TRUQAP Film-coated tablet Ref.[111589] Active ingredients: Capivasertib

Hyperglycaemia

The safety and efficacy of TRUQAP in patients with pre-existing Type 1 diabetes or Type 2 diabetes requiring insulin and/or in patients with HbA1C ˃8.0% (63.9 mmol/mol) has not been studied as these patients were excluded from the phase III clinical study. This study included 21 (5.9%) patients in the TRUQAP plus fulvestrant arm with HbA1C ≥6.5%. Hyperglycaemia was more frequently reported in patients with a baseline HbA1C ≥6.5% (28.6% of patients) than those with a baseline HbA1C <6.5% (15.4%). Severe hyperglycaemia, associated with ketoacidosis, occurred in patients treated with TRUQAP. Patients with history of diabetes mellitus may require intensified anti-diabetic treatment and should be closely monitored. Consultation with a diabetologist or a healthcare professional experienced in the treatment of hyperglycaemia is recommended for patients with diabetes.

Before initiating treatment with TRUQAP, patients should be informed about TRUQAP’s potential to cause hyperglycaemia (see section 4.8) and to immediately contact their healthcare professional if hyperglycaemia symptoms (e.g. excessive thirst, urinating more often than usual or greater amount of urine than usual, or increased appetite with weight loss) occur. Patients should be tested for fasting blood glucose (FG) levels and HbA1C prior to treatment with capivasertib and at regular intervals during treatment (Table 7).

Table 7. Schedule of fasting glucose monitoring and HbA1c:

^* All glucose monitoring should be performed at the physician’s discretion as clinically indicated.
¹ More frequent FG testing is required in patients with medical history of diabetes mellitus, in patients without prior history of diabetes mellitus and showing FG of >ULN 160 mg/dL (>ULN 8.9 mmol/L) during treatment, in patient with concomitant use of corticosteroids, or in those with intercurrent infections, or other conditions which may require intensified glycaemia management to prevent worsening of impaired glucose metabolism and potential complications, namely diabetic ketoacidosis. Monitoring of HbA1C, ketones (preferably in blood) and other metabolic parameters (as indicated), in addition to FG, is recommended in these patients.

Diarrhoea

Diarrhoea has been reported in the majority of the patients treated with TRUQAP (see section 4.8). Clinical consequences of diarrhoea may include dehydration, hypokalaemia and acute kidney injury which have all, together with cardiac arrhythmias (with hypokalaemia as risk factor) been reported during treatment with TRUQAP. Based on the severity of diarrhoea, TRUQAP dosing may be interrupted, reduced, or permanently discontinued (see section 4.2, Table 4). Advise patients to start anti-diarrhoeal treatment at the first sign of diarrhoea, increase oral fluids if diarrhoea symptoms occur while taking TRUQAP. Maintenance of normovolemia and electrolyte balance is required in patients with diarrhoea to avoid complications related to hypovolemia and low electrolyte levels.

Rash and other skin drug reactions

Skin drug reactions, including erythema multiforme and dermatitis exfoliative generalised, were reported in patients receiving TRUQAP (see section 4.8). Patients should be monitored for signs and symptoms of rash or dermatitis and based on severity of skin drug reactions, the dosing may be interrupted, reduced, or permanently discontinued (section 4.2, Table 5). Early consultation with a dermatologist is recommended to ensure greater diagnostic accuracy and appropriate management.

Patients excluded from the study

The efficacy and safety of this medicinal product have not been studied in patients with symptomatic visceral disease. The patients with history of clinically significant cardiac disease including QTcF >470 msec, any factors that increased the risk of QTc prolongation or risk of arrhythmic events or risk of cardiac function impairment, or patients with pre-existing Type 1 diabetes and Type 2 diabetes requiring insulin, and patients with HbA1C ˃8.0% (63.9 mmol/mol) were excluded from CAPItello-291. This should be considered if TRUQAP is prescribed in these patients.

Other medicinal products

Co-administration of strong or moderate CYP3A4 inhibitors with TRUQAP may lead to increased capivasertib exposure and consequently a higher risk of toxicity. Refer to section 4.2 regarding TRUQAP dose modification when co-administered with CYP3A4 inhibitors.

On the contrary, co-administration of strong and moderate CYP3A4 inducers may lead to decreased capivasertib exposure. Concomitant administration of strong and moderate CYP3A4 inducers and TRUQAP should be avoided.

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

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

Medicinal products that may increase capivasertib plasma concentrations

Strong CYP3A4 inhibitors

Co-administration of TRUQAP with strong CYP3A4 inhibitors increases capivasertib concentration, which may increase the risk of TRUQAP toxicity. Co-administration with strong CYP3A4 inhibitors should be avoided (e.g. boceprevir, ceritinib, clarithromycin, cobicistat, conivaptan, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, mibefradil, mifepristone, nefazodone, nelfinavir, posaconazole, ribociclib, ritonavir, saquinavir, telaprevir, telithromycin, troleandomycin, tucatinib, voriconazole, grapefruit or grapefruit juice). If co-administration cannot be avoided, TRUQAP dose should be reduced (see section 4.2). Co-administration of multiple 200 mg doses of the strong CYP3A4 inhibitor itraconazole increased capivasertib total exposure (AUC_inf) and the peak concentration (C_max) by 95% and 70%, respectively, relative to capivasertib given alone.

