experienced medical professional.

    It is not possible to inject the preparation of Tecentric® in a jet or bolus.

    The recommended dose of the drug Tecentric® is 1200 mg in the form of an IV infusion every 3 weeks.

    The first dose of the drug Tecentric® should be administered within 60 minutes.

    If the first infusion is well tolerated, all subsequent infusions can be carried out within 30 minutes.

    Duration of therapy

    Patients should receive therapy with Tecentric® until the disease progresses or signs of unacceptable toxicity develop.

    Skipping in the planned introduction

    If you miss the planned introduction of the drug Tecentric®, it is necessary to inject the drug at the recommended dose in the shortest possible time, without waiting for the next planned introduction. The schedule of injections of the preparation Tecentric® should be adjusted to maintain a 3-week interval between administrations.

    Correction of dose

    Decrease in the dose of the drug Tecentric® is not recommended.

    Suspension of therapy or delayed administration of subsequent doses

    Table 1. Recommendations for correcting the dosage regimen for individual adverse reactions.

    Unwanted reaction

    Degree of severity

    Correction therapy

    Pneumonitis

    2nd degree

    Suspend therapy with Tecentric®. Therapy can be resumed after the severity of the phenomenon is reduced to 0 or 1 degree for 12 weeks, and after a reduction in the dose of glucocorticosteroids (prednisolone or its equivalent) to ≤10 mg orally per day.

    3rd or 4th degree

    Completely stop the treatment with Tecentric®.

    Hepatitis

    2-nd degree (ALT or ACT level is 3-5 times higher than the upper limit of the norm (VGN) or bilirubin in the blood is 1.5-3 times higher than UGN)

    Suspend therapy with Tecentric®.Therapy can be resumed after the severity of the phenomenon has been reduced to 0 or 1 degree for 12 weeks, and also after a decrease in the dose of glucocorticosteroids (prednisolone or its equivalent) to ≤10 mg orally per day.

    3rd or 4th degree (ALT or ACT level> 5 times higher than ULN or bilirubin in blood> 3 times higher than UHN)

    Completely stop the treatment with Tecentric®.

    Colitis

    Diarrhea 2nd or 3rd degree (increased stoolness ≥4 times a day or clinically expressed colitis)

    Suspend therapy with Tecentric®. Therapy can be resumed after the severity of the phenomenon is reduced to 0 or 1 degree for 12 weeks, and after a reduction in the dose of glucocorticosteroids (prednisolone or its equivalent) to ≤10 mg orally per day.

    Diarrhea of ​​the 4th degree or colitis (life threatening state, urgent medical intervention is indicated)

    Completely stop the treatment with Tecentric®.

    Hypothyroidism and hyperthyroidism

    Symptomatic

    Suspend therapy with Tecentric®.

    Hypothyroidism

    Therapy can be resumed after a decrease in the level of TSH with the help of appropriate replacement therapy.

    Hyperthyroidism

    Therapy can be resumed after an improvement in thyroid function with the help of antithyroid drugs.

    Adrenal insufficiency

    Symptomatic

    Suspend therapy with Tecentric®. Therapy can be resumed after the severity of the phenomenon has decreased to 0 or 1 degree for 12 weeks, and after a reduction in the dose of glucocorticosteroids (prednisolone or its equivalent) to ≤10 mg orally per day; while the patient's condition remains stable on replacement therapy.

    Hypophysitis

    2nd or 3rd degree

    Suspend therapy with Tecentric®. Therapy can be resumed after the severity of the phenomenon has decreased to 0 or 1 degree for 12 weeks, and after a reduction in the dose of glucocorticosteroids (prednisolone or its equivalent) to ≤10 mg orally per day; while the patient's condition should remain stable on replacement therapy.

    4th degree

    Completely stop the treatment with Tecentric®.

    Diabetes mellitus type 1

    Hyperglycemia of the 3rd or 4th degree (fasting glucose level> 250 mg / dL or 13.9 mmol / L)

    Suspend therapy with Tecentric®.Therapy can be resumed after the establishment of metabolic control with the help of insulin replacement therapy.

    Infusion reactions

    1st or 2nd degree

    Reduce the rate of infusion or interrupt the infusion. Therapy can be resumed after the resolution of the phenomenon.

    3rd or 4th degree

    Completely stop the treatment with Tecentric®.

