Tagrisso (Tagrisso)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceOsimertinibOsimertinib
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  • Tagrisso
    pills inwards 
    AstraZeneca AB     Sweden
    • Dosage form: & nbspfilm coated tablets
    Composition:

    One tablet, film-coated, 40 mg contains:

    Active substance: osmertinib mesylate * 47.7 mg, which corresponds to osmertinib 40 mg.

    Excipients: mannitol 147 mg, microcrystalline cellulose 37.5 mg, giprolose with a low degree of substitution of 12.5 mg, sodium stearyl fumarate 5.0 mg; tablet shell** ***/ polyvinyl alcohol 5.00 mg, titanium dioxide 2.98 mg, macrogol 3350 2.53 mg, talc 1.85 mg, iron dye oxide yellow (E 172) 0.113 mg, ferric iron oxide red (E 172) 0.028 mg, iron oxide dye black (E 172) 0.008 mg.

    One tablet, film-coated, 80 mg contains:

    Active substance: osmertinib mesylate * 95.4 mg, which corresponds to osmertinib 80 mg.

    Excipients: mannitol 295 mg, microcrystalline cellulose 75.0 mg, giprolose with a low degree of substitution 25.0 mg, sodium stearyl fumarate 10.0 mg; shell tablets * ***: polyvinyl alcohol 8.00 mg, titanium dioxide 4.76 mg, macrogol 3350 4.04 mg, talc 2.96 mg, iron dye oxide yellow (E 172) 0.180 mg, ferric iron oxide red (E 172) 0.044 mg, iron oxide dye black (E 172) 0.012 mg. 1.192 mg of osmertinib mesylate corresponds to 1 mg of osmertinib.

    The components can be added as a finished mixture to form a shell (Opadrai II beige).

    For tablets of 40 mg, the desired amount corresponds to about 5% (w / w) of the tablet core weight. For tablets of 80 mg, the desired amount corresponds to about 4% (w / w) based on the weight of the tablet core.

    Description:

    The tablets covered with a film membrane, 40 mg:

    Round, biconvex tablets, covered with a film membrane of light brown color, with engraving AZ on one side.

    40

    The tablets covered with a film membrane, 80 mg:

    Oval, biconvex tablets, covered with a film membrane of light brown color, with engraving "AZ 80 "on one side.

    Pharmacotherapeutic group:Antitumor agent, protein kinase inhibitor
    ATX: & nbsp

    L.01.X.E.35   Osimertinib

    Pharmacodynamics:

    Mechanism of action and pharmacodynamic effects

    Mechanism of action

    Osimertinib is an inhibitor of tyrosine kinase. This is an irreversible inhibitor of epidermal growth factor receptor tyrosine kinase (EGFR), Effective in the presence of sensitizing gene mutations EGFR and mutations of T790M. associated with the development of resistance to tyrosine kinase inhibitors.

    Pharmacodynamic effects

    In studies in vitro it was demonstrated that osteertinib has a high activity and inhibitory action against EGFR in all clinically significant non-small cell lung cancer (NSCLC) cell lines carrying sensitizing mutations EGFR and a T790M resistance mutation (apparent half-maximal inhibitory concentrations (IC50) 6-54 nmol relative to phosphorylated EGFR). This leads to suppression of cell growth, while much less activity is observed with respect to cell lines having a wild type EGFR (seeming IC50 480 nmol - 1.8 μmol with respect to phosphorylated EGFR). In vivo Oral administration of osertertib is accompanied by a decrease in the size of the tumor, both in xenografts of NSCLC with activating mutations EGFR and mutations of T790M, and in models of lung tumors in transgenic mice.
    Pharmacokinetics:

    Parameters of pharmacokinetics of osertertib were determined in healthy volunteers and patients with NSCLC. According to the results of the analysis of population pharmacokinetics, the apparent plasma clearance of osertertinib is 14.2 l / h, the apparent volume of distribution is 986 L and the half-life is approximately 48 hours. Values AUC (the area under the concentration-time curve) and the maximum concentration (CmOh) increased in proportion to the dose taken in the dose range of 20 to 240 mg.The administration of osmertinib once a day every day leads to approximately threefold accumulation with the attainment of an equilibrium state by the 15th day of admission. In the equilibrium state, plasma concentrations were usually maintained at a 1.6-fold range during the 24-hour inter-dose interval.

