Tagrisso, 80 mg 30 pcs

Osimertinib

Indications

adjuvant therapy for non-small cell lung cancer in adult patients after complete resection of the tumor in the presence of a mutation in the EGFR gene in the tumor cells (deletion in exon 19 or substitution L858R in exon 21);
first line of treatment for locally advanced or metastatic non-small cell lung cancer in the presence of a mutation in the EGFR gene (deletion in exon 19 or substitution L858R in exon 21) in adult patients;
locally advanced or metastatic non-small cell lung cancer with the T790M mutation in the EGFR gene in adult patients.

Pharmacological effect

Pharmacotherapeutic group: Antitumor agents; protein kinase inhibitors; epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors

Pharmacological action

Mechanism of action

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

Pharmacodynamic effects

In in vitro studies, osimertinib has been demonstrated to be highly active and EGFR inhibitory in all clinically relevant non-small cell lung cancer (NSCLC) cell lines harboring EGFR sensitizing mutations and the T790M resistance mutation (apparent half-maximal inhibitory concentrations (IC50) of 6 – 54 nmol relative to phosphorylated EGFR). This results in inhibition of cell growth, with significantly less activity observed in cell lines harboring wild-type EGFR (apparent IC50 480 nmol – 1.9 µmol relative to phosphorylated EGFR). In vivo, oral osimertinib was associated with a reduction in tumor size both in NSCLC xenografts with activating EGFR mutations and the T790M mutation, and in transgenic mouse models of lung tumors.

Pharmacokinetics
The pharmacokinetic parameters of osimertinib were determined in healthy volunteers and patients with NSCLC. Based on the results of population pharmacokinetics analysis, the apparent plasma clearance of osimertinib is 14.3 l/h, the apparent Vd is 918 l and T1/2 is approximately 44 hours. The AUC and Cmax values ​​increased in proportion to the dose taken in the dose range from 20 to 240 mg. Taking osimertinib once a day every day leads to an approximately 3-fold accumulation, reaching a steady state by the 15th day of administration. At steady state, plasma concentrations were generally maintained in the 1.6-fold range during the 24-hour dosing interval.

Absorption

After oral administration, the median Tmax of osimertinib in plasma is 6 (3-24) hours, and in some patients Cmax was achieved within the first 24 hours. The absolute bioavailability of Tagrisso is 70% (90% confidence interval (CI) 67-73). According to a clinical pharmacokinetic study in patients receiving the drug at a dose of 80 mg, food does not have a clinically significant effect on the bioavailability of osimertinib (AUC increases by 6% (90% CI: 5-19), and Cmax decreases by 7% (90% CI: 19-6)). In healthy volunteers, increasing gastric pH by taking omeprazole for 5 days did not affect exposure to osimertinib 80 mg tablet (AUC and Cmax increased by 7% and 2%, respectively), and the 90% CI for the exposure ratio was within the range of 80-125%.

Distribution

In a population-based analysis, the mean volume of distribution at steady state (Vss/F) of osimertinib is 918 L, indicating significant tissue distribution. The binding of osimertinib to plasma proteins according to in vitro studies is 94.7%. Osimertinib has also been shown to form covalent bonds with rat and human plasma proteins, human serum albumin, and rat and human hepatocytes.

Metabolism

In vitro studies have shown that osimertinib is metabolized primarily by the cytochrome isoenzymes CYP3A4 and CYP3A5. In in vitro studies, in preclinical models, and during oral administration of osimertinib in humans, two pharmacologically active metabolites were detected in plasma: AZ7550 and AZ5104; AZ7550 demonstrated a similar pharmacological profile to Tagrisso, while AZ5104 had greater activity against both mutated and wild-type EGFR.

