Trucap

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TRUQAP (TRUQAP)

Composition:

Active substance: capivasertib;

One film-coated tablet contains 160 mg or 200 mg of capivasertib;

Excipients: microcrystalline cellulose, calcium hydrogen phosphate, sodium croscarmellose, magnesium stearate; tablet coating: hypromellose, copovidone, polyethylene glycol 3350, polidextrose, medium-chain triglycerides, titanium dioxide, iron oxide yellow, iron oxide red, iron oxide black.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

160 mg: round, biconvex, film-coated tablets, beige in color, with embossing "CAV" above "160" on one side and smooth on the other side;

200 mg: capsule-shaped, biconvex, film-coated tablets, beige in color, with embossing "CAV 200" on one side and smooth on the other side.

Pharmacotherapeutic group.

Antineoplastic and immunomodulating agents. Antineoplastic agents. Protein kinase inhibitors. Other protein kinase inhibitors.

ATC code L01E X27.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

Capivasertib is a potent, selective inhibitor of the kinase activity of all three isoforms of the serine/threonine kinase AKT (AKT1, AKT2, and AKT3). AKT is a key component of the phosphatidylinositol-3-kinase (PI3K) signaling cascade, which regulates numerous cellular processes, including cell survival, proliferation, cell cycle, metabolism, gene transcription, and cell migration. Activation of AKT in tumors results from activation of other signaling pathways, AKT1 mutations, loss of function of the phosphatase and tensin homolog (PTEN), and mutations in the catalytic subunit of PI3K (PIK3CA).

Capivasertib reduces the growth of cell lines derived from solid tumors and hematological malignancies, including breast cancer cell lines with or without PIK3CA or AKT1 mutations and with or without PTEN alterations.

The combination of capivasertib and fulvestrant has demonstrated antitumor activity in several patient-derived xenograft models representative of various subtypes of ER-positive breast cancer, including models harboring mutations or alterations in PIK3CA, PTEN, or AKT1, as well as those without such alterations.

Cardioelectrophysiology

An exposure–response analysis based on data from 180 patients with advanced solid tumors who received capivasertib at doses ranging from 80 to 800 mg showed a predicted QTcF interval prolongation of 3.87 ms at the mean steady-state Cmax following a 400 mg twice-daily dose.

Clinical Efficacy

CAPItello-291 is a randomized, double-blind, placebo-controlled trial involving 708 patients designed to evaluate the efficacy and safety of Truqap in combination with fulvestrant in adult premenopausal or postmenopausal women and adult men with locally advanced (inoperable) or metastatic ER-positive and HER2-negative (defined as IHC 0 or 1+ or IHC 2+/ISH-) breast cancer. Among these, 289 patients had tumors with one or more relevant alterations in PIK3CA, AKT1, or PTEN following disease recurrence or progression on or after aromatase inhibitor (AI)-based therapy.

Patients were excluded from the study if they had received more than two lines of endocrine therapy or more than one line of chemotherapy for locally advanced (inoperable) or metastatic disease, had prior treatment with AKT, PI3K, or mTOR inhibitors, prior fulvestrant or other selective estrogen receptor degraders, had clinically significant glucose metabolism disorders (defined as type 1 or type 2 diabetes requiring insulin therapy and/or HbA1c > 8.0% [63.9 mmol/mol]), had clinically significant cardiac disease in their medical history, symptomatic internal organ disease, or any condition rendering endocrine therapy unsuitable.

Patients were randomized in a 1:1 ratio to receive Truqap 400 mg (N = 355) or placebo (N = 353) twice daily for 4 days followed by a 3-day break each week of the 28-day treatment cycle. Fulvestrant 500 mg was administered on day 1 and day 15 of cycle 1, and thereafter on day 1 of each 28-day cycle.

Premenopausal or perimenopausal women received luteinizing hormone-releasing hormone (LHRH) agonist therapy. Randomization was stratified by presence of liver metastases, prior CDK4/6 inhibitor treatment, and geographic region. Treatment continued until disease progression, death, withdrawal of consent, or occurrence of unacceptable toxicity. Tumor samples were collected prior to randomization for retrospective central testing to determine PIK3CA/AKT1/PTEN alteration status.

Demographic and baseline disease characteristics were well balanced between treatment groups. The median age of study participants (708 patients) was 58 years (range: 26–90 years; 30.7% of patients were over 65 years of age); 99% of patients were female; 57.5% were White, 26.7% were Asian, and 1.1% were Black; 65.7% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 and 34.2% had a score of 1; 21.8% of women were premenopausal or perimenopausal. All patients had prior endocrine therapy (100% had received AI-based therapy, 44.1% had received tamoxifen). Prior CDK4/6 inhibitor therapy was received by 70.1% of patients. Chemotherapy for locally advanced (inoperable) or metastatic cancer was received by 18.2% of patients. Demographic characteristics in the subgroup with PIK3CA/AKT1/PTEN alterations were generally representative of the overall study population.