    Rash (see section "Side effect")

    3rd degree

    Suspend therapy with Tecentric®. Therapy can be resumed after the resolution of the rash and a reduction in the dose of glucocorticosteroids (prednisolone or its equivalent) to ≤10 mg orally per day.

    4th degree

    Completely stop the treatment with Tecentric®.

    Myasthenic syndrome / malignant myasthenia gravis, Guillain-Barre syndrome and meningoencephalitis

    All severity levels

    Completely stop the treatment with Tecentric®.

    Pancreatitis

    An increase in the level of amylase or lipase in the serum of the third or fourth degree (> 2 times higher than UGN) or pancreatitis of the 2nd or 3rd degree

    Suspend therapy with Tecentric®. Therapy can be resumed after a decrease in the severity of the phenomenon (increased levels of amylase and lipase) to 0 or 1 degree within 12weeks or relief of pancreatitis symptoms and a reduction in the dose of glucocorticosteroids (prednisolone or its equivalent) to ≤10 mg orally per day.

    4th degree or any degree of recurrent pancreatitis

    Completely stop the treatment with Tecentric®.

    The toxicity criteria are indicated in accordance with the general criteria for the terminology of the National Cancer Institute for Adverse Events, c. 4.0.

    Therapy with Tecentric® should be completely discontinued if the following conditions occur:

    - toxicity of the 4th degree of severity with the exception of endocrinopathies, which are controlled by hormone replacement therapy;

    - any recurrent phenomenon ≥ 3 degrees of severity;

    - if the degree of toxicity associated with therapy does not decrease to 0 or 1 within 12 weeks after the onset of the event;

    - if, 12 weeks after the onset of the onset of the phenomenon, a dose of glucocorticosteroids> 10 mg (prednisolone or its equivalent) orally per day is required to stop the toxicity associated with therapy.

    Special instructions for dosing

    Children

    The effectiveness and safety of the use of the drug Tecentric® in children and adolescents (<18 years) have not been studied.

    Elderly and old age

    Correction of the dose of the drug Tecentric® in patients aged ≥65 years is not required (see subsection "Use in special patient groups" in the section "Pharmacokinetic properties").

    Impaired renal function

    Dose adjustments in patients with impaired renal function of mild and moderate severity are not required (see subsection "Use in special patient groups" in the section "Pharmacokinetic properties"). The use of the drug in patients with impaired renal function of severe severity has not been studied.

    Impaired liver function

    Dose adjustments in patients with mild liver function are not required. The use of the drug Tecentric® in patients with impaired liver function moderate and severe degrees of severity have not been studied (see subsection "Use in special patient groups" in the section "Pharmacokinetic properties").

    Rules for the preparation and storage of a solution for infusions

    Dilution of the drug Tecentric® should be performed by medical personnel in aseptic conditions. The product does not contain preservatives, each vial is for single use only.

    1. Remove 20 ml of the drug Tecentric ® from the vial.

    2. Dilute the drug in an infusion bag made of polyvinyl chloride (PVC), polyethylene (PE) or polyolefin containing 250 ml of 0.9% sterile sodium chloride solution for injection. After dilution, 1 ml of the resulting solution contains about 4.4 mg of atezolizumab (1200 mg / 270 ml). Dilute only 0.9% with a sterile sodium chloride solution for injection.

    1. Infusion pack gently invert to stir the solution, while avoiding foaming. The prepared infusion solution should be used immediately after its preparation.
    2. The solution for parenteral administration before use should be visually checked for particles and discoloration. In the event of particle detection or discoloration, the solution can not be used.

    From the point of view of microbiological purity, the infusion solution should be used immediately after preparation. In exceptional cases, the finished solution can be stored for no more than 24 hours at a temperature of 2-8 ° C or 8 hours at room temperature (≤30 ° C). If the preparation is not used immediately, the time and storage conditions of the prepared solution are the responsibility of the user.

    Compatibility

    The preparation of Tecentric® is compatible with infusion bags with a contact surface made of polyvinyl chloride (PVC), polyethylene (PE) or polyolefin, and also with membranes of infusion filters made of polyethersulfone or polysulfone. infusion systems and other devices for infusion of PVC, PE, polybutadiene or polyesterurethane.