Both metabolites appear slowly in the blood plasma of patients after taking Tagrisso, and the median Tmax is 24 (4-72) and 24 (6-72) hours, respectively. In blood plasma, unchanged osimertinib accounts for 0.8%, and its two metabolites account for 0.08% and 0.07% of total radioactivity, with the bulk of the radioactivity covalently bound to plasma proteins. The geometric mean exposure of AZ5104 and AZ7550 based on AUC was approximately 10% of osimertinib exposure at steady state for each metabolite.

The main route of metabolism of osimertinib is oxidation and dealkylation. At least 12 compounds were detected in human urine and fecal samples, with 5 compounds accounting for more than 1% of the administered dose, of which unchanged osimertinib, AZ5104 and AZ7550 accounted for approximately 1.9%, 6.6% and 2.7% of the dose, respectively, while the cysteinyl adduct (M21) and unknown metabolite (M25) accounted for 1.5% and 1.9% of the dose, respectively.

Based on the results of in vitro studies, osimertinib at clinically significant concentrations is a competitive inhibitor of the isoenzyme CYP3A4/5, but not CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6 and 2E1. Based on in vitro studies, osimertinib at clinically relevant concentrations does not inhibit UGT1A1 and UGT2B7 in the liver. It is possible that UGT1A1 activity in the intestine may be suppressed, but the clinical significance of this process is unknown.

Removal

After a single oral dose of 20 mg, 67.8% of the dose was excreted through the intestine (1.2% as unchanged substance), and 14.2% of the administered dose (0.8% as unchanged substance) was determined in the urine after collecting urine samples for 84 days. Approximately 2% of osimertinib is excreted unchanged – 0.8% by the kidneys and 1.2% by the intestine.

Interaction with transport proteins

In vitro studies have shown that osimertinib is not a substrate of OATP1B1 and OATP1B3. In vitro, osimertinib at clinically relevant concentrations does not inhibit P glycoprotein (P-gp), OAT1, OAT3, OATP1B1, OATP1B3, MATE1, OCT2, and MATE2K.

Effect of osimertinib on P-gp and breast cancer resistance protein (BCRP)

Based on in vitro studies, osimertinib is a substrate of P-gp and BCRP, but osimertinib at clinically relevant doses is unlikely to cause clinically significant drug interactions with the active substances. Osimertinib is a BCRP inhibitor based on in vitro studies (see Drug Interactions section).

Pharmacokinetics in special groups of patients

In population pharmacokinetics analyzes (n=1367), no clinically significant associations were identified between the calculated steady-state exposure (AUCss) and patient age (range: 25-91 years), gender (65% women), ethnicity (including Caucasian, Asian, Japanese, Chinese and other patients), line of therapy, and smoking status (n=34 active smokers, n=419 former smokers). Population pharmacokinetics analysis showed that body weight was a significant covariate; The change in AUCss of osimertinib is expected to be within 20% in the body weight range of 88 kg to 43 kg, respectively (95% to 5% quantiles), compared with the AUCss at a median body weight of 61 kg. Taking into account body weight limits of 89 kg, the proportion of the AZ5104 metabolite varied from 11.8% to 9.6%, and the AZ7550 metabolite from 12.8% to 8.1%, respectively. Population pharmacokinetics analysis showed that serum albumin concentration was a significant covariate; The change in osimertinib AUCss is expected to be within 30% over the albumin concentration range of 29 to 46 g/L, respectively (95% to 5% quantiles), compared with the AUCss at a median baseline albumin concentration of 39 g/L. These changes in exposure based on body weight and baseline serum albumin concentration are not considered to be clinically significant.