    Absorption

    After ingestion of the median time to reach the maximum concentration of osmertinib in plasma (min-max) tmax is 6 (3-24) hours, and in some patients the maximum concentrations were reached within the first 24 hours. Absolute bioavailability of the drug Tagrisso was not determined. According to the clinical pharmacokinetic study in patients receiving the drug at a dose of 80 mg, eating does not have a clinically significant effect on the bioavailability of osertertib (AUC increases by 6% (90% CI 5-19), and CmOh decreases by 7% (90% CI 19-6)). In healthy volunteers, increasing the pH of gastric juice by taking omeprazole for 5 days did not affect the exposure of osertermanib taken in the form of a tablet of 80 mg (AUC and CmOh increased by 7% and 2%, respectively), and 90% CI for the exposure ratio was within the 80-125% range.

    Distribution

    According to the population analysis, the average volume of distribution in the equilibrium state (Vss/F) osmertinib is 986 liters, indicating a significant distribution in the tissues. The connection with plasma proteins can not be measured due to instability, however, based on the physico-chemical properties of osertertib, it is possible to assume a pronounced relationship with proteins. It was shown that osteertinib can also form a covalent bond with rat and human plasma proteins, human and rat serum albumin and human hepatocytes.

    Metabolism

    Research in vitro showed that osteertinib it is metabolized, isoenzymes of cytochrome CYP3A4 and CYP3A5. In this case, the metabolism involving isoenzyme CYP3A4, probably, is of less importance. Alternative metabolic pathways may exist that have not been fully described.

    In studies in vitro, on preclinical models and with oral administration of osmertinib in humans in the plasma, two pharmacologically active metabolites were detected: AZ7550 and AZ5104; AZ7550 demonstrated a pharmacological profile similar to the Tagrisso drug, while AZ5104 was more active in relation to both the mutated and wild type EGFR.

    Both metabolites slowly appear in the blood plasma of patients after taking the drug Tagrisso, and the median (min-max) tmax is 24 (4 - 72) and 24 (6 - 72) hours, respectively. In blood plasma unchanged osteertinib is 0.8%, and its two metabolites are 0.08% and 0.07% of total radioactivity, with the bulk of radioactivity covalently bound to plasma proteins. Geometric mean exposure AZ5104 and AZ7550 based AUC was approximately 10% of the exposure of osmertinib in equilibrium for each metabolite.

    The main way of metabolism of ismerthinib is oxidation and dealkylation. In urine and feces of human specimens, no less than 12 compounds were found, with 5 compounds accounting for more than 1% of the dose taken, of which unchanged osteertinib, AZ5104 and AZ7550 are approximately 1.9%, 6.6% and 2.7% of the dose, respectively, while the adduct of cysteinyl (M21) and the unknown metabolite (M25) are 1.5% and 1.9% of the dose, respectively.

    Based on research results in vitro osmertinib at clinically significant concentrations is a competitive inhibitor of the isoenzyme CYP 3A4 / 5, but not CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6 and 2E1.According to research data in vitro, osteertinib in clinically significant concentrations does not suppress UGT1A1 and UGT2B7 in the liver. Possible suppression of activity UGT1A1 in the intestine, but the clinical significance of this process is unknown.

    Excretion

    After a single dose of the drug inside at a dose of 20 mg, 67.8% of the dose was excreted through the intestine (1.2% in the form of unchanged substance), and 14.2% of the dose (0.8% as unchanged substance) was detected in the urine after collection of samples urine for 84 days. Approximately 2% of osertertib is excreted unchanged - 0.8% by the kidneys and 1.2% - through the intestine.

    Interactions with transport proteins

    Research in vitro showed that osteertinib is not a substratum of OATP1B1 and 0ATP1B3. In vitro, osmertinib in clinically significant concentrations does not suppress OAT1, OATZ, OATP1B1, OATP1B3 and MATE2K. However, interactions with substrates MATE1 and OST2 can not be ruled out.

    The effect of ismertinib on glycoprotein P and breast cancer resistance protein

    Based on research results in vitro osmertinib is the substrate of the glycoprotein P (P-gp) and breast cancer resistance protein (BCRP), but it is unlikely that osteertinib in clinically significant doses enters into a drug interaction with the active substances.According to research in vitro, osmertinib is an inhibitor BCRP and P-gp. Interactions with enzymes regulated by the pregnan-X receptor have not been studied (PXR), Besides CYP3A4 (see section "Interaction with other drugs").

    Pharmacokinetics in specific patient groups

    In analyzes of population pharmacokinetics (n= 778) there were no clinically significant connections between the calculated equilibrium exposure (AUCSS) and the age of patients (range: 21-89 years), sex, ethnicity (including patients European, Asian population, including Japanese, Chinese and patients not belonging to these groups) and smoking (n= 24 active smokers, n= 232 former smokers). An analysis of population pharmacokinetics showed that body weight was an essential covariate; there was a change from -20% to + 30% AUCSS osmertinib in the body weight range from 90 kg to 43 kg, respectively (from 95% to 5% quantiles) compared with AUCSS with a median body weight of 62 kg. Taking into account the limits of body weight from <43 kg to> 90 kg, the proportion of metabolite AZ5104 ranged from 11.8% to 9.6%, and the metabolite AZ7550 from 12.8% to 9.9%, respectively. These changes in exposure, depending on body weight, are not considered clinically significant.