Dual primary endpoints were progression-free survival (PFS) in the overall population and PFS in the PIK3CA/AKT1/PTEN-altered subgroup, assessed by investigators according to Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1).

As of the data cutoff date (DCO) of August 15, 2022, statistically significant improvement in PFS was observed in patients receiving Truqap plus fulvestrant compared to those receiving placebo plus fulvestrant, both in the overall population and in the PIK3CA/AKT1/PTEN-altered subgroup (see Table 1). A prespecified exploratory analysis of PFS in a subset of 313 (44%) patients without PIK3CA/AKT1/PTEN alterations showed a hazard ratio (HR) of 0.79 (95% CI: 0.61, 1.02), suggesting that the benefit observed in the overall population was primarily driven by outcomes in patients whose tumors harbored PIK3CA/AKT1/PTEN alterations. Investigator-assessed PFS results were confirmed by robust results from blinded independent central review (BICR). The objective response rate (ORR), as assessed by investigators, was 22.9% and 12.2% in the Truqap plus fulvestrant and placebo plus fulvestrant groups, respectively, in the overall population, and 28.8% and 9.7%, respectively, in the altered subgroup.

A preplanned interim overall survival (OS) analysis (as of DCO April 15, 2024, with 59% of patients deceased) showed an HR of 0.88 (95% CI: 0.65, 1.19) in the PIK3CA/AKT1/PTEN-altered subgroup.

Efficacy results are presented in Table 1 and Figure 1.

Table 1. Progression-Free Survival in the PIK3CA/AKT1/PTEN-Altered Subgroup (Investigator Assessment)

a Stratified Cox proportional hazards model. Hazard ratio < 1 indicates benefit for the capivasertib + fulvestrant combination. For the overall population — log-rank test and Cox model stratified by presence of liver metastases (yes or no), prior use of CDK4/6 inhibitors (yes or no), and geographic region (region 1: USA, Canada, Western Europe, Australia, and Israel; region 2: Latin America, Eastern Europe, and Russia compared to region 3: Asia). For the altered population — log-rank test and Cox model stratified by presence of liver metastases (yes or no) and prior use of CDK4/6 inhibitors (yes or no).

b Stratified log-rank test.

Fig. 1. Kaplan–Meier progression-free survival curve, CAPItello-291 study (investigator-assessed in the PIK3CA/AKT1/PTEN altered subgroup)

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Truqap in all paediatric subgroups of patients with breast cancer (information on use of the medicinal product in children is provided in section "Posology and method of administration").

Pharmacokinetics

The pharmacokinetics of capivasertib were evaluated in healthy volunteers and in patients with solid tumours. Following single-dose administration in the dose range of 80 to 800 mg in patients, systemic exposure (AUC and Cmax) increased proportionally with dose. After multiple dosing in the range of 80 to 600 mg twice daily, AUC increased slightly more than proportionally with dose. With intermittent administration of capivasertib 400 mg twice daily for 4 days followed by a 3-day treatment break, steady-state concentrations of capivasertib with AUC of 8069 ng·h/mL (37 %) and Cmax of 1371 ng/mL (30 %) were predicted to be reached on days 3 and 4 of drug intake each week, starting from week 2. During the drug-free days, plasma concentrations were low (approximately 0.5–15 % of steady-state Cmax).

Absorption

Capivasertib is rapidly absorbed, with maximum concentration (Cmax) observed in patients approximately 1–2 hours after administration. The mean absolute bioavailability is 29 %.

Effect of food

When capivasertib was administered after a high-calorie, high-fat meal (approximately 1000 kcal), the ratio of AUC and Cmax after and before food intake was 1.32 and 1.23, respectively, compared to administration after overnight fasting. When capivasertib was administered after a low-calorie, low-fat meal (approximately 400 kcal), exposure was similar to that after fasting: the ratio of AUC and Cmax after and before food intake was 1.14 and 1.21, respectively. Administration with food did not result in clinically significant changes in drug exposure.

Distribution

The mean volume of distribution after intravenous administration in healthy volunteers was 2.6 L/kg. Capivasertib does not bind extensively to plasma proteins (the unbound fraction is 22 %), and the ratio of drug concentration in plasma to blood is 0.71.

Metabolism

Capivasertib is primarily metabolized by CYP3A4 and UGT2B7 enzymes. The main metabolite in human plasma is the glucuronide ether, accounting for 83 % of the total drug-related material. A minor oxidative metabolite was quantified at 2 %, and the fraction of capivasertib was 15 % of the total circulating drug-related material. No active metabolites have been identified.

