Tagrisso - Instructions For Use Of The Drug, Reviews, Price, Analogues

2024 Author: Rachel Wainwright | [email protected]. Last modified: 2023-12-15 07:39

Tagrisso

Tagrisso: instructions for use and reviews

1. 1. Release form and composition
2. 2. Pharmacological properties
3. 3. Indications for use
4. 4. Contraindications
5. 5. Method of application and dosage
6. 6. Side effects
7. 7. Overdose
8. 8. Special instructions
9. 9. Application during pregnancy and lactation
10. 10. Use in childhood
11. 11. In case of impaired renal function
12. 12. For violations of liver function
13. 13. Use in the elderly
14. 14. Drug interactions
15. 15. Analogs
16. 16. Terms and conditions of storage
17. 17. Terms of dispensing from pharmacies
18. 18. Reviews
19. 19. Price in pharmacies

Latin name: Tagrisso

ATX code: L01XE35

Active ingredient: osimertinib (Osimertinib)

Manufacturer: AstraZeneca, AB (AstraZeneca, AB) (Sweden)

Description and photo updated: 30.11.2018

Prices in pharmacies: from 300,482 rubles.

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Tagrisso is an antineoplastic drug, an inhibitor of protein tyrosine kinase.

Release form and composition

The drug is available in the form of film-coated tablets: biconvex, light brown, round (dosage 40 mg) engraved on one side "AZ 40" or oval (dosage 80 mg) engraved on one side "AZ 80" (by 10 pcs. In blisters: at a dosage of 40 mg - in a cardboard box with first opening control 3 blisters; at a dosage of 80 mg - in a cardboard box with first opening control 1 or 3 blisters; each pack also contains instructions for using Tagrisso).

1 film-coated tablet contains:

• active substance: osimertinib mesylate - 47.7 or 95.4 mg, which is equivalent to 40 or 80 mg of osimertinib, respectively;
• auxiliary components: sodium stearyl fumarate, microcrystalline cellulose, mannitol, hyprolosis with a low degree of substitution;
• film shell: polyvinyl alcohol, macrogol 3350, titanium dioxide, iron dye red oxide (E172), iron dye yellow oxide (E172), iron dye black oxide (E172), talc.

Pharmacological properties

Pharmacodynamics

Tagrisso is an anticancer drug, the active ingredient of which is osimertinib, an irreversible inhibitor of epidermal growth factor receptor tyrosine kinase (EGFR). The results of in vitro studies have demonstrated the pharmacodynamic efficacy of osimertinib in all clinically significant non-small cell lung cancer (NSCLC) cell lines carrying sensitizing EGFR mutations and the T790M mutation associated with the development of resistance to tyrosine kinase inhibitors. The high activity and inhibitory effect of osimertinib causes suppression of cell growth [with respect to phosphorylated EGFR, the apparent half-maximum inhibitory concentration (IC ₅₀) are 6–54 nmol]. At the same time, in relation to cell lines with wild type EGFR, significantly lower activity is observed (in relation to phosphorylated EGFR, an apparent IC _{50 of} 480–1800 nmol). In vivo, oral osimertinib reduces tumor size both in NSCLC xenografts with activating EGFR mutations and T790M mutations and in transgenic mouse lung tumor models.

Pharmacokinetics

After oral administration of Tagrisso, the maximum plasma concentration (C _max) of osimertinib is achieved within a period of 3 to 24 hours. Absolute bioavailability has not been established. Simultaneous food intake on the bioavailability of osimertinib at a dose of 80 mg has no clinically significant effect. The exposure of osimertinib is not disturbed by an increase in gastric acidity. In the dose range from 20 to 240 mg, an increase in C _max valuesand AUC (area under the plasma concentration-time curve) is proportional to the dose taken. Daily use of Tagrisso once a day causes approximately three-fold accumulation of osimertinib, with an equilibrium state achieved by 15 days of therapy. Plasma concentrations in equilibrium are maintained in the range of multiples of 1.6 for 24 hours (interval between doses).