    Patients with impaired hepatic function

    Osimertinib is eliminated mainly by the liver, therefore in patients with impaired liver function its exposure can increase. Pharmacokinetic studies involving patients with impaired liver function have not been completed. According to the results of the analysis of the population pharmacokinetics data there is no correlation between the markers of the liver function (alanine aminotransferase (ALT), aspartate aminotransferase (ACT), bilirubin) and the exposure of osertertinib. This indicator of liver function as serum albumin affects the pharmacokinetic parameters of osertertib. Clinical trials did not include patients with active ACT or ALT exceeded the upper limit of the norm (VGN) by more than 2.5 times, as well as patients in whom the activity ACT or ALT exceeded UGN due to tumor lesion of the liver more than 5 times, as well as patients whose total bilirubin concentration exceeded UGN more than 1.5 times. According to the results of pharmacokinetic analysis, the exposure of osertertib in 44 patients with mild liver function disorder and 330 patients with normal liver function was similar.Data on the use of the drug in patients with impaired liver function are limited (see section "Method of administration and dose").

    Patients with impaired renal function

    Pharmacokinetic studies involving patients with impaired renal function have not been completed. According to the population pharmacokinetic analysis, including 330 patients with mild renal dysfunction (creatinine clearance from 60 ml / min to less than 90 ml / min), 149 patients with impaired renal function of moderate severity (QC from 30 ml / min to less than 60 ml / min), 3 patients with impaired renal function of a serious degree (SC from 15 ml / min to less than 30 ml / min) and 295 patients with normal renal function (QC not less than 90 ml / min), in all subgroups, the exposure of osertertinib was similar. Violation of the function of the kidneys of a severe degree can affect the elimination of medications that are excreted through the liver. Patients with SC less than 15 mL / min were not included in the clinical trials.

    Indications:

    Locally distributed or metastatic non-small cell lung cancer with a T790M mutation in the epidermal growth factor receptor gene (EGFR) in adult patients.

    Contraindications:

    Hypersensitivity to osmertinib or any of the components of the drug.

    Pregnancy and the period of breastfeeding.

    Severe renal dysfunction, terminal stage of chronic renal failure, including patients on hemodialysis.

    Violation of the liver function of medium and severe degree.

    Children and adolescents under the age of 18 (data not available).

    The intake of St. John's wort products perforated against the background of therapy with the drug Tagrisso is contraindicated.

    Joint application of powerful inductors CYP3A (eg, phenytoin. Rifampicin and carbamazepine).

    Carefully:Interstitial lung disease, lengthening interval QTc, joint application with moderate inductors CYP3A4 (for example, bosetans, efavirenz, etravirine, modafinil).
    Pregnancy and lactation:

    Contraception in men and women

    Women with preserved reproductive potential should avoid pregnancy during treatment with Tagrisso. Patients should be advised to use effective contraception after treatment with the drug: for at least 2 months after the end of therapy for women and 4 months for men.It is impossible to exclude the risk of reducing the exposure of hormonal contraceptives.

    Pregnancy Period

    There are no data on the use of osertertib in pregnant women. Studies in animals have shown the presence of reproductive toxicity (embryo-emotionality, delayed fetal development, death of newborns). Given the mechanism of action and pre-clinical data, the use of osertertib in pregnancy can cause harm to the fetus. Do not use the drug Tagrisso during pregnancy.

    Breastfeeding period

    It is not known whether osteertinib or its metabolites into breast milk. There is insufficient information about the excretion of osertertib or its metabolites in the milk of animals. but osteertinib and its metabolites were found in puppies who received breastfeeding, which had a negative impact on their growth and survival. It is impossible to exclude the risk for children who are breastfeeding. It is necessary to stop breastfeeding during therapy with the drug Tagrisso.

    Fertility

    There is no data on the effect of the drug Tagrisso on human fertility. According to the results of studies conducted on animals, osteertinib affects male and female reproductive organs, and can reduce fertility.

    Dosing and Administration:

    Therapy with Tagrisso should be started under the supervision of a doctor who has experience in treating antitumor drugs.

    Prior to the appointment of Tagrisso in patients with locally advanced or metastatic non-small cell lung cancer, the T790M mutation in the gene should be confirmed EGFR. Determination of the T790M mutation in the gene EGFR it is necessary to carry out with the help of the validated test (see section "Special instructions").