Patients with liver dysfunction

Osimertinib is eliminated primarily by the liver. In a clinical study in patients with mild (Child-Pugh class A, n=7) and moderate hepatic impairment (Child-Pugh class B, n=5) there was no increase in exposure after a single dose of Tagrisso 80 mg compared to patients with normal liver function (n=10). Based on the results of analysis of population pharmacokinetics data, there is no relationship between liver function markers (ALT, AST, bilirubin) and osimertinib exposure. An indicator of liver function, serum albumin, influences the pharmacokinetic parameters of osimertinib. Clinical studies did not include patients whose AST or ALT activity exceeded the ULN by more than 2.5 times, as well as patients whose AST or ALT activity exceeded the ULN by more than 5 times due to tumor lesions of the liver, as well as patients whose total bilirubin concentration exceeded the ULN by more than 1.5 times. According to the results of a pharmacokinetic analysis, the exposure of osimertinib in 134 patients with mild hepatic impairment (total bilirubin concentration does not exceed ULN, AST activity exceeds ULN, or total bilirubin concentration exceeds ULN, but less than 1.5 ULN at any value of AST activity), 8 patients with moderate liver dysfunction (total bilirubin concentration ranges from 1.5 to 3 ULN at any activity value) AST) and 1216 patients with normal liver function (the concentration of total bilirubin and the value of AST activity did not exceed ULN) was similar. There are no data on the use of the drug in patients with severe liver dysfunction (see section “Dosage regimen”).

Patients with impaired renal function

In clinical studies in patients with severe renal impairment (creatinine clearance from 15 to <30 ml/min; n=7), after a single dose of Tagrisso at a dose of 80 mg, an increase in AUC and Cmax of 1.85 and 1.19 times, respectively, was observed compared with patients with normal renal function (creatinine clearance not less than 90 ml/min; n=8). In addition, according to a population pharmacokinetic analysis, which included 593 patients with mild renal impairment (creatinine clearance 60 to <90 ml/min), 254 patients with moderate renal impairment (creatinine clearance 30 to <60 ml/min), 5 patients with severe renal impairment (creatinine clearance 15 to <30 ml/min) and 502 patients with normal renal function kidneys (creatinine clearance not less than 90 ml/min), osimertinib exposure was similar in all subgroups. Patients with CC less than 10 ml/min were not included in clinical studies.

Special instructions

Determination of mutation status in the EGFR gene

To prescribe Tagrisso as adjuvant therapy for NSCLC after complete tumor resection, it is necessary to confirm the presence of a mutation in the EGFR gene (deletion in exon 19 or substitution L858R in exon 21). Mutation status must be determined in tumor DNA obtained from a tumor tissue sample (biopsy or surgical specimen) using a validated test in a clinical laboratory.

When considering the use of Tagrisso for locally advanced or metastatic NSCLC, it is important to confirm the presence of a mutation in the EGFR gene. Mutation status should be determined in tumor DNA obtained from a tumor tissue sample or in freely circulating tumor DNA obtained from a blood plasma sample using a validated test in a clinical laboratory. Only reliable, valid and sensitive research methods with proven diagnostic value in determining the status of the mutation in the EGFR gene should be used.

Detection of a mutation in the EGFR gene in a patient (deletion in exon 19 or substitution L858R in exon 21 – in the case of first-line therapy, or the T790M mutation – in case of disease progression during or after therapy with an EGFR tyrosine kinase inhibitor) in tumor tissue or blood plasma indicates the presence of an indication for the use of Tagrisso. In case of a negative result of blood plasma testing, it is recommended to determine the mutation in the tumor tissue to exclude a possible false-negative result when analyzing freely circulating tumor DNA.

Interstitial lung disease

Interstitial lung disease or related adverse events (eg, pneumonitis) occurred in 3.7% of patients and resulted in death in 0.3% (n=5) of 1479 patients treated with Tagrisso in the ADAURA, FLAURA, and AURA clinical studies. The incidence of interstitial lung disease was 10.9% in Japanese, 1.6% in other Asian patients, and 2.5% in non-Asian patients. The median duration of treatment until the development of interstitial lung disease or similar adverse reactions was 2.8 months.