Moderate CYP3A4 inhibitors

Co-administration of TRUQAP with moderate CYP3A4 inhibitors increases capivasertib concentration, which may increase the risk of TRUQAP toxicity. TRUQAP dose should be reduced when co-administered with moderate CYP3A4 inhibitor (e.g aprepitant, ciprofloxacin, cyclosporine, diltiazem, erythromycin, fluconazole, fluvoxamine, tofisopam, verapamil) (see section 4.2).

Medicinal products that may decrease capivasertib plasma concentrations

Strong CYP3A4 inducers

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

Moderate CYP3A4 inducers

Co-administration of capivasertib with moderate CYP3A4 inducer has the potential to decrease the concentration of capivasertib. This may reduce the efficacy of TRUQAP. Co-administration of moderate CYP3A4 inducers should be avoided (e.g. bosentan, cenobamate, dabrafenib, elagolix, etravirine, lersivirine, lesinurad, lopinavir, lorlatinib, metamizole, mitapivat, modafinil, nafcillin, pexidartinib, phenobarbital, rifabutin, semagacestat, sotorasib, talviraline, telotristat ethyl, thioridazine).

Medicinal products whose plasma concentrations may be altered by capivasertib

Substrates of CYP3A

Concentration of medicinal products that are primarily eliminated via CYP3A metabolism may increase when co-administered with TRUQAP which may then lead to increased toxicity depending on their therapeutic window. Capivasertib increased the midazolam AUC by 15% to 77% and is therefore a weak CYP3A inhibitor (see section 5.2). Dose adjustment may be required for medicinal products that are primarily eliminated via CYP3A metabolism and have narrow therapeutic window (e.g. carbamazepine, cyclosporine, fentanyl, pimozide, simvastatin, tacrolimus).The SmPC of the other medicinal products should be consulted for the recommendations regarding co-administration with weak CYP3A4 inhibitors.

CYP2D6 substrates with a narrow therapeutic index

In vitro evaluations indicated that capivasertib has a potential to inhibit the activities of CYP2D6 enzymes. Capivasertib should be used with caution in combination with sensitive substrates of CYP2D6 enzymes which exhibit a narrow therapeutic index because capivasertib may increase the systemic exposure of these substrates.

CYP2B6 substrates with a narrow therapeutic index

In vitro evaluations indicated that capivasertib has a potential to induce the activities of CYP2B6 enzymes. Capivasertib should be used with caution in combination with sensitive substrates of CYP2B6 enzymes which exhibit a narrow therapeutic index (e.g. bupropion) because capivasertib may decrease the systemic exposure of these substrates.

UGT1A1 substrates with a narrow therapeutic index

In vitro evaluations indicated that capivasertib has a potential to inhibit the activities of UGT1A1 enzymes. Capivasertib should be used with caution in combination with sensitive substrates of UGT1A1 enzymes which exhibit a narrow therapeutic index (e.g. irinotecan) because capivasertib may increase the systemic exposure of these substrates.

Interactions with hepatic transporters (BCRP, OATP1B1, OATP1B3)

The exposure of medicinal products that are sensitive to inhibition of BCRP, OATP1B1 and/or OATP1B3, if they are metabolised by CYP3A4, may increase by co-administration with TRUQAP. This may lead to increased toxicity. Depending on their therapeutic window, dose adjustment may be required for medicinal products that are sensitive to inhibition of BCRP, OATP1B1 and/or OATP1B3 if they are metabolised by CYP3A4 (e.g. simvastatin). The SmPC of the other medicinal products should be consulted for the recommendations regarding co-administration with CYP3A4, BCRP, OATP1B1 and OATP1B3 inhibitors.

Interactions with renal transporters (MATE1, MATE2K, OCT2)

The exposure of medicinal products that are sensitive to inhibition of MATE1, MATE2K and/or OCT2 may increase by co-administration with TRUQAP. This may lead to increased toxicity. Depending on their therapeutic window, dose adjustment may be needed for medicinal products that are sensitive to inhibition of MATE1, MATE2K and OCT2 (e.g. dofetilide, procainamide). The SmPC of the other medicinal products should be consulted for the recommendations regarding co-administration with MATE1, MATE2K and/or OCT2 inhibitors. Transient serum creatinine increases may be observed during treatment with TRUQAP due to inhibition of OCT2, MATE1 and MATE2K by capivasertib.

Women of childbearing potential/Contraception in males and females

Women of childbearing potential should be advised to avoid becoming pregnant while receiving TRUQAP. A pregnancy test should be performed on women of childbearing potential prior to initiating treatment and verified as negative. Re-testing should be considered throughout treatment.