    Doses

    The recommended dose of osmertinib is 80 mg once daily. Therapy is continued until the onset of disease progression or the development of unacceptable toxicity. The drug should be taken every day at the same time, regardless of food intake. In case of skipping the drug, the missed dose should be taken if the remaining dose remains at least 12 hours before the next dose.

    Correction of the dose of the drug

    Depending on the individual tolerability of the drug and adverse reactions, it may be necessary to suspend therapy and / or reduce the dose of the drug.The recommended reduced dose of the drug is 40 mg once a day.

    Table 1 provides recommendations for correcting the dose of the drug in the event of undesired reactions.

    Table 1. Correction of the dose of the drug Tagrisso in case of undesirable reactions

    Target organ

    Unwanted reaction1

    Correction of dose

    Lungs

    Interstitial lung disease / pneumonitis

    Termination of therapy with Tagrisso

    A heart

    Interval lengthening QTc more than 500 msec, marked at least twice (with repeated ECG registrations)

    Suspension of Tagrisso therapy until the interval is shortened QTc below 481 msec or up to the original value (if the initial duration of the interval QTc was no less than 481 msec), then the resumption of therapy with a reduced dose of the drug (40 mg)

    Interval lengthening QTc with signs / symptoms of severe arrhythmia

    Termination of therapy with Tagrisso

    Other

    Undesirable reaction of grade 3 or higher

    Suspension of therapy with the drug Tagrisso for up to 3 weeks

    With a decrease in the degree of adverse reaction from grade 3 or higher to 0-2 degrees after suspension of therapy with Tagrisso for up to 3 weeks

    It is possible to resume therapy with the Tagrisso drug at the previous dose (80 mg) or in a reduced dose (40 mg)

    The degree of adverse reaction after suspension of therapy for 3 weeks did not decrease from 3 or higher to 0-2 degrees

    Termination of therapy with Tagrisso

    1 The intensity of adverse events is indicated in accordance with the Common Terminology Criteria for Adverse Events (STAAE) of the National Cancer Institute (NCI) version 4.0.

    Special patient groups

    It is not necessary to adjust the dose of the drug depending on age, body weight, sex, ethnicity and smoking status (see the section "Pharmacokinetics").

    Patients with impaired hepatic function

    Clinical studies on the study of pharmacokinetics in patients with impaired liver function have not been completed. Patients with impaired liver function of mild severity (the concentration of total bilirubin does not exceed VGN., Activity of aspartate aminotransferase (ACT) exceeds the VGN, or the concentration of total bilirubin exceeds the VGN, but less than 1.5 VGN at any activity value ACT) dose adjustment is not recommended, but caution should be used with Tagrisso in these patients.The efficacy and safety of osmertinib in patients with impaired liver function of medium and severe severity has not been studied, therefore, the use of Tagrisso in such patients is contraindicated (see the section "Pharmacokinetics").

    Patients with impaired renal function

    Clinical studies on the study of pharmacokinetics in patients with impaired renal function have not been completed. Correct the dose of the drug to patients with impaired renal function of mild and moderate severity is not recommended. Data on the use of osertertib in patients with impaired renal function are severely limited. The safety and efficacy of osertermanib have not been established in patients with end-stage renal failure (creatinine clearance, calculated according to the Cockcroft-Gault formula, less than 15 ml / min) or receiving dialysis, therefore, the use of Tagrisso in these patients is contraindicated (see section "Pharmacokinetics").

    Children

    The safety and effectiveness of the drug Tagrisso in children and adolescents under the age of 18 years are not established. No data available.

    Mode of application

    Inside.

    Tablets should be swallowed whole, washed down with water. Do not share, crush or chew tablets.

    If the patient is difficult to swallow the tablet, it can be dispersed in 50 ml of still water. Other liquids can not be used. The tablet should be lowered into water without crushing, stirring until it is completely destroyed and immediately drink the resulting suspension. Residue mixed with additional 100 ml of water and drink the resulting suspension. Do not use other liquids.

    A suspension of the Tagrisso drug can also be administered via a nasogastric tube. In this case, the suspension is prepared in a similar manner, but the tablet is dispersed in 15 ml of water, and the remainder of the preparation is mixed with another 15 ml of water. The resulting 30 ml suspension of the drug must be administered according to the instructions of the nasogastric tube manufacturer and rinse the probe with a suitable volume of water. Dispersed drug and dissolved residues should be administered within 30 minutes from the moment the tablets are immersed in water.