All patients with acute development and/or unexplained worsening of pulmonary symptoms (shortness of breath, cough, fever) should be immediately evaluated to rule out interstitial lung disease. Therapy with Tagrisso should be suspended for the period of examination to clarify these symptoms. If interstitial lung disease is diagnosed, therapy with Tagrisso should be discontinued.

Erythema multiforme and Stevens-Johnson syndrome

Case reports of erythema multiforme and Stevens-Johnson syndrome in association with Tagrisso have been reported infrequently and rarely, respectively. Before initiating therapy, patients should be informed of the signs and symptoms of erythema multiforme and Stevens-Johnson syndrome. If possible signs and symptoms of erythema multiforme appear, close medical monitoring of the patient should be carried out and consideration should be given to suspending or discontinuing therapy with Tagrisso. If possible signs and symptoms of Stevens-Johnson syndrome occur, therapy with Tagrisso should be immediately suspended or discontinued.

Prolongation of the QTc interval

If possible, osimertinib should be avoided in patients with congenital long QT syndrome. Patients with chronic heart failure, electrolyte imbalances, and patients taking drugs that prolong the QTc interval should have an ECG and electrolyte concentrations measured periodically. Therapy should be suspended in patients with QTc interval values ​​above 500 ms, detected at least twice during repeated ECG registrations, until the QTc interval duration decreases to less than 481 ms or to the initial value (if the initial QTc interval duration was at least 481 ms), and then resume therapy with a reduced dose of the drug (see Table 1). If torsade de pointes (TdP), torsade de pointes (TdP), or signs/symptoms of severe cardiac arrhythmias develop in the setting of QT prolongation, osimertinib therapy should be discontinued.

Cardiac contractility disorders

A decrease in LVEF of at least 10 percentage points to less than 50% was observed in 3.2% of patients (40/1233) treated with Tagrisso in clinical studies in which LVEF was assessed before initiation of therapy and at least once during therapy. In the placebo-controlled ADAURA study, 1.6% (5/312) of patients treated with Tagrisso and 1.5% (5/331) of patients in the placebo group experienced a decrease in LVEF of at least 10 percentage points to less than 50%.

Available data from clinical studies do not allow us to draw a conclusion about the cause-and-effect relationship between the decrease in cardiac contractility and the use of Tagrisso. Patients with risk factors for heart disease and concomitant conditions that may affect LVEF should monitor cardiovascular function, including LVEF, before and during treatment. Patients who experience significant cardiac symptoms during treatment should monitor the function of the cardiovascular system, incl. LVEF.

Keratitis

Keratitis was reported in 0.7% (n=10) of 1479 patients treated with Tagrisso in the ADAURA, FLAURA and AURA studies. If possible symptoms of keratitis appear, such as acute development or worsening of eye inflammation, lacrimation, photosensitivity, blurred vision, eye pain and/or redness of the eyes, you should immediately consult an ophthalmologist (see section “Dosage regimen”, Table 1).

Aplastic anemia

Rare reports have been received of the development of aplastic anemia, in some cases with a fatal outcome, in connection with therapy with Tagrisso. Before initiating therapy, patients should be informed of the signs and symptoms of aplastic anemia, including but not limited to ongoing fever, bruising, bleeding, and pallor. If possible signs and symptoms of aplastic anemia appear, close medical monitoring of the patient should be carried out and consideration should be given to suspending or discontinuing therapy with Tagrisso. If the diagnosis of aplastic anemia is confirmed, therapy with Tagrisso should be discontinued.

Impact on the ability to drive vehicles and machinery

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

Active ingredient

Osimertinib

Composition

Active substance: osimertinib

Pregnancy

Contraception in men and women

Women with preserved reproductive potential should avoid pregnancy during therapy with Tagrisso. Patients should be advised to use effective contraception after completion of treatment with this drug: for at least 6 weeks after the end of therapy for women and 4 months for men.