Elimination

The effective half-life of the drug after multiple dosing in patients was 8.3 hours. The mean total plasma clearance after single intravenous administration in healthy volunteers was 38 L/h. The mean total plasma clearance after single oral administration was 60 L/h and decreased by 8 % after multiple dosing at 400 mg twice daily.

After a single oral dose of 400 mg of radiolabelled drug, mean total elimination was 45 % in urine and 50 % in faeces. Renal clearance accounted for 21 % of total clearance. Capivasertib is primarily eliminated via metabolism.

Use in special patient populations

Effect of race, age, gender, and body weight

Based on population pharmacokinetic analysis, AUC and Cmax were found not to be significantly influenced by patient race (including European and Japanese ancestry), gender, or age. A statistically significant correlation was observed between apparent oral clearance of capivasertib and patient body weight. It is predicted that a patient with a body weight of 47 kg will have a 12 % higher AUC than a patient with a body weight of 66 kg. There is no need for dose adjustment based on body weight, as the predicted impact on capivasertib exposure was not clinically significant.

Renal impairment

Population pharmacokinetic analysis showed that in patients with mild renal impairment (creatinine clearance 60–89 mL/min), AUC and Cmax were 1 % higher compared to those in patients with normal renal function. In patients with moderate renal impairment (creatinine clearance 30–59 mL/min), AUC and Cmax were 16 % higher compared to those in patients with normal renal function.

There are no data in patients with severe renal impairment or end-stage renal disease (creatinine clearance < 30 mL/min).

Hepatic impairment

Population pharmacokinetic analysis showed that in patients with mild hepatic impairment (bilirubin ≤ ULN and aspartate aminotransferase (AST) > ULN, or bilirubin > 1× ULN to ≤ 1.5× ULN), AUC and Cmax were 5 % higher compared to those in patients with normal hepatic function (bilirubin ≤ ULN and AST ≤ ULN). In patients with moderate hepatic impairment (bilirubin > 1.5× ULN to ≤ 3× ULN), AUC was 17 % and Cmax was 13 % higher compared to those in patients with normal hepatic function. Data in patients with moderate hepatic impairment are limited, and data in patients with severe hepatic impairment are lacking.

Drug-drug interactions

Concomitant administration of a single 400 mg dose of capivasertib after multiple doses of the acid-reducing agent rabeprazole 20 mg twice daily for 3 days in healthy volunteers did not result in clinically significant changes in capivasertib exposure.

In vitro studies showed that capivasertib is primarily metabolized by CYP3A4 and UGT2B7 enzymes. Results from clinical drug-drug interaction (DDI) studies investigating potential DDI based on CYP3A4 interactions (itraconazole and enzalutamide) are provided below in section "Interaction with other medicinal products and other forms of interactions".

Clinical studies on potential DDI based on UGT2B7 interactions have not been conducted.

In vitro studies indicate that capivasertib inhibits CYP2C9, CYP2D6, CYP3A4, and UGT1A1, and induces the metabolizing enzymes CYP1A2, CYP2B6, and CYP3A4. The drug also inhibits the drug transporters BCRP, OATP1B1, OATP1B3, OAT3, OCT2, MATE1, and MATE2K in vitro. Results from a clinical DDI study investigating potential DDI based on CYP3A4 interactions (midazolam) are provided below in section "Interaction with other medicinal products and other forms of interactions". Clinical studies on potential DDI based on interactions with CYP1A2, CYP2B6, CYP2C9, CYP2D6, UGT1A1, BCRP, OATP1B1, OATP1B3, OAT3, OCT2, MATE1, and MATE2K have not been conducted.

Clinical characteristics

Indications

The medicinal product Truqap is indicated in combination with fulvestrant for the treatment of adult patients with estrogen receptor (ER)-positive, HER2-negative locally advanced or metastatic breast cancer with one or more alterations in the PIK3CA/AKT1/PTEN genes following disease recurrence or progression during or after endocrine therapy (see section "Pharmacological properties").

For women in the premenopausal or perimenopausal period, the combination of Truqap plus fulvestrant should be administered in combination with a luteinizing hormone-releasing hormone agonist (LHRH).

Men should consider the use of LHRH agonists according to current standards of clinical practice.

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in the section "Composition".

Safety precautions

Any unused medicinal product and waste material should be disposed of in accordance with local requirements.

Interaction with other medicinal products and other forms of interaction

Capivasertib is metabolized predominantly by CYP3A4 and UGT2B7 enzymes. In vivo, capivasertib is a time-dependent weak inhibitor of CYP3A.