    Side effects:

    Security Profile Overview

    Information about the safety profile of the drug Tagrisso reflects the experience of its use in 690 patients with NSCLC mutation T790M, who previously received therapy with tyrosine kinase inhibitor EGFR. All of these patients took the drug at a dose of 80 mg per day in a randomized phase III study (second line therapy in the study AURA 3) and two studies conducted in one group (AURAex and second or subsequent lines of therapy in the study AURA 2). Most of the adverse reactions were 1 or 2 degrees of severity. The most frequent undesirable drug reactions were diarrhea (44%) and rash (41%). Undesirable effects of 3 and 4 severity in both studies were 26% and 2%, respectively, 2.3% patients who received the preparation of Tagrisso at a dose of 80 mg per day, required a dose reduction because of the development of unwanted drug reactions. In 6.5% of patients, therapy was discontinued due to the development of unwanted reactions or laboratory abnormalities.

    List of unwanted reactions in the form of a table

    Table 2 shows the incidence of adverse reactions that are often observed in patients who received at least one dose of Tagrisso in clinical trials AURAex (II phase), AURA 2 and AURA 3.

    Undesirable drug reactions are listed by the class of systems and organs, and within each class are distributed according to the frequency of occurrence, with the most frequent reactions being listed first.Within each group of frequency, undesirable drug reactions are presented in descending order of severity. In addition, the appropriate frequency categories for each unwanted drug reaction are determined as follows: very often (≥1 / 10); often (from ≥1 / 100 to <1/10); infrequently (from ≥1 / 1000 to <1/100); rarely (from ≥1 / 10000 to <1/1000); very rarely (<1/10000); unknown (can not be estimated from available data).

    Table 2. Undesirable drug reactions noted in the studies AURA1

    Classes of systems and organs

    Unwanted drug reactions

    The total frequency of unwanted drug reactions of all degrees of STAAE2

    Frequency of undesirable drug reactions of 3-4 degrees according to CACAE

    Disturbances from the respiratory system, chest and mediastinal organs

    Interstitial lung disease3

    Often (3.2%)4

    1,3%

    Disorders from the gastrointestinal tract

    Diarrhea

    Very often (44%)

    1%

    Stomatitis

    Very often (15%)

    0%

    Disturbances on the part of the organ of sight

    Keratite5

    Infrequently (0.9%)

    0%

    Disturbances from the skin and subcutaneous tissue

    Rash6

    Very often (41%)

    0,7%

    Dryness of the skin7

    Very often (29%)

    0%

    Paronychia8

    Very often (27%)

    0%

    Itching9

    Very often (15%)

    0%

    Changes in the parameters of laboratory and instrumental studies (the results of studies presented as a change in the degree of CACAE)

    Interval lengthening QTc10

    Infrequently (0.7%)

    Decreased platelet count11

    Very often (54%)

    2,1%

    Reducing the number of leukocytes11

    Very often (66%)

    2,4%

    Decreased neutrophil count11

    Very often (32%)

    4,3%

    1 The data were obtained in Phase III studies (AURA 3) and Phase II (AURAex and AURA 2); the data on the phenomena which have arisen at the patients which have received, as a minimum, one dose of preparation Тагриссо are resulted.

    2 General terminological criteria for adverse events of the National Cancer Institute, version 4.0.

    3 Includes cases noted within the group terms: interstitial lung disease and pneumonitis.

    4 Four phenomena of the 5th degree of STAAE (lethal) were registered.

    5 Includes cases noted within the group terms: keratitis, pinpoint keratitis, corneal erosion, corneal epithelial defect, corneal defect.

    6 Includes cases noted within the group term rash: rash, generalized rash, erythematous rash, macular rash, maculopapular rash, papular rash, pustular rash, erythema, folliculitis, acne, dermatitis and acneiform dermatitis.

    7 Includes cases noted within the group terms: dry skin, cracks in the skin, xeroderma, eczema.

    8 Includes cases noted within the group terms: disease of the nail bed, inflammation of the nail bed, tenderness of the nail bed, discoloration of the nails, nail disease, nail dystrophy, nail infection, tuberosity of the nails, onychoclasia, onycholysis, onychomadesis, paronychia.

    9 Includes cases noted within the group terms: itching, generalized itching, itchy eyelids.

    10 Interval lengthening frequency QTcF > 500 msec.

    11 Reflects the frequency of laboratory abnormalities, and not the frequency of noted undesirable phenomena.

    Table 3. Undesirable drug reactions noted in the study AURA 31

    Classes of systems and organs

    Tagrisso common frequency (N = 279)

    Chemotherapy (pemetrexed / cisplatin or pemetrexed / carboplatin) total frequency (N=136)

    Degree on NCI

    Any degree (%)

    Degree 3 and above (%)

    Any degree (%)

    Degree 3 and above (%)