    Side effects:

    Table 2 summarizes the combined data on adverse reactions (HP), observed with the use of the preparation of Tecentric® in patients with MR / MWD and MR / MNRL, as well as in clinical studies in patients with other types of tumors.

    To describe the frequency of undesired reactions, the following classification is used: very frequent (≥1 / 10), frequent (≥1 / 100 and <1/10), infrequent (≥1 / 1000 and <1/100), rare (≥ 1/10000 and <1/1000) and very rare (<1/10000).

    Table 2. HP in patients who received therapy with the drug Tecentric ® during clinical trials.

    Class of organ systems

    Often

    Often

    Infrequently

    Rarely

    Violations of the blood and lymphatic system


    Thrombocytopenia



    Immune system disorders


    		Hypersensitivity reactions



    Disorders from the endocrine system


    Hypothyroidism1, hyperthyroidism2

    Adrenal insufficiency3 , diabetes4

    Hypophysitis

    Metabolic disorders

    Decrease appetite

    		 Hypokalemia, hyponatremia



    Disturbances from the nervous system



    Guillain-Barre Syndrome5, non-infectious meningitis7

    Non-infectious encephalitis6, myasthenic syndrome8

    Disorders from the cardiovascular system


    		Reduction of blood pressure



    Disturbances from the respiratory system, chest and mediastinal organs

    Dyspnea

    Hypoxia, nasal congestion, pneumonitis4



    Disorders from the gastrointestinal tract

    		 Diarrhea, nausea, vomiting

    Dysphagia, colitis10, abdominal pain

    Pancreatitis11, an increase in the concentration of lipase

    		 Increase in the concentration of amylase
    Disturbances from the liver and bile ducts


    		Increased ALT activity, increased ACT activity

    Hepatitis


    Disturbances from the skin and subcutaneous tissues

    Rash13, itching




    Disturbances of musculoskeletal and connective tissue

    Arthralgia

    Pain in muscles and bones



    General disorders and disorders at the site of administration

    		 Increased fatigue, asthenia, fever
    		 Chills, flu-like syndrome, infusion reactions



    1 - reports included hypothyroidism, increased thyroid stimulating hormone activity in the blood, decreased thyroid-stimulating hormone activity in the blood, thyroiditis, myxedema, abnormalities in thyroid function tests, acute thyroiditis, and decreased thyroxine activity.

    2 - reports included hyperthyroidism, increased thyroid stimulating hormone activity in the blood, decreased thyroid-stimulating hormone activity in the blood, thyroiditis, endocrine ophthalmopathy, exophthalmos, abnormalities in thyroid function tests, acute thyroiditis, and decreased thyroxine activity.

    3 - reports included adrenal insufficiency, primary adrenal insufficiency and Addison's disease.

    4 - reports included diabetes mellitus and type 1 diabetes mellitus.

    5 - reports included Guillain-Barre syndrome and demyelinating polyneuropathy.

    6 - messages included encephalitis.

    7 - reports included meningitis.

    8 - data from studies not included in the joint database. The frequency of occurrence is based on the exposure of the drug throughout the program.

    9 - reports included pneumonitis, lung infiltration, bronchiolitis, interstitial lung disease, radiation pneumonitis.

    10 - reports included colitis, autoimmune colitis, ischemic colitis, microscopic colitis.

    11 - reports included pancreatitis and acute pancreatitis.

    12 - reports included autoimmune hepatitis, hepatitis, acute hepatitis.

    13 - reports included maculopapular rash, erythema, itchy rash, acneiform dermatitis, eczema, papular rash, macular rash, dermatitis, erythematous rash, acne, pustular rash, skin peeling, skin ulcer, seborrheic dermatitis, erythema multiforme, bullous dermatitis , generalized rash, toxic skin lesion, exfoliative rash, allergic dermatitis, drug dermatitis, exfoliative dermatitis, palmar-plantar erythrodysesthesia syndrome, papulosquamous rash, toxic skin rash, erythema to Ms eyelids, skin rash century, folliculitis, boils and rashes.

    Description of individual adverse reactions

    For additional information on monitoring the following conditions, see "Special instructions".