Medicinal products that may increase plasma concentrations of capivasertib

Strong CYP3A4 inhibitors

Concomitant administration of Truqap with strong CYP3A4 inhibitors increases capivasertib concentrations, which may increase the risk of toxicity of Truqap. Concomitant use with strong CYP3A4 inhibitors (such as boceprevir, ceritinib, clarithromycin, cobicistat, conivaptan, enzalutamide, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, mibefradil, mifepristone, nefazodone, nelfinavir, posaconazole, ribociclib, ritonavir, saquinavir, telaprevir, telithromycin, troglitazone, tucatinib, voriconazole, grapefruit or grapefruit juice) should be avoided. If concomitant use cannot be avoided, the dose of Truqap should be reduced (see section "Dosage and administration"). Repeated co-administration of the strong CYP3A4 inhibitor itraconazole at a dose of 200 mg increased total exposure (AUCinf) and maximum concentration (Cmax) of capivasertib by 95% and 70%, respectively, compared to capivasertib monotherapy.

Moderate CYP3A4 inhibitors

Concomitant administration of Truqap with moderate CYP3A4 inhibitors increases capivasertib concentrations, which may increase the risk of toxicity of Truqap. When co-administered with a moderate CYP3A4 inhibitor (e.g., aprepitant, ciprofloxacin, cyclosporine, diltiazem, erythromycin, fluconazole, fluvoxamine, tofisopam, verapamil), the dose of Truqap should be reduced (see section "Dosage and administration").

Medicinal products that may decrease capivasertib plasma concentrations

Strong CYP3A4 inducers

Concomitant use of Truqap with strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampicin, St John’s wort) should be avoided. Concomitant administration of capivasertib with the strong CYP3A4 inducer enzalutamide decreased capivasertib AUC by approximately 40–50%.

Moderate CYP3A4 inducers

Concomitant administration of capivasertib with moderate CYP3A4 inducers has the potential to reduce capivasertib concentrations. This may reduce the efficacy of Truqap. Concomitant use of moderate CYP3A4 inducers (e.g., bosentan, cenobamate, dabrafenib, elagolix, etravirine, lerisivirine, lesinurad, lopinavir, lorlatinib, metamizole, mipavat, modafinil, nafcillin, pexidartinib, phenobarbital, rifabutin, semagacestat, sotorasib, talveraline, telotristat ethyl, thioridazine) should be avoided.

Medicinal products whose plasma concentrations may be affected by capivasertib

CYP3A substrates

Plasma concentrations of medicinal products that are primarily eliminated via CYP3A metabolism may increase when co-administered with Truqap, potentially leading to increased toxicity depending on their therapeutic index. Capivasertib increased midazolam AUC by 15–77%, thus it is a weak inhibitor of CYP3A (see section "Pharmacological properties"). Dose adjustment may be required for medicinal products primarily metabolized by CYP3A and with a narrow therapeutic index (e.g., carbamazepine, cyclosporine, fentanyl, pimozide, simvastatin, tacrolimus). Recommendations for concomitant use with weak CYP3A inhibitors are provided in the medical instructions for the respective medicinal products.

CYP2D6 substrates with a narrow therapeutic index

In vitro assessments have shown that capivasertib is capable of inhibiting CYP2D6 enzyme activity. Capivasertib should be used with caution in combination with sensitive CYP2D6 substrates that have a narrow therapeutic index, as capivasertib may increase systemic exposure to these substrates.

CYP2B6 substrates with a narrow therapeutic index

In vitro assessments have shown that capivasertib is capable of inducing CYP2B6 enzyme activity. Capivasertib should be used with caution in combination with sensitive CYP2B6 substrates that have a narrow therapeutic index (e.g., bupropion), as capivasertib may reduce systemic exposure to these substrates.

UGT1A1 substrates with a narrow therapeutic index

In vitro assessments have shown that capivasertib is capable of inhibiting UGT1A1 enzyme activity. Capivasertib should be used with caution in combination with sensitive UGT1A1 substrates that have a narrow therapeutic index (e.g., irinotecan), as capivasertib may increase systemic exposure to these substrates.

Interaction with hepatic transporters (BCRP, OATP1B1, OATP1B3)

Exposure to medicinal products sensitive to inhibition of BCRP, OATP1B1 and/or OATP1B3, if they are metabolized by CYP3A4, may increase when co-administered with Truqap. This may lead to increased toxicity. Dose adjustment may be required for medicinal products sensitive to inhibition of BCRP, OATP1B1 and/or OATP1B3, if they are metabolized by CYP3A4 (e.g., simvastatin), depending on their therapeutic index. Recommendations for concomitant use with inhibitors of CYP3A4, BCRP, OATP1B1 and OATP1B3 are provided in the medical instructions for the respective medicinal products.