The apparent volume of distribution is 986 liters, which indicates a significant tissue distribution. A pronounced binding to plasma proteins is assumed, since due to instability, binding cannot be accurately measured. Osimertinib is able to form a covalent bond with human and rat serum albumin, rat and human plasma proteins, and human hepatocytes.

Osimertinib metabolism is carried out mainly with the participation of cytochrome CYP3A5 isoenzymes and, to a lesser extent, CYP3A4. It is assumed that alternative metabolic pathways may take place. The main metabolic pathways of osimertinib are oxidation and dealkylation, as a result of which two pharmacologically active metabolites are detected in human plasma: AZ7550, which demonstrated a pharmacological profile similar to that of osimertinib, and AZ5104, which has greater activity against both mutated and wild-type EGFR. After taking Tagrisso in the blood plasma of patients, both metabolites appear slowly, over approximately 24 hours.

In the blood plasma, osimertinib in unchanged form is 0.8%, in the form of the AZ7550 metabolite - 0.08%, AZ5104 - 0.07% of the total radioactivity, at the same time, the main share of radioactivity is characterized by a covalent bond with blood plasma proteins.

At least 12 compounds are found in human urine and feces, 5 of them account for more than 1% of the dose taken: unchanged osimertinib is approximately 1.9%, AZ5104 - 6.6%, AZ7550 - 2.7%, cysteinyl adduct (M21) - 1.5%, unknown metabolite (M25) - 1.9%.

At clinically significant concentrations, osimertinib is a competitive inhibitor of isoenzymes CYP3A4 and CYP3A5, but not CYP1A2, 2A6, 2D6, 2E1, 2B6, 2C8, 2C9, 2C19. Does not suppress genes UGT1A1 and UGT2B7 in the liver. In the intestine, suppression of UGT1A1 activity is possible; the clinical significance of this process is unknown.

The apparent plasma clearance of osimertinib is 14.2 L / h.

The half-life (T _½) is about 48 hours.

After a single dose of 20 mg of osimertinib, up to 67.8% of the dose taken is excreted through the intestines, of which approximately 1.2% is unchanged. Kidneys excreted 14.2%, unchanged - 0.8%.

The results of in vitro studies have demonstrated that osimertinib is not a substrate for OATP1B1 and OATP1B3, and in clinically significant concentrations does not inhibit MATE2K, OAT1, OATZ, OATP1B3, OATP1B1. But interaction with substrates MATE1 or OST2 cannot be completely excluded.

Osimertinib is a substrate for glycoprotein P (Pgp) and breast cancer resistance protein (BCRP), but in clinically relevant doses, its interaction with active substances of other drugs is unlikely.

Analysis of population pharmacokinetics studies, which involved 778 people, showed that patient weight, age (range 21 to 89 years), gender, ethnicity, or smoking did not have a clinically significant effect on the calculated equilibrium exposure (AUC _SS).

If liver function is impaired, the exposure of osimertinib may increase. Its pharmacokinetic parameters are influenced by serum albumin, there is no relationship between markers of liver function such as alanine aminotransferase (ALT), aspartate aminotransferase (ACT) and bilirubin, and osimertinib exposure is absent. Clinical trials did not include patients with ACT or ALT activity exceeding the upper limit of normal (ULN) more than 2.5 times.

In addition, the pharmacokinetics of the drug has not been studied with an increase in the activity of ACT or ALT by more than 5 times from VGN against the background of tumor damage to the liver and an excess of the concentration of total bilirubin by more than 1.5 times from VGN. With a mild degree of impairment and normal liver function, there is a similarity in the exposure of osimertinib.

With a mild degree of renal impairment with creatinine clearance (CC) 60–90 ml / min, moderate (CC 30–60 ml / min) or severe (CC 15–30 ml / min), the exposure of osimertinib does not change. The effect of the drug with CC less than 15 ml / min has not been established.

Indications for use

The use of Tagrisso is indicated for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer with a T790M mutation in the epidermal growth factor receptor (EGFR) gene.