Pregnancy

There are no data on the use of osimertinib in pregnant women. Animal studies have shown reproductive toxicity (embryolethality, fetal growth retardation, neonatal death). Based on the mechanism of action and preclinical data, the use of osimertinib during pregnancy may cause harm to the fetus. Tagrisso should not be used during pregnancy and in women with preserved reproductive potential who do not use contraception.

Breastfeeding period

It is unknown whether osimertinib or its metabolites are excreted in breast milk. There is insufficient information on the excretion of osimertinib or its metabolites into animal milk. However, osimertinib and its metabolites were detected in breastfed pups and were noted to have a negative effect on their growth and survival. A risk to breastfed children cannot be excluded. It is necessary to stop breastfeeding during therapy with Tagrisso.

Fertility

There is no data on the effect of Tagrisso on human fertility. Based on animal studies, osimertinib affects male and female reproductive organs and may reduce fertility.

Contraindications

hypersensitivity to osimertinib or any of the components of the drug;
pregnancy and breastfeeding;
end-stage chronic renal failure, including patients on hemodialysis;
severe liver dysfunction;
children under 18 years of age (data not available);
taking St. John’s wort preparations during therapy with Tagrisso is contraindicated;
concomitant use of potent CYP3A inducers (for example, phenytoin, rifampicin and carbamazepine)

With caution: interstitial lung disease; prolongation of the QTc interval; co-administration with moderate CYP3A4 inducers (for example, bosentan, efavirenz, etravirine, modafinil).

Side Effects

Disorders of the respiratory system, chest and mediastinal organs
Nosebleed
Interstitial lung disease

Gastrointestinal disorders
Diarrhea
Stomatitis
Visual disorders
Keratitis
Disorders of the skin and subcutaneous tissue
Rash
Dry skin
Paronychia
Itching
Palmoplantar erythrodysesthesia syndrome
Often
Alopecia
Erythema multiforme
Uncommon
StevensJohnson syndrome
Rarely
Cutaneous vasculitis
Changes in laboratory and instrumental parameters
Prolongation of the QTc14 interval

Study results presented as change in CTCAE severity
Decreased platelet count
Decreased white blood cell count
Decreased lymphocyte count
Decreased neutrophil count
Increased creatinine concentration in the blood
1 Pooled data from the ADAURA, FLAURA and AURA studies (AURA 3, AURAex, AURA 2 and AURA 1); Provides information about events that occurred in patients who received at least 1 dose of Tagrisso as randomized therapy.

2 National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0.

3 Includes: interstitial lung disease, pneumonitis.

4 5 CTCAE grade 5 events (fatal) were recorded.

5 Includes: oral ulceration, stomatitis.

6 Includes: corneal erosion, corneal epithelial defect, keratitis, punctate keratitis.

7 Includes: acne, dermatitis, acneiform dermatitis, drug rash, erythema, folliculitis, pustule, rash, rash erythematous, rash follicular, rash generalized, rash maculosa, rash maculopapular, rash papular, rash pruritic, rash pustular, vesicular rash, skin erosion.

8 Includes: nail bed disease, nail bed infection, nail bed inflammation, nail discoloration, nail disease, nail dystrophy, nail infection, nail pigmentation, nail tuberosity, nail toxicity, onychalgia, onychoclasia, onycholysis, onychomadesis, onychomalacia, paronychia.

9 Includes: dry skin, eczema, cracked skin, xeroderma, xerosis.

10 Includes: eyelid itching, pruritus, generalized pruritus.

11 Erythema multiforme was noted in 5 of 1479 patients in the ADAURA, AURA, and FLAURA studies. Post-marketing reports of cases of erythema multiforme have also been received, incl. 7 reports in post-marketing surveillance study (N=3578).

12 Estimated frequency. The upper limit of the 95% CI for the estimated value is 3/1479 (0.2%).

13 One case was reported in a post-marketing study; frequency was estimated from ADAURA, FLAURA, AURA and post-marketing studies (N=5057).