Interaction with renal transporters (MATE1, MATE2K, OCT2)

Exposure to medicinal products sensitive to inhibition of MATE1, MATE2K and/or OCT2 may increase when co-administered with Truqap. This may lead to increased toxicity. Dose adjustment may be required for medicinal products sensitive to inhibition of MATE1, MATE2K and OCT2 (e.g., dofetilide, procainamide), depending on their therapeutic index. Recommendations for concomitant use with inhibitors of MATE1, MATE2K and/or OCT2 are provided in the medical instructions for the respective medicinal products. During treatment with Truqap, transient increases in serum creatinine levels may occur due to inhibition of OCT2, MATE1 and MATE2K by capivasertib.

Special Warnings and Precautions

Hypoglycemia

The safety and efficacy of Truqap in patients with pre-existing type 1 diabetes or type 2 diabetes requiring insulin therapy, and/or in patients with HbA1c > 8.0% (63.9 mmol/mol), have not been studied, as such patients were excluded from the phase III clinical trial. In this trial, 21 (5.9%) patients in the Truqap plus fulvestrant group had HbA1c ≥ 6.5%. Hyperglycemia occurred more frequently in patients with baseline HbA1c ≥ 6.5% (33.3% of patients) than in those with baseline HbA1c < 6.5% (16.0%). Cases of severe hyperglycemia associated with diabetic ketoacidosis (DKA), some with fatal outcomes, have been reported in patients receiving Truqap (see section "Adverse Reactions"). DKA may occur at any time during treatment with Truqap. In some reported cases, DKA developed within less than 10 days. Patients with a history of diabetes may require intensified antidiabetic therapy and should be closely monitored. Patients with diabetes are advised to consult with an endocrinologist or a healthcare provider experienced in managing hyperglycemia.

Before initiating treatment with Truqap, patients should be informed that this medicinal product may cause hyperglycemia (see section "Adverse Reactions") and advised to contact their physician immediately if symptoms of hyperglycemia occur (e.g., excessive thirst, increased frequency or volume of urination, increased appetite with weight loss). The risk of progression from hyperglycemia to diabetic ketoacidosis may be higher in the presence of concomitant conditions or medications (e.g., dehydration, inadequate nutrition, concomitant chemotherapy/steroid use, sepsis). DKA should be considered among differential diagnoses if non-specific symptoms occur, such as nausea, vomiting, abdominal pain, dyspnea, fruity breath odor, confusion, unusual fatigue, or somnolence. Treatment with Truqap should be discontinued immediately in patients suspected of having DKA. If DKA is confirmed, Truqap must be permanently discontinued.

Fasting blood glucose (FG) and HbA1c levels should be assessed in all patients prior to starting Truqap and at intervals specified in Table 2. Depending on the severity of hyperglycemia, interruption, dose reduction, or permanent discontinuation of Truqap may be necessary (see section "Dosage and Administration", Table 5).

More frequent monitoring of blood glucose is recommended in patients who develop hyperglycemia during treatment, in patients with baseline risk factors for DKA (e.g., diabetes, prediabetes, regular use of oral steroids), and in patients who develop risk factors for DKA during treatment (e.g., infection, sepsis, elevated HbA1c) (see Table 2). In addition to FG monitoring, measurement of ketone levels (preferably in blood) and other metabolic parameters is recommended in patients with hyperglycemia, as clinically indicated.

In addition to the recommended management of hyperglycemia described in section "Dosage and Administration", Table 5, patients with baseline risk factors and those who develop hyperglycemia during Truqap therapy should be advised on lifestyle modifications.

Table 2. Monitoring schedule for fasting glucose and HbA1c levels in patients receiving Truqap

Diarrhea

Diarrhea has been reported in the majority of patients receiving Truqap (see section "Adverse reactions"). Clinical consequences of diarrhea may include dehydration, hypokalemia, and acute kidney injury, which have been observed during treatment with Truqap, along with cardiac arrhythmias (hypokalemia being a risk factor). Depending on the severity of diarrhea, treatment with Truqap may be interrupted, the dose reduced, or treatment permanently discontinued (see section "Dosage and administration", Table 6). Patients should be advised that if symptoms of diarrhea occur during treatment with Truqap, anti-diarrheal therapy should be initiated promptly and fluid intake increased. Patients with diarrhea should maintain euvolemia and electrolyte balance to prevent complications associated with hypovolemia and low electrolyte levels.

Skin rash and other drug-related skin reactions

Drug-related skin reactions, including erythema multiforme and generalized exfoliative dermatitis, have been observed in patients receiving Truqap (see section "Adverse reactions"). Patients should be monitored for signs and symptoms of rash or dermatitis; depending on the severity of skin reactions, treatment may be interrupted, the dose reduced, or treatment permanently discontinued (see section "Dosage and administration", Table 7). Early dermatological consultation is recommended to ensure accurate diagnosis and appropriate management.