    Unwanted drug reactions

    Disturbances from the respiratory system, chest and mediastinal organs

    Interstitial lung disease2,3

    3,6

    0,4

    0,7

    0,7

    Disturbances on the part of the organ of sight

    Keratite4

    1,1

    0

    0,7

    0

    Disorders from the gastrointestinal tract

    Diarrhea

    41

    1,1

    11

    1,5

    Stomatitis

    15

    0

    15

    1,5

    Disturbances from the skin and subcutaneous tissue

    Rash5

    34

    0,7

    5,9

    0

    Dryness of the skin6

    23

    0

    4,4

    0

    Paronychia7

    22

    0

    1,5

    0

    Itching8

    13

    0

    5,1

    0

    Changes in the parameters of laboratory and instrumental studies

    QTc interval extension9

    1,4

    0

    0,7

    0

    The results of the studies, presented as a change in the degree of CACAE

    Decreased platelet count10

    46

    0,7

    48

    7,4

    Reducing the number of leukocytes10

    61

    1,1

    75

    5,3

    Decreased neutrophil count10

    27

    2,2

    49

    12

    1 Data obtained in the study AURA 3 in patients who received at least one dose of the drug Tagrisso.

    2 Includes cases noted within the group terms: interstitial lung disease and pneumonitis.

    3 One phenomenon of the 5th degree of STAAE (lethal) was registered.

    4 Includes cases noted within the group terms: keratitis, pinpoint keratitis, corneal erosion, corneal epithelial defect, corneal defect.

    5 Includes cases noted within the group term rash: rash, generalized rash, erythematous rash, macular rash, maculopapular rash, papular rash, pustular rash, erythema, folliculitis, acne, dermatitis and acneiform dermatitis.

    6 Includes cases noted within the group terms: dry skin, cracks in the skin, xeroderma, eczema.

    7 Includes cases noted within the group terms: nail diseases, diseases of the nail bed, inflammation of the nail bed,soreness of the nail bed, discoloration of the nails, nail disease, nail dystrophy, nail infection, nail tuberosity, onychoclasia, onycholysis, onychomadesis, paronychia.

    8 Includes cases noted within the group terms: itching, generalized itching, itchy eyelids.

    9 Interval lengthening frequency QTcF > 500 msec.

    10 Reflects the frequency of laboratory abnormalities, and not the frequency of noted undesirable phenomena.

    Safety profile in Phase II studies AURAex and AURA 2, in general, was consistent with the safety profile of patients treated with Tagrisso in the study AURA 3. There were no new or unexpected toxicity manifestations, and the side effects were balanced by type, severity and frequency.

    Description of some unwanted reactions

    Interstitial lung disease

    In studies AURA the incidence of interstitial lung disease was 8.2% in Japanese patients, 1.9% in other Asian patients, and 2.9% in non-Asian patients. The median time to the onset of the development of interstitial lung disease and similar adverse reactions was 2.8 months (see section "Special instructions").

    Interval lengthening QTc

    Of the 833 patients who received the Tagrisso drug, 80 mg in studies AURA, in 6 (0.7%) the value of the interval QTc more than 500 msec, and in 24 patients (2.9%) the value of the interval QTc increased by more than 60 ms from the original value. According to the pharmacokinetic analysis, an interval QTc with increasing drug concentration. Heart rhythm disorders associated with lengthening the interval QTc, in studies AURA not noted (see the sections "Pharmacodynamics" and "Special instructions").

    Undesirable phenomena from the gastrointestinal tract

    In studies AURA Diarrhea was noted in 43.5% of patients, of which 36.8% had grade 1 toxicity, 5.5% had grade 2, and 1.0% had grade 3. There were no toxicity manifestations of grade 4 or 5. Dose reduction was required in 0.3% of patients, temporary discontinuation of the drug - 0.7% of patients. In one case (0.1%), therapy was abolished. In the study AURA 3 median time before the onset of an undesirable phenomenon was 22 days, and the average duration for a 2-degree event was 5.5 days.

    Elderly patients

    In the study AURA 3 (N= 279), 41% of patients were 65 years of age or older; of which 15% were aged 75 years and over. Patients aged 65 years and over, according to

    compared with patients under the age of 65, there were more frequent adverse reactions leading to a change in the dosing regimen (suspension of therapy or drug withdrawal) (5.3% and 4.2%, respectively). The types of unwanted reactions were not different depending on the age. Patients of the elderly age experienced more frequent reactions of grade 3 and higher, compared with younger patients (5.3% compared to 2.4%). The effectiveness of therapy in this group of patients did not differ from that in younger patients. In Phase II studies AURA consistent data on efficiency and safety were obtained.