    Immunosuppressed pneumonitis

    The development of pneumonitis was observed in 3.1% of patients with metastatic urothelial carcinoma (MUR) and non-small cell lung cancer (NSCLC) who received the drug Tecentric®; in one patient (0.05%), this undesirable reaction led to a fatal outcome.The median time before the onset of signs of pneumonitis was 3.5 months (range: 3 days - 20.5 months). The median duration of pneumonitis was 1.5 months (range: 0 days to 15.1 months). In 0.5% of patients pneumonitis caused the continuous withdrawal of the drug Tecentric ®. Pneumonitis requiring concomitant use of glucocorticosteroids was registered in 1.6% of patients receiving the drug.

    Immunopreparated hepatitis

    The development of hepatitis was observed in 0.3% of patients with MUR and NSCLC who received the drug Tecentric ®. The median time to the onset of manifestation of hepatitis signs was 1.1 months (range: 9 days - 7.9 months). The median duration of hepatitis was 1 month (range: 9 days - 1.9 months). <0.1% of patients had hepatitis abolition of the drug Tecentric ®. Hepatitis, requiring concomitant use of glucocorticosteroids, was registered in 0.2% of patients receiving the drug.

    Immuno-mediated colitis

    The development of colitis was observed in 1.1% of patients with MUR and NSCLC who received the drug Tecentric®. The median time before the manifestation of symptoms of colitis was 4 months (range: 15 days - 15.2 months).The median duration of colitis flow was 1.4 months (range: 3 days - 17.8 months). In 0.2% of patients, colitis caused the withdrawal of the drug Tecentric®. Colitis requiring concomitant use of glucocorticosteroids was registered in 0.5% of patients receiving the drug.

    Immunopreparated endocrinopathies

    The development of hypothyroidism was observed in 4.7% of patients with MDR and NSCLC. who received the drug Tecentric ®. The median time to manifestations of hypothyroidism was 5.5 month (range: from 15 days to 31.3 months).

    The development of hyperthyroidism was observed in 1.7% of patients with MUR and NSCLC who received the drug Tecentric®. The median time to manifestations of hyperthyroidism was 3.5 month (range: from 21 days to 31.3 months).

    The development of adrenal insufficiency was observed in 0.3% of patients with MDR and NSCLC, who received the drug Tecentric ®. The median time to manifestations of adrenal insufficiency was 5.7 months (range: from 3 days to 19 months). Adrenal insufficiency requiring concomitant use of glucocorticosteroids was registered in 0.3% of patients receiving the drug.The development of hypophysitis was observed in <0.1% of patients with MUR and NSCLC receiving the preparation of Tecentric®. The time to manifestations of hypophysitis was 13.7 months.

    The development of diabetes mellitus was observed in 0.3% of patients with MUR and NSCLC who received the drug Tecentric ®. The time to manifestations of diabetes mellitus varied from 3 days to 6.5 months. In 1 patient (<0.1%), diabetes mellitus caused the withdrawal of the drug Tecentric®.

    Immuno-mediated meningoencephalitis

    The development of meningitis was observed in 3 patients (0.1%) with MUR and NSCLC receiving the preparation Tecentric ®. The time to the onset of manifestation of meningitis ranged from 15 to 16 days. All patients required the use of glucocorticosteroids, and therapy with the drug Tecentric® was discontinued.

    The development of encephalitis was observed in 2 patients (<0.1%). The time until the manifestation of signs of encephalitis was 14 and 16 days. One patient required the use of glucocorticosteroids. In 1 patient (<0.1%) encephalitis caused the withdrawal of the drug Tecentric®.

    Immunopreparated neuropathies

    The development of neuropathy, including Guillain-Barre syndrome and demyelinating polyneuropathy, was observed in 0.2% of patients with MUR and NSCLC who received the drug Tecentric®.The median time to manifestations of neuropathy was 7 months (range: 18 days to 8.1 months). The median duration of the course of neuropathy was 4.6 months (from 0 days to 8.6 months). In 1 patient (<0.1%) Guillain-Barre syndrome caused the withdrawal of the drug Tecentric®. Guillain-Barre syndrome requiring the use of glucocorticosteroids was registered in 2 patients (<0.1%).

    Immune-mediated pancreatitis

    The development of pancreatitis, including increased activity of amylase and lipase, was observed in 0.5% of patients with MUR and NSCLC receiving the preparation of Tecentric®. The median time to manifestations of pancreatitis was 5.5 months (range: 9 days to 16.9 months). Median duration of pancreatitis was 18 days (range: from 3 days to 11.2 months). Pancreatitis, requiring concomitant use of glucocorticosteroids, was registered in 2 patients (<0.1%) who received the drug.