Contraindications

Absolute:

• severe renal dysfunction, end-stage chronic renal failure, including patients on hemodialysis;
• moderate and severe liver dysfunction;
• the simultaneous use of St. John's wort preparations;
• concomitant therapy with potent CYP3A inducers (including phenytoin, rifampicin, carbamazepine);
• age up to 18 years;
• period of pregnancy;
• pregnancy and breastfeeding;
• hypersensitivity to the components of the drug.

Tagrisso should be used with caution in patients with interstitial lung disease, prolongation of the QTc interval, when combined with moderate inducers of CYP3A4 (including bosentan, modafinil, efavirenz, etravirine).

Tagrisso, instructions for use: method and dosage

The use of the drug Tagrisso should be monitored by a physician with experience in treatment with anticancer drugs.

The tablets are taken orally, swallowing whole (damage to the film membrane must not be allowed), washed down with a sufficient amount of water, always at the same time of day, regardless of food intake. If you accidentally miss the next dose of Tagrisso, the missed pill can be taken if the period before taking the next dose is 12 hours or more.

If it is difficult to swallow the tablet, it can be taken after dissolving in 50 ml of still water. Do not use other liquids for dispersion! A whole (not crushed) tablet is dipped in water and stirred until complete dissolution, the resulting suspension is immediately drunk. An additional 100 ml of water is poured into the residues in the glass and also drunk.

Tagrisso in the form of a suspension, if necessary, can be administered through a nasogastric tube. In this case, the tablet is dispersed in 15 ml of water, and another 15 ml of water is added to the rest of the preparation. The resulting suspension in a volume of 30 ml is injected in accordance with the requirements of the manufacturer's instructions for the nasogastric tube and the tube is washed with an appropriate amount of water. The finished suspension and dissolved residues should be administered to the patient within 0.5 hours from the moment the tablet is immersed in water.

Recommended dosage: 80 mg once a day daily. Treatment is long-term and is discontinued if unacceptable toxicity develops or disease progresses.

In case of individual intolerance to the drug and the development of adverse reactions, a temporary cessation of taking the tablets and / or a decrease in the dose of osimertinib to 40 mg once a day is indicated.

In the event of the development of undesirable reactions, the dose of Tagrisso is adjusted taking into account the target organ and the specific side effect:

• pneumonitis or interstitial lung disease: discontinuation of drug therapy is required;
• lengthening of the QTc interval on the electrocardiogram (ECG) of more than 500 msec, noted at least twice (with repeated ECG registrations): temporary cancellation of Tagrisso. After reaching the duration of the QTc interval of less than 481 msec or the initial QTc value, if it was at least 481 msec, the treatment is resumed with a dose of 40 mg;
• lengthening of the QTc interval, accompanied by symptoms of serious arrhythmia: withdrawal of therapy is required;
• third degree of any adverse reaction and above: cessation of the use of tablets for a period of up to 21 days. If during this period the degree of the side effect that has arisen has decreased to 0-2 degrees, treatment can be resumed using the previous dose (80 mg) or reduced (40 mg). If the degree of adverse event within 21 days of the break has not decreased to the second degree and below, Tagrisso therapy should be completely discontinued.

With a mild degree of liver dysfunction (the level of total bilirubin does not exceed ULN, and the ACT activity exceeds the ULN, or the level of total bilirubin exceeds the ULN by no more than 1.5 times for any value of ACT activity), dose adjustment is required.

With mild to moderate renal impairment, there is no need to adjust the dose of osimertinib.