14 Frequency of QTcF interval prolongation >500 ms.

15 Reflects the frequency of laboratory abnormalities, not the frequency of noted adverse events

Interaction

Pharmacokinetic interactions

Potent CYP3A4 inducers may reduce osimertinib exposure. Osimertinib may increase exposure to BCRP and P-gp substrates.

Active substances that may increase plasma concentrations of osimertinib

In vitro studies have shown that phase I metabolism of osimertinib occurs mainly through the isoenzymes CYP3A4 and CYP3A5. In a clinical pharmacokinetic study in patients co-administering osimertinib and itraconazole 200 mg twice daily (a strong CYP3A4 inhibitor), there was no clinically significant effect on osimertinib exposure (AUC increased by 24% and Cmax decreased by 20%). Therefore, CYP3A4 inhibitors do not appear to have an effect on osimertinib exposure.

Active substances that may decrease osimertinib plasma concentrations

In a clinical pharmacokinetic study, the steady-state AUC of osimertinib decreased by 78% in patients coadministered with rifampicin (600 mg/day for 21 days). The combined use of strong CYP3A inducers (for example, phenytoin, rifampicin and carbamazepine, St. John’s wort preparations) with Tagrisso is contraindicated. Based on data from physiologically based pharmacokinetic modeling, dose adjustment of Tagrisso is not required when used concomitantly with moderate and weak CYP3A inducers.

Effect of drugs that reduce gastric acidity on osimertinib

In a clinical pharmacokinetic study, coadministration of omeprazole did not result in clinically significant changes in osimertinib exposure. Drugs that change gastric pH can be used simultaneously with Tagrisso without restrictions.

Active substances whose plasma concentrations may be affected by Tagrisso

Based on in vitro studies, osimertinib is a competitive inhibitor of the BCRP transporter protein. In a clinical pharmacokinetic study, coadministration of Tagrisso with rosuvastatin (a sensitive BCRP substrate) increased the AUC and Cmax of rosuvastatin by 35% and 72%, respectively. Patients taking drugs whose distribution depends on BCRP, with a narrow therapeutic index, should be carefully monitored during therapy with Tagrisso to identify symptoms of impaired tolerance to these drugs as a result of their increased exposure (see section “Pharmacokinetics”).

In a clinical pharmacokinetic study, coadministration of Tagrisso with simvastatin (a sensitive CYP3A4 substrate) decreased the AUC and Cmax of simvastatin by 9% and 23%, respectively. These changes are quite small and are probably not clinically significant. Pharmacokinetic interactions with substrates of the CYP3A4 isoenzyme are unlikely.

In a clinical pharmacokinetic study, coadministration of Tagrisso with fexofenadine (pregnane X receptor (PXR) and P-gp substrate) increased the AUC and Cmax of fexofenadine by 56% and 76% after a single dose, and by 27% and 25% at steady state, respectively. Patients taking concomitant drugs with a narrow therapeutic index whose distribution is dependent on P-gp (eg, digoxin, dabigatran, aliskiren) should be closely monitored for signs of altered tolerability resulting from increased exposure to concomitant drugs with Tagrisso (see Pharmacokinetics section).

Overdose

Symptoms: In clinical studies of Tagrisso, a limited number of patients received the drug in daily doses of up to 240 mg, and no dose-limiting toxicity was detected. Patients receiving Tagrisso at daily doses of 160 mg and 240 mg in these studies experienced an increase in the incidence and severity of certain common adverse events associated with EGFR inhibition (primarily diarrhea and skin rash) compared with the 80 mg dose.

Treatment: There is no specific treatment for an overdose of Tagrisso. If an overdose of Tagrisso is suspected, general supportive measures and symptomatic therapy should be carried out.

Storage conditions

The drug should be stored out of the reach of children at a temperature not exceeding 30°C.

Shelf life

Shelf life – 3 years. Do not use after expiration date.

Manufacturer

AstraZeneca Industries LLC, Russia