Patients should be advised to use effective contraception during the use of TRUQAP and for the following periods after completion of treatment with TRUQAP: at least 4 weeks for females and 16 weeks for males.

Pregnancy

There are no data from the use of TRUQAP in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Therefore, TRUQAP is not recommended during pregnancy and in women of childbearing potential not using contraception.

Breast-feeding

It is not known whether capivasertib or its metabolites are excreted in human milk. Exposure to capivasertib was confirmed in suckling rat pups which may indicate the excretion of capivasertib in milk. A risk to the breast-fed child cannot be excluded (see section 5.3). Breast-feeding should be discontinued during treatment with TRUQAP.

Fertility

There are no clinical data on fertility. In animal studies, no adverse effect on female reproductive organs was observed, but the effect on female fertility in rats was not studied. Capivasertib has resulted in testicular toxicity and may impair fertility in males of reproductive potential (see section 5.3).

Please refer to section 4.6 of the prescribing information for fulvestrant.

TRUQAP may have a minor influence on the ability to drive and use machines because fatigue, dizziness and syncope have been reported during treatment with capivasertib (see section 4.8).

Summary of safety profile

The summary of safety profile of TRUQAP is based on data from 355 patients who received TRUQAP plus fulvestrant in the phase III (CAPItello-291) study. The median duration of exposure to capivasertib in CAPItello-291 was 5.42 months, with 27% patients exposed ≥12 months.

The most common adverse reactions were diarrhoea (72.4%), rash (40.3%), nausea (34.6%), fatigue (32.1%), vomiting (20.6%), stomatitis (17.2%), hyperglycaemia (16.9%), headache (16.9%) and decreased appetite (16.6%).

The most common grade 3 or 4 adverse reactions were rash (12.4%), diarrhoea (9.3%), hyperglycaemia (2.3%), hypokalaemia (2.3%), anaemia (2.0%) and stomatitis (2.0%).

Serious adverse reactions were seen in 6.8% of patients receiving TRUQAP plus fulvestrant. Most common serious adverse reactions reported in patients receiving TRUQAP plus fulvestrant included rash (2.3%), diarrhoea (1.7%) and vomiting (1.1%).

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

Treatment discontinuation due to adverse reactions occurred in 9.6% of patients. The most common adverse reactions leading to treatment discontinuation were rash (4.5%), diarrhoea (2%) and vomiting (2%).

Tabulated list of adverse reactions

Table 8 lists the adverse reactions based on pooled data from patients treated with TRUQAP plus fulvestrant in clinical studies at the recommended dose.

Adverse drug reactions (ADRs) are organised by MedDRA System Organ Class (SOC). Within each SOC, preferred terms are arranged by decreasing frequency and then by decreasing seriousness. Frequencies of occurrence of adverse reactions are defined as: 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 8. Adverse drug reactions observed in patients treated with TRUQAP:

¹ Urinary tract infection includes urinary tract infection and cystitis.
² Includes other related terms.
³ Stomatitis includes stomatitis, aphthous ulcer and mouth ulceration.
⁴ Rash includes erythema, rash, rash erythematous, rash macular, rash maculo-papular, rash papular and rash pruritic.
⁵ Fatigue includes fatigue and asthenia.

Description of selected adverse reactions

Hyperglycaemia

Hyperglycaemia of any grade occurred in 60 (16.9%) patients and grade 3 or 4 occurred in 8 (2.3%) patients receiving TRUQAP. The median time to first occurrence of hyperglycaemia was 15 days (range: 1 to 367). In the study, dose reduction was required in 2 (0.60%) patients and 1 (0.30%) patient discontinued treatment due to hyperglycaemia. In the 60 patients with hyperglycaemia, 28 (46.7%) patients were treated using anti-hyperglycaemic medication (including insulin in 16.7%). See section 4.4.

Diarrhoea

Diarrhoea occurred in 257 (72.4%) patients receiving TRUQAP. Grade 3 and/or 4 diarrhoea occurred in 33 (9.3%) patients. The median time to first occurrence was 8 days (range 1 to 519). Dose reduction was required in 28 (7.9%) patients and 7 (2.0%) patients discontinued TRUQAP due to diarrhoea. In the 257 patients with diarrhoea, anti-diarrheal medication was required in 59% (151/257) of patients to manage diarrhoea symptoms.

Rash

Rash (including erythema, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, and rash pruritic) 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 occurred in 44 (12.4%) of patients who received capivasertib. Erythema multiforme occurred in 6 (1.7%) patients and the highest grade was grade 3 in 3 (0.8%) of the patients. Dermatitis exfoliative generalised occurred in 2 (0.6%) patients, these events were grade 3 in severity. Dose reduction was required in 16 (4.5%) patients and 16 (4.5%) patients discontinued TRUQAP due to rash.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Not applicable.