Side effects

Adverse events from systems and organs (classified as follows: very often - ≥ 1/10, often - from ≥ 1/100 to <1/10, infrequently - from ≥ 1/1000 to <1/100):

• on the part of the respiratory system, chest and mediastinal organs: often - interstitial lung disease, including with a fatal outcome;
• from the gastrointestinal tract: very often - diarrhea, stomatitis;
• on the part of the organ of vision: infrequently - keratitis, punctate keratitis, epithelial corneal defect, corneal erosion, corneal defect;
• on the part of the skin and subcutaneous tissue: very often - itchy skin (including itching of the eyelids, generalized itching), rash (including generalized rash, erythematous rash, macular rash, maculopapular rash, papular rash, pustular rash, folliculitis, dermatitis, acneformitis, acne, dermatitis), dry skin (including cracks in the skin, xeroderma, eczema), paronychia (including discoloration of the nails, disease of the nail bed, inflammation and / or soreness of the nail bed, nail disease, nail dystrophy, nail infection, onychoclasia, onycholysis, tuberosity nails, onychomadesis);
• laboratory and instrumental studies: very often - a decrease in the number of platelets, a decrease in the number of leukocytes, a decrease in the number of neutrophils; infrequently - lengthening of the QTc interval by more than 500 msec.

Overdose

Symptoms: Taking an increased dose of osimertinib (160 or 240 mg per day) may aggravate the severity of adverse events typical for EGFR tyrosine kinase inhibitors, such as diarrhea and skin rash.

Treatment: there are no specific recommendations for the treatment of Tagrisso overdose. You should stop taking the pills, if necessary, the appointment of symptomatic therapy is indicated.

special instructions

The appointment of the drug Tagrisso to patients with locally advanced or metastatic non-small cell lung cancer should be performed only after confirmation of the T790M mutation in the EGFR gene. To determine it, you should use only a sensitive, reliable and reasonable research method - a validated test.

The T790M mutation status is determined in tumor DNA (deoxyribonucleic acid) isolated from a tumor tissue or blood plasma sample. If the blood plasma test showed a negative result, then in order to exclude a false negative result when analyzing circulating tumor DNA, it is recommended to conduct an additional test to determine the mutation in the tumor tissue. The indication for the use of Tagrisso is the detection of a T790M mutation in the tumor tissue or blood plasma in a patient.

The results of clinical studies indicate the possibility of developing severe, life-threatening and fatal cases of interstitial lung disease or pneumonitis. In most cases, the patient's condition improved upon discontinuation of therapy. There is no experience with the use of Tagrisso in patients with any clinical symptoms of interstitial lung disease, including a history. Therefore, in order to exclude interstitial lung disease, it is recommended to very carefully evaluate patients with acute development and / or worsening of pulmonary symptoms such as shortness of breath, fever, cough. For the period of clarification of these symptoms, therapy should be suspended, and if interstitial lung disease is diagnosed, it should be completely stopped.

Avoid the use of Tagrisso in congenital long QT syndrome. Treatment of patients with chronic heart failure, electrolyte imbalance or taking drugs that prolong the QTc interval should be accompanied by periodic determination of electrolyte concentration and ECG. If, during repeated ECG recordings, the QTc interval values exceed 500 msec, therapy should be suspended until the QTc interval decreases to less than 481 msec or to the initial value if it was at least 481 msec. The therapy should be resumed with a reduced dose of the drug. If, against the background of prolongation of the QT interval, the development of pirouette-type ventricular tachycardia, polymorphic ventricular tachycardia, or signs of severe cardiac arrhythmias are diagnosed, Tagrisso therapy should be canceled.

Before starting treatment and during therapy with osimertinib, the function of the cardiovascular system should be monitored in patients with risk factors for heart disease or concomitant conditions that may affect the left ventricular ejection fraction, and in patients with significant cardiac symptoms arising during treatment.

In connection with the presence of cases of development of keratitis, it is recommended to urgently consult an ophthalmologist if photosensitivity, lacrimation, acute inflammation of the eyes, accompanied by pain in the eyes and / or their redness, blurred vision while taking pills, is recommended.

Influence on the ability to drive vehicles and complex mechanisms

The use of Tagrisso does not affect the patient's ability to drive vehicles and complex mechanisms.

Application during pregnancy and lactation

The use of Tagrisso is contraindicated during the period of gestation and breastfeeding.