    Overdose:

    In clinical trials I/II phase a limited number of patients received the drug in daily doses up to 240 mg, with no dose-limiting toxicity. In patients who received in these studies, the preparation of Tagrisso in daily doses of 160 mg and 240 mg, there was an increase in the frequency and severity of some typical tyrosine kinase inhibitors EGFR adverse events (mainly diarrhea and skin rash), compared with a dose of 80 mg. Information on accidental overdoses of the drug in patients is limited.All cases were separate episodes of admission by mistake by patients of an additional daily dose of the drug Tagrisso without clinical consequences.

    There is no specific treatment for an overdose of Tagrisso. If you suspect an overdose, you should stop taking Tagrisso and start symptomatic therapy.

    Interaction:

    Pharmacokinetic interactions

    Powerful inducers of isoenzyme CYP3A4 can reduce the exposure of osertermanib. Osimertinib can increase the exposure of protein substrates to breast cancer resistance (BCRP).

    Active substances, which can increase the concentration of osertertib in plasma Research in vitro showed that the I phase of isomeritinib metabolism proceeds mainly with the help of isoenzymes CYP3A4 and CYP3A5. In a clinical pharmacokinetic study in patients who simultaneously took osteertinib and itraconazole 200 mg twice daily (potent inhibitor CYP3A4), there was no clinically significant effect on the exposure of osmertinib (area under the concentration-time curve (AUC) increased by 24%, and CmOh decreased by 20%). Therefore, inhibitors CYP3A4, probably, do not have an effect on the exposure of osertertinib. Additional catalyzing enzymes are not identified.

    Active substances, which can reduce the concentration of osertertib in plasma

    In a clinical pharmacokinetic study, the significance of AUC osmertinib in the equilibrium state was reduced by 78% in patients with simultaneous use with rifampicin (600 mg per day for 21 days). Similarly, exposure of the metabolite AZ5104 decreased by 82% (AUC) and 78% (CmOh). Joint application of powerful inductors CYP3A (eg, phenytoin, rifampicin and carbamazepine) with the preparation of Tagrisso is contraindicated.

    Moderate inducers CYP3A4 (for example, bozetan. efavirenz, etravirine, modafinil) may also reduce the exposure of osertertinyl, therefore, caution should be exercised simultaneously with osertertib and, if possible, avoid such a combination of drugs. The clinical data, which allow to recommend the correction of the dose of the drug Tagrisso, are absent. The intake of preparations of St. John's wort perforated against the background of therapy with the drug Tagrisso is contraindicated (see the section "Contraindications").

    Effect of drugs, reducing acidity of gastric juice, on osteertinib

    In a clinical pharmacokinetic study, the combined use of omeprazole did not result in clinically significant changes in the exposure of osertertib. Drugs that change the pH of the stomach can be used simultaneously with the preparation of Tagrisso without restrictions.

    Active substances, the concentration of which in the plasma can be influenced by the drug Tagrisso

    According to research in vitro osmertinib is a competitive inhibitor BCRP transporters.

    In a clinical pharmacokinetic study, the joint use of the drug Tagrisso with rosuvastatin (sensitive substrate BCRP) increased AUC and CmOh rosuvastatin by 35% and 72%, respectively. Careful monitoring of patients taking drugs whose distribution depends on BCRP, with a narrow therapeutic index, against the background of therapy with the preparation of Tagrisso to exclude the symptoms of a violation of the tolerance of these medicines as a result of their increased exposure (see the section "Pharmacokinetic properties").

    In a clinical pharmacokinetic study, simultaneous use of the Tagrisso preparation with simvastatin (sensitive substrate CYP3A4) lowered AUC and CmOh simvastatin by 9% and 23%, respectively.These changes are small enough and probably have no clinical significance. The occurrence of pharmacokinetic interactions with isoenzyme substrates is unlikely CYP3A4. Interactions with enzymes regulated by PXR, Besides CYP3A4. The risk of reducing the exposure of hormonal contraceptives with simultaneous use with the drug Tagrisso can not be ruled out.

    Special instructions:

    Determining the status of a mutation T79QM in the gene EGFR

    When considering the appointment of Tagrisso as a therapy for locally advanced or metastatic NSCLC, it is important to determine the status of the T790M mutation in the gene EGFR. The status of the T790M mutation must be determined in tumor DNA obtained from a tumor tissue sample or in circulating tumor DNA derived from a plasma sample using a validated test. Only reliable, well-founded and sensitive methods of investigation with confirmed diagnostic significance in determining the status of the T790M mutation in tumor DNA (isolated from a tumor or blood plasma sample) should be used. Detection of a patient in the T790M mutation in the tumor tissue or plasma indicates the presence of an indication for the use of the drug Tagrisso.In the case of a negative result of blood plasma testing, a mutation in the tumor tissue is recommended to exclude a possible false negative result in the analysis of circulating tumor DNA.