    Overdose:

    Information on the overdose of the drug Tecentric ® is absent.

    Interaction:

    There were no separate pharmacokinetic studies of the interaction of atezolizumab with other drugs.

    Because the atezolizumab is excreted by catabolism, metabolic drug interaction is not expected.

    Before using atezolizumab, use of systemic glucocorticosteroids or immunosuppressants should be avoided because of their potential effect on the pharmacodynamic activity and the efficacy of atezolizumab. However, after initiating athezolizumab therapy, systemic glucocorticosteroids or other immunosuppressants can be used to treat adverse reactions from the immune system (see section "Special instructions" and "Dosage and administration").

    Special instructions:

    The patient's medical records should contain the trade name (TechCentric®) and the serial number of the product administered.

    Immunosuppressed pneumonitis

    In the course of clinical trials of the preparation, there were cases of pneumonitis, including death (see section "Side effect"). It is necessary to carefully monitor patients for signs and symptoms of pneumonitis.

    In case of development of pneumonitis of the 2nd (moderate) degree of severity, therapy with the drug Tecentric® should be stopped and treatment with prednisolone (or its equivalent) at a dose of 1-2 mg / kg per day orally.After the severity of pneumonitis symptoms decreased to ≤1 (mild) severity, the dose of glucocorticosteroids should be gradually reduced for ≥1 months.

    Therapy with Tecentric® can be resumed if the severity of pneumonitis decreases to ≤1 (mild) severity within 12 weeks, and the dose of glucocorticosteroids (prednisolone or its equivalent orally) will be reduced to ≤10 mg per day. With the development of pneumonitis of 3rd (severe) or 4th (life-threatening) severity, therapy with Tecentric® should be discontinued and not restarted in the future.

    Immunopreparated hepatitis

    In clinical trials of the drug Tecentric ®, hepatitis cases, including those with a fatal outcome, were observed (see section "Side effect"). It is necessary to carefully monitor the appearance of signs and symptoms of hepatitis. The activity of aspartate aminotransferase (ACT), alanine aminotransferase (ALT) and bilirubin levels prior to the initiation of therapy with Tecentric® and periodically during treatment. In patients with abnormal liver function (PFS), identified at the baseline, consideration should be given to appropriate treatment. If the deviations of the second-degree PFD (ALT or ACT > 3-5 x VGN or bilirubin level> 1.5-3 x VGN) persist for more than 5-7 days, stop treatment with Tecentric® and begin treatment with prednisolone or its equivalent at a dose of 1-2 mg / kg per day orally. After the results of PFS improve to ≤1th degree, it is necessary to reduce the dose of glucocorticosteroids for ≥1 months. Therapy with the drug Tecentric® can be resumed if the severity of the phenomenon decreases to ≤1 degree of severity within 12 weeks, and the dose of glucocorticosteroids (prednisolone or its equivalent orally) will be reduced to ≤10 mg per day.

    In the case of hepatitis 3 or 4 severity (ALT or ACT > 5.0 x VGN or a level of bilirubin in the blood> 3 x VGN), therapy with Tecentric® should be discontinued and not restarted in the future.

    Immuno-mediated colitis

    In clinical studies of the preparation of Tecentric®, cases of diarrhea and colitis have been observed (see section "Side effect"). Patients should be carefully monitored for signs / symptoms of colitis.

    It is necessary to suspend the therapy with the drug Tecentric® in case of diarrhea development of 2nd (moderate) or 3rd (severe) severity (increase in the stool count ≥4 times a day) or clinically expressed colitis.If diarrhea or colitis develops in the 2nd degree of severity, and the symptoms persist or appear wavy for> 5 days, it is necessary to begin therapy with prednisolone orally or its equivalent at a dose of 1-2 mg / kg per day. Diarrhea or colitis of the 3rd (severe) degree of severity should be suppressed by the application of glucocorticosteroids intravenously (IV) (methylprednisolone or its equivalent at a dose of 1-2 mg / kg per day). After improvement, oral glucocorticosteroids should be used (prednisolone or its equivalent of 1-2 mg / kg per day). With a decrease in the severity of symptoms to ≤1 degree, you should gradually reduce the dose of glucocorticosteroids for ≥1 months. Therapy with the drug Tecentric® can be resumed if the severity of the phenomenon decreases to ≤1 degree for 12 weeks, and the dose of glucocorticosteroids (prednisolone or its equivalent) orally will be reduced to ≤10 mg per day. With the development of diarrhea or colitis of the 4th degree of severity (life-threatening), emergency care should be given, and therapy with Tecentric® should be canceled and not renewed in the future.