Patient populations not included in clinical trials

The efficacy and safety of this medicinal product have not been studied in patients with symptomatic organ diseases. Patients with clinically significant cardiovascular disease, including those with QTcF > 470 msec, any factors increasing the risk of QTc prolongation, arrhythmia risk, or risk of impaired cardiac function, were excluded from the CAPItello-291 study. Additionally, patients with pre-existing type 1 diabetes, type 2 diabetes requiring insulin therapy, and patients with HbA1c > 8.0% (63.9 mmol/mol) were not included. This should be taken into consideration when prescribing Truqap to such patients.

Other medicinal products

Concomitant use of strong or moderate CYP3A4 inhibitors with Truqap may increase capivasertib exposure and, consequently, the risk of toxicity. Dose adjustment recommendations for Truqap when used concomitantly with CYP3A4 inhibitors are provided in the section "Dosage and administration".

Conversely, concomitant use of strong or moderate CYP3A4 inducers may reduce capivasertib exposure. Concomitant use of strong or moderate CYP3A4 inducers with Truqap should be avoided.

Sodium content

This medicinal product contains less than 1 mmol (23 mg) of sodium per dose, i.e., essentially sodium-free.

Use during pregnancy or breastfeeding

Women of reproductive potential / contraception in men and women

Women of reproductive potential are advised to avoid pregnancy during treatment with Truqap. A pregnancy test should be performed before initiating treatment in women of reproductive potential, and a confirmed negative result should be obtained. Repeating the test during treatment should be considered.

Patients are advised to use effective contraception during treatment with Truqap and for the following periods after completion of treatment: at least 4 weeks for women and 16 weeks for men.

Pregnancy

There are no data on the use of Truqap in pregnant women. Reproductive toxicity was observed in animal studies. Therefore, Truqap is not recommended during pregnancy or in women of reproductive potential who are not using contraception.

Breastfeeding

It is unknown whether capivasertib or its metabolites are excreted in human breast milk. Capivasertib has been detected in the plasma of suckling rat pups, suggesting excretion into milk. A risk to the breastfed infant cannot be ruled out. Breastfeeding should be discontinued during treatment with Truqap.

Fertility

There are no clinical data on fertility. In animal studies, no adverse effects on female reproductive organs were observed, but the effect on fertility in female rats was not studied. Capivasertib causes testicular toxicity and may impair fertility in men with reproductive potential.

See section "Use during pregnancy or breastfeeding" for information on effects on fertility in the fulvestrant product information.

Ability to affect the speed of reactions when driving or operating machinery

Truqap may have a minor influence on the ability to drive and use machines, as fatigue, dizziness, and syncope have been reported during capivasertib treatment (see section "Adverse reactions").

Dosage and Administration

Treatment with the medicinal product Truqap must be prescribed and supervised by a physician experienced in the use of anticancer medicinal products.

Patients with ER-positive, HER2-negative advanced breast cancer should be selected for therapy with Truqap based on the presence of one or more alterations in the PIK3CA, AKT1, or PTEN genes, which should be assessed using a laboratory diagnostic test with a corresponding intended use and meeting the essential requirements of EU directives. In the absence of such a diagnostic test, an alternative validated test should be used.

Dosage

The recommended dose of Truqap is 400 mg (two 200 mg tablets) twice daily, approximately 12 hours apart (total daily dose 800 mg), administered for 4 consecutive days followed by a 3-day treatment-free interval (see Table 3).

Table 3. Weekly administration schedule for the medicinal product Truqap

* On days 5, 6, and 7, the medicinal product is not administered.

The medicinal product Truqap should be taken in combination with fulvestrant. The recommended dose of fulvestrant is 500 mg on days 1, 15, and 29, followed by once monthly administration. More detailed information is provided in the fulvestrant product information.

Missed dose

If a dose of Truqap is missed, it may be taken within 4 hours after the usual dosing time. If more than 4 hours have passed, the dose should be omitted. The next dose of Truqap should be taken at the usual time. There should be at least an 8-hour interval between doses of the medicinal product.

Vomiting

If vomiting occurs, the patient should not take an additional dose. The next dose of Truqap should be taken at the usual time.

Duration of treatment

Treatment with capivasertib should be continued until disease progression or until unacceptable toxicity occurs.

Dose adjustment

Treatment with Truqap may be interrupted to manage adverse reactions, and dose reduction should be considered. Dose reductions of Truqap should follow the scheme provided in Table 4. The dose of capivasertib may be reduced up to two times. Recommendations for dose adjustments in the event of specific adverse reactions are provided in Tables 4–6.