    Interstitial lung disease

    With the use of the Tagrisso drug, severe, life-threatening and lethal cases of interstitial lung disease or similar undesirable reactions (for example, pneumonitis) have been recorded in clinical studies. In most cases, discontinuation of therapy improved the patient's condition, or this undesirable reaction was resolved. Clinical studies did not include patients with interstitial lung disease in history, interstitial lung disease caused by medication, radiation pneumonitis requiring the appointment of glucocorticosteroids. as well as with any clinical symptoms of interstitial lung disease (see the "Side effect" section).

    Interstitial lung disease or similar adverse reactions (eg, pneumonitis) were noted in 3.5% of patients and resulted in a fatal outcome in 0.6% of the 833 patients who received the Tagrisso drug in clinical trials AURA. The incidence of interstitial lung disease was 8.2% in Japanese, 1.9% in other Asian patients, and 2.9% in non-Asian patients (see "Side effect").

    All patients with acute development and / or unexplained worsening of pulmonary symptoms (dyspnea, cough, fever) should be carefully evaluated to rule out interstitial lung disease. Therapy with Tagrisso should be suspended for the duration of the examination to clarify these symptoms. If interstitial lung disease is diagnosed, it is necessary to cancel therapy with Tagrisso and begin appropriate treatment.

    Elongation of the OTT interval

    When taking the drug Tagrisso observed lengthening interval QTc. Interval lengthening QTc may increase the risk of developing ventricular tachyarrhythmias (eg, ventricular pirouette tachycardia) or sudden death. In studies AURAex or AURA 2, there were no undesirable phenomena associated with cardiac arrhythmias (see section "Side effect"). Patients with clinically significant disturbances of rhythm and conductivity when recording the ECG at rest (for example, the value of the interval QTc more than 470 msec), were excluded from these studies (see the "Side effect" section).

    If possible, osertermanib should be avoided in patients with congenital long-interval syndrome QT. Patients with chronic heart failure, electrolyte dysfunction and patients taking drugs, lengthening the interval QTc, should periodically perform the ECG and determine the concentration of electrolytes. Therapy should be stopped in patients with interval values QTc above 500 msec, detected at least twice during repeated ECG registrations, until the interval is shortened QTc less than 481 msec or up to the original value (if the initial duration of the interval QTc was at least 481 msec), and then resume therapy with a reduced dose of the drug (see Table 1). If against the background of lengthening the interval QT develops ventricular tachycardia such as "pirouette", polymorphic ventricular tachycardia or signs / symptoms of severe cardiac arrhythmia, therapy with ossexertinib should be abolished.

    Violations of contractility of the heart

    Reduction of the left ventricular ejection fraction (LVEF) by at least 10% and to less than 50% was observed in 4.0% of patients(26/655) who received Tagrisso in clinical trials in whom LVEF was assessed prior to initiation of therapy and at least once during therapy. The available data from clinical studies do not allow us to conclude that there is a causal relationship between the decrease in heart contractility and the use of Tagrisso. Patients with risk factors for heart disease and concomitant conditions that may affect LVEF. as well as patients who have significant cardiac symptoms during treatment, the function of the cardiovascular system, including LVEF, should be monitored before treatment and against therapy.

    Keratite

    Keratitis was noted in 0.7% (n= 6) of the 833 patients who received the Tagrisso drug in studies AURA. If there are any possible symptoms of keratitis, such as acute development or increased inflammation of the eyes, lacrimation, photosensitivity, blurred vision, eye pain and / or redness of the eyes, you should urgently consult an ophthalmologist (see "Dosage and Administration." Table 1).

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

    The drug Tagrisso does not affect the ability to drive vehicles andmechanisms.

    Form release / dosage:Pills, film-coated, 40 mg, 80 mg.
    Packaging:

    For tablets 40 mg: 10 tablets in a perforated aluminum blister. 3 blisters with instructions for medical use in a cardboard box with control of the first autopsy.

    For tablets 80 mg: 10 tablets in a perforated aluminum blister. 1 or 3 blisters with instructions for medical use in a cardboard box with the control of the first autopsy.

    Storage conditions:

    At a temperature of no higher than 25 ° C.

    Keep out of the reach of children.

    Shelf life:2 years. Do not use after the expiration date.
    Terms of leave from pharmacies:On prescription
    Registration number:LP-004492
    Date of registration:18.10.2017
    Expiration Date:18.10.2022
    The owner of the registration certificate:AstraZeneca ABAstraZeneca AB Sweden
    Manufacturer: & nbsp
    Representation: & nbspAstraZeneca Pharmaceuticals Ltd.AstraZeneca Pharmaceuticals Ltd.
    Information update date: & nbsp24.10.2017
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