    Immunopreparated endocrinopathies

    In the course of clinical studies of the preparation, there were cases of hypothyroidism, hyperthyroidism, hypophysitis, adrenal insufficiency and type 1 diabetes mellitus, including diabetic ketoacidosis (see "Side effect"). Patients should be carefully monitored for signs and symptoms of endocrinopathies. It is necessary to observe changes in thyroid function before the beginning of therapy with the drug Tecentric® and periodically during treatment. In patients with thyroid functional abnormalities at baseline, appropriate treatment should be considered. Patients with asymptomatic abnormalities of thyroid functional parameters can receive therapy with Tecentric®.

    In clinically expressed hypothyroidism, therapy with the drug Tecentric® should be suspended and, if necessary, started with thyroid hormone replacement therapy. Isolated hypothyroidism can be controlled by substitution therapy without the use of glucocorticosteroids.

    In the case of clinically pronounced hyperthyroidism, therapy with Tecentric® should be stopped andneed to start treatment with thyreostatic drug (eg, methimazole). Therapy with Tecentric® can be resumed after the control of symptoms and the improvement of thyroid function.

    With clinically pronounced adrenal insufficiency, therapy with the drug Tecentric® should be stopped and treatment with methylprednisolone IV or its equivalent should be started at a dose of 1-2 mg / kg per day. After reducing the severity of symptoms, it is necessary to continue therapy with prednisolone or its equivalent orally at a dose of 1-2 mg / kg per day. After the severity of symptoms decreases to ≤1 degree, you should gradually reduce the dose of glucocorticosteroids for ≥1 months. The therapy with the drug can be resumed if the severity of the phenomenon decreases to ≤1th degree for 12 weeks, and the dose of glucocorticosteroids (prednisolone or its equivalent) will be reduced to ≥ 10 mg per day orally and (if necessary, replacement therapy) will be achieved stable state of the patient on the background of substitution therapy.

    With the development of hypophysitis 2nd or 3rd degree of severity, therapy with atezolizumab is necessaryinterrupt and start treatment with glucocorticosteroids (1-2 mg / kg / day of methylprednisolone or its analog, intravenously). If necessary, also start hormone replacement therapy. After improving clinical symptoms, continue therapy with prednisolone or its analogs at a dose of 1-2 mg / kg / day. If the severity of symptoms decreases to ≤1 degree, the dose of glucocorticosteroids should be gradually reduced over ≥1 months. The therapy with atezolizumab can be resumed after the severity of the phenomenon has decreased to ≤1 degree for 12 weeks, and after a reduction in the dose of glucocorticosteroids (prednisolone or its equivalent) to ≤10 mg orally per day; while the patient's condition should remain stable on replacement therapy (if needed).

    If hypophysitis of the 4th degree of severity arises, therapy with atezolizumab should completely stop.

    When developing type 1 diabetes, you should begin treatment with insulin. For hyperglycaemia ≥3 degree (fasting glucose ≥250 mg / dl), therapy with Tecentric® should be stopped. Therapy can be resumed when metabolic control is achieved against the background of insulin replacement therapy.

    Immuno-mediated meningoencephalitis

    During the clinical trials of the drug Tecentric ®, cases (meningitis / encephalitis) were observed (see section "Side effect"). Patients should be carefully monitored for signs and symptoms of meningitis or encephalitis.

    The use of the drug Tecentric® should be discontinued and not be resumed in the future with the development of meningitis or encephalitis of any severity. You should start treatment with methylprednisolone IV or its equivalent at a dose of 1-2 mg / kg per day. After improving the patient's condition, you should switch to oral administration of prednisolone or its equivalent at a dose of 1-2 mg / kg per day. If the severity of symptoms decreases to ≤1th degree, then gradually reduce the dose of glucocorticosteroids for ≥1 months.