Table 4. Recommendations for dose reduction of Truqap in the event of adverse reactions

Hyperglycemia

Table 5. Recommended dose adjustment of Trukap in case of hyperglycemia^a

a For information on the management of suspected or confirmed diabetic ketoacidosis (DKA), see section "Special precautions for use".

b Grade according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.03.

c Monitoring of HbA1C levels should also be considered.

d Additional recommendations for the control of glycaemia and other metabolic parameters are provided in section "Special precautions for use".

e When selecting an antidiabetic medicinal product, consultation with a diabetologist is recommended. The possibility of hypoglycaemia should be considered when antidiabetic medicinal products are used on days when Truqap is not administered. In addition, patients should consult a dietitian regarding lifestyle modifications to reduce the risk of hyperglycaemia (see section "Special precautions for use").

Currently, metformin is the recommended preferred antidiabetic agent for the treatment of hyperglycaemia occurring in patients participating in capivasertib clinical trials. Dosing and management of patients receiving a combination of metformin and capivasertib should be performed with caution. Due to the potential interaction between metformin and capivasertib (caused by inhibition of renal transporters [e.g., OCT2] involved in metformin elimination), weekly monitoring of creatinine levels is recommended for 3 weeks after initiation of metformin treatment and then on day 1 of each subsequent cycle when capivasertib and metformin are co-administered.

Metformin should be taken only on days when capivasertib is also administered (the elimination half-life of capivasertib is approximately 8 hours), and should be discontinued when capivasertib treatment is stopped (unless there are other clinical indications).

d The experience with insulin use in patients during Truqap treatment is limited.

Diarrhoea

In patients with recurrent diarrhoea, consideration should be given to secondary prophylaxis (see section "Special precautions for use").

Table 6. Recommended dose adjustment of Truqap in case of diarrhoea

a Grade according to NCI CTCAE, version 5.0.

Skin rash and other drug-related skin reactions

In case of skin reactions of any grade, regardless of severity, consultation with a dermatologist should be considered. For patients with persistent rash and/or prior occurrence of grade 3 rash, secondary prophylaxis should be considered through long-term use of oral antihistamines and/or topical steroids (see section "Special precautions for use").

Table 7. Recommended dose adjustment of Truqap in case of skin rash and other drug-related skin reactions

a Grade according to CTCAE, version 5.0.

Other toxicity manifestations

Table 8. Recommended dose adjustment and management for other toxicity manifestations (excluding hyperglycemia, diarrhea, rash, and other skin reactions to the medicinal product)

Grade was defined according to CTCAE, version 5.0.

Concomitant use with strong and moderate CYP3A4 inhibitors

Concomitant use of Trukap with strong CYP3A4 inhibitors should be avoided. If concomitant use cannot be avoided, the dose of Trukap should be reduced to 320 mg twice daily (equivalent to a total daily dose of 640 mg).

When used concomitantly with moderate CYP3A4 inhibitors, the dose of Trukap should be reduced to 320 mg twice daily (equivalent to a total daily dose of 640 mg).

After discontinuation of a strong or moderate CYP3A4 inhibitor, Trukap dosing should be resumed (after 3–5 inhibitor half-lives) to the dose used prior to initiating the strong or moderate CYP3A4 inhibitor.

Additional information is provided in section "Interaction with other medicinal products and other forms of interaction".

Use in special patient groups

Geriatric patients

Dose adjustment is not required in elderly patients (see section "Pharmacological properties"). Data on use of the medicinal product in patients aged ≥75 years are limited.

Renal impairment

No dose adjustment is required for patients with mild or moderate renal impairment. Trukap is not recommended for patients with severe renal impairment, as the safety and pharmacokinetics of the medicinal product have not been studied in such patients (see section "Pharmacological properties").

Hepatic impairment

No dose adjustment is required for patients with mild hepatic impairment. Data in patients with moderate hepatic impairment are limited; Trukap should be administered to these patients only if the benefit outweighs the risk, and patients should be closely monitored for signs of toxicity. Trukap is not recommended for patients with severe hepatic impairment, as the safety and pharmacokinetics of the medicinal product have not been studied in such patients (see section "Pharmacological properties").

Method of administration

Trukap is intended for oral use. Tablets may be taken independently of food intake (see section "Pharmacological properties"). They should be swallowed whole, without chewing, crushing, dissolving, or dividing, and taken with water. A tablet must not be taken if it is broken, cracked, or otherwise damaged, as such methods of administration have not been studied in clinical trials.

Children

Safety and efficacy of Trukap in children (aged 0–18 years) have not been established. No data are available.

Overdose

There is no specific treatment for overdose with Trukap. Exceeding the recommended doses of capivasertib may increase the risk of adverse drug reactions, including diarrhea. Physicians should implement general supportive measures and provide symptomatic treatment to patients.

Adverse Reactions

▼ This medicinal product is subject to additional monitoring. This will allow for rapid identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.

Summary of safety profile

The summary of the safety profile of Truqap is based on data from 355 patients who received Truqap plus fulvestrant in a Phase III study (CAPItello-291). The median duration of treatment with capivasertib in the CAPItello-291 study was 5.42 months, with 27% of patients receiving the medicinal product for ≥ 12 months.