Women of reproductive age are advised to use barrier methods of contraception due to the fact that exposure to hormonal contraceptives may be reduced. Conception should be avoided during the entire period of therapy and for at least two months after discontinuation of the drug in women and four months in men.

The results of studies of osimertinib in animals indicate the effect of the drug on the male and female reproductive organs, which reduces human fertility.

Pediatric use

Due to the lack of data on the safety and efficacy of using Tagrisso in children and adolescents, prescribing the drug for the treatment of patients under the age of 18 is contraindicated.

With impaired renal function

The use of Tagrisso is contraindicated for the treatment of patients with severe renal impairment, end-stage chronic renal failure, including patients on hemodialysis.

With mild to moderate renal impairment, there is no need to adjust the dose of osimertinib.

For violations of liver function

The appointment of Tagrisso is contraindicated in case of moderate and severe liver dysfunction.

With a mild degree of liver dysfunction (the level of total bilirubin does not exceed ULN, and the ACT activity exceeds the ULN, or the level of total bilirubin exceeds the ULN by no more than 1.5 times for any value of ACT activity), dose adjustment is required.

Use in the elderly

It should be borne in mind that in patients aged 65 years and older, the development of adverse events (including reactions of grade 3 and higher), requiring the suspension of therapy or discontinuation of Tagrisso, occurs more often than in younger patients.

The types of adverse reactions and the therapeutic efficacy of Tagrisso in elderly patients do not differ from those in younger patients.

Drug interactions

• itraconazole (a potent inhibitor of CYP3A4) at a dose of 200 mg 2 times a day: no clinically significant effect on osimertinib exposure;
• rifampicin, phenytoin, carbamazepine (powerful inducers of CYP3A): cause a clinically significant decrease in the AUC of osimertinib in equilibrium and exposure to the AZ5104 metabolite, therefore, the combination with these agents is contraindicated;
• bosentan, modafinil, efavirenz, etravirine (moderate inducers of CYP3A4): it is recommended to avoid their appointment due to the existing risk of decreased exposure of osimertinib; if necessary, combined use should be used with caution;
• omeprazole and other drugs that change the acidity of gastric juice: do not cause a clinically significant change in the exposure of osimertinib, therefore, the dose should not be limited;
• rosuvastatin (a sensitive substrate of BCRP): increases its exposure, and therefore, for the timely detection of symptoms of impaired tolerance, careful monitoring of patients taking rosuvastatin and other drugs with a narrow therapeutic index, the distribution of which depends on the BCRP, is required;
• simvastatin (sensitive substrate CYP3A4): a decrease in AUC and C _{max of} simvastatin is possible; these changes are insignificant and have no clinically significant effect;
• hormonal contraceptives: there is a risk of reducing their contraceptive effect.

Analogs

Analogues of Tagrisso are: Albitinib, Afinitor, Bosulif, Vargatef, Votrient, Genfatinib, Gefitinib, Giotrif, Gistamel, Glemikhib, Gleevec, Dasatinib-Nativ, Jakavi, Iglib, Taiverb, Tarlenib, etc.

Terms and conditions of storage

Keep out of the reach of children.

Store at temperatures up to 25 ° C.

Shelf life is 2 years.

Terms of dispensing from pharmacies

Dispensed by prescription.

Reviews about Tagrisso

Reviews of Tagrisso from patients taking the drug are currently not available.

Price for Tagrisso in pharmacies

The price of Tagrisso for a package containing 30 tablets at a dose of 80 mg can range from 555,000 rubles.

Tagrisso: prices in online pharmacies

Drug name Price Pharmacy

Tagrisso tab. p / o captivity. 80 mg No. 30 RUB 300 482 Buy

Tagrisso 80 mg film-coated tablets 30 pcs. RUB 300 482 Buy

Anna Kozlova Medical journalist About the author

Education: Rostov State Medical University, specialty "General Medicine".

Information about the drug is generalized, provided for informational purposes only and does not replace the official instructions. Self-medication is hazardous to health!