    Immunopreparated neuropathies

    During the clinical trials of the preparation, there were cases of myasthenic syndrome / malignant myasthenia gravis or Guillain-Barre syndrome, which could have a life-threatening character (see section "Side effect"). Patients should be carefully monitored for symptoms of motor and sensory neuropathy.

    Therapy with Tecentric® should be discontinued and not resumed in the future with the development of myasthenic syndrome / malignant myasthenia gravis or Guillain-Barre syndrome of any severity. Consider the possibility of treatment with systemic glucocorticosteroids (prednisolone orally or its equivalent) at a dose of 1-2 mg / kg per day.

    Immune-mediated pancreatitis

    In clinical trials of the preparation, there were cases of pancreatitis, including increased activity of amylase and serum lipase (see "Side effect"). Patients should be carefully monitored for signs and symptoms of acute pancreatitis.

    If serum amylase or lipase activity is increased ≥3 degree of severity (> 2.0 × VGN) or development of pancreatitis of the 2nd or 3rd degree of severity, stop treatment with Tecentric® and begin treatment with methylprednisolone IV or its equivalent at a dose of 1-2 mg / kg per day. After reducing the severity of symptoms, it is necessary to continue treatment with prednisolone or its equivalent orally at a dose of 1-2 mg / kg per day.Therapy with Tecentric® can be resumed if the activity of serum amylase and lipase decreases to ≤1 degree for 12 weeks or after resolution of the symptoms of pancreatitis, and the dose of glucocorticosteroids (prednisolone or its equivalent orally) will be reduced to ≤10 mg per day. With the development of pancreatitis of the 4th degree or recurrence of pancreatitis of any severity, therapy with Tecentric® should be discontinued and not resumed in the future.

    Infusion reactions

    In the course of clinical studies of the preparation, there were observed cases of infusion reactions (IR) (see "Side effect").

    In patients with MI of 1 st or 2 nd degree of severity, the speed of infusion should be reduced or the drug should be discontinued. Patients with IR of the 3rd or 4th degree of severity with the drug Tecentric® should be discontinued and not renewed in the future. Patients with MI of 1st or 2nd degree of severity can continue therapy with Tecentric® under close supervision. It should be considered the expediency of conducting a premedication with antipyretics and antihistamines.

    Special populations of patients

    Patients with autoimmune diseases were not included in the program of clinical trials of the drug Tecentric®, data of the study of the efficacy and safety of the drug in such patients are absent. In patients with autoimmune diseases, the drug Tecentric® should be used with caution after evaluating the potential risk and benefit.

    Instructions for the destruction of an unused preparation or product with expired shelf life

    The exposure of the medication to the environment should be minimized. Do not dispose of the product with sewage or with household waste. Destruction of an unused preparation or product with expired shelf life should be carried out in accordance with the requirements of the medical institution.

    The following points should be strictly observed regarding the use and disposal of syringes and other acute medical items:

    1 never reuse needles and syringes;

    2 All used needles and syringes should be placed in the sharps container (disposable container, piercing resistant).

    Effect on the ability to drive transp. cf. and fur:

    The effect of the drug Tecentric® on the ability to drive and work with machinery has not been studied.

    Form release / dosage:

    Concentrate for the preparation of a solution for infusions of 60 mg / ml.

    Packaging:

    For 1200 mg / 20 ml of the drug in a bottle of colorless glass (hydrolytic class 1 EF / FSA / JAF), sealed with a plug of butyl rubber laminated with fluoropolymer, crimped with an aluminum cap and closed with a plastic lid.

    1 bottle with the drug, along with instructions for use, is placed in a cardboard box.

    Storage conditions:

    Store at 2-8 ° C in a cardboard box for protection from light.

    Keep out of the reach of children.

    Shelf life:

    2 years.

    Do not use after the expiration date printed on the package.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-004652
    Date of registration:18.01.2018
    Expiration Date:18.01.2023
    The owner of the registration certificate:Hoffmann-La Roche Ltd.Hoffmann-La Roche Ltd. Switzerland
    Manufacturer: & nbsp
    Representation: & nbspROSH-MOSCOW, CJSCROSH-MOSCOW, CJSCRussia
    Information update date: & nbsp26.02.208
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