The most commonly reported adverse reactions were diarrhea (72.4%), rash (40.3%), nausea (34.6%), fatigue (32.1%), vomiting (20.6%), stomatitis (17.2%), hyperglycemia (17.2%), headache (16.9%), and decreased appetite (16.6%).

The most frequent adverse reactions of Grade 3 or 4 were rash (12.4%), diarrhea (9.3%), hyperglycemia (2.3%), hypokalemia (2.3%), anemia (2.0%), and stomatitis (2.0%).

Serious adverse reactions occurred in 7.0% of patients receiving Truqap plus fulvestrant. The most common serious adverse reactions reported in patients receiving Truqap plus fulvestrant were rash (2.3%), diarrhea (1.7%), and vomiting (1.1%).

Dose reductions due to adverse reactions were required in 17.7% of patients. The most common adverse reactions leading to dose reduction of Truqap were diarrhea (7.9%) and rash (4.5%).

Treatment was permanently discontinued due to adverse reactions in 9.9% of patients. The most common adverse reactions leading to discontinuation of treatment were rash (4.5%), diarrhea (2.0%), and vomiting (2.0%).

List of adverse reactions presented in tabular form

Table 9 presents adverse reactions based on pooled data from patients who received Truqap plus fulvestrant at the recommended dose in clinical trials.

The adverse reactions listed below are classified by System Organ Class (SOC) according to the Medical Dictionary for Regulatory Activities (MedDRA). Within each SOC, preferred terms are listed in descending order of frequency and severity. Adverse reactions are categorized by frequency as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), and not known (cannot be estimated from available data).

Table 9. Adverse reactions reported in patients receiving Truqap

1 Urinary tract infection includes urinary tract infection and cystitis.

2 Includes other related terms.

3 Hyperglycemia includes increased blood glucose, diabetes mellitus, hyperglycemia, and type 2 diabetes mellitus.

4 Hypokalemia includes decreased blood potassium and hypokalemia.

5 Diabetic ketoacidosis includes diabetic ketoacidosis and ketoacidosis.

6 Stomatitis includes aphthous ulcers, oral ulcers, and stomatitis.

7 Rash includes erythema, rash, erythematous rash, macular rash, maculopapular rash, papular rash, and pruritic rash.

8 Fatigue includes asthenia and exhaustion.

9 Pyrexia includes increased body temperature and fever.

Description of selected adverse reactions

Hyperglycemia

Hyperglycemia of any grade was observed in 61 (17.2%) patients, and grade 3 or 4 hyperglycemia in 8 (2.3%) patients receiving the medicinal product Truqap. The median time to first occurrence of hyperglycemia was 15 days (range: 1–367). During the study, dose reduction due to hyperglycemia was required in 2 (0.6%) patients, and 1 (0.3%) patient discontinued treatment. Of the 61 patients with hyperglycemia, 29 (47.5%) received antihyperglycemic medicinal products (including insulin in 16.4%) (see section "Special precautions for use").

Diarrhea

Diarrhea occurred in 257 (72.4%) patients receiving the medicinal product Truqap. Grade 3 and/or 4 diarrhea occurred in 33 (9.3%) patients. The median time to first occurrence was 8 days (range: 1–519). Dose reduction due to diarrhea was required in 28 (7.9%) patients, and 7 (2.0%) patients discontinued treatment with Truqap. Of the 257 patients with diarrhea, 59% (151/257) required antidiarrheal medicinal products to manage diarrhea symptoms.

Rash

Rash (including erythema, rash, erythematous rash, macular rash, maculopapular rash, papular rash, and pruritic rash) was reported in 143 (40.3%) patients. The median time to first occurrence of rash was 12 days (range: 1–226). Grade 3 and/or 4 rash occurred in 44 (12.4%) patients receiving capivasertib. Multiform erythema was observed in 6 (1.7%) patients, with the most severe reaction being grade 3, reported in 3 (0.8%) patients. Generalized exfoliative dermatitis developed in 2 (0.6%) patients, with these events being grade 3 in severity. Dose reduction due to rash was required in 16 (4.5%) patients, and another 16 (4.5%) patients discontinued treatment with Truqap.

Reporting of suspected adverse reactions

Reporting of adverse reactions after medicinal product authorization is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report any suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life

48 months.

Storage conditions

The medicinal product does not require special storage conditions.

Packaging

16 film-coated tablets in a blister; 4 blisters in a cardboard box with labeling in Ukrainian.

Prescription status

Prescription only.

Manufacturer

AstraZeneca AB / AstraZeneca AB

Manufacturer's location and address of its place of business

Gertunavägen, 152 57, Södertälje, Sweden /
Gartunavagen, 152 57, Sodertalje, Sweden