Capivasertib

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.

The exposure of medicinal products that are sensitive to inhibition of MATE1, MATE2K and/or OCT2 may increase by co-administration with capivasertib. 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 capivasertib due to inhibition of OCT2, MATE1 and MATE2K by capivasertib.

Co-administration of capivasertib with moderate CYP3A4 inducer has the potential to decrease the concentration of capivasertib. This may reduce the efficacy of capivasertib. 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).

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.

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 capivasertib. 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.

Concentration of medicinal products that are primarily eliminated via CYP3A metabolism may increase when co-administered with capivasertib 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. 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.

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.

Co-administration of capivasertib with strong CYP3A4 inhibitors increases capivasertib concentration, which may increase the risk of capivasertib 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, capivasertib dose should be reduced. 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.

Co-administration of capivasertib with strong CYP3A4 inhibitors should be avoided. If co-administration cannot be avoided, the dose of capivasertib should be reduced to 320 mg twice daily (equivalent to a total daily dose of 640 mg).

After discontinuation of a strong CYP3A4 inhibitor, capivasertib dosage (after 3 to 5 half-lives of the inhibitor) that was taken prior to initiating the strong CYP3A4 inhibitor should be resumed.

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

Capivasertib dose should be reduced to 320 mg twice daily (equivalent to a total daily dose of 640 mg) when co-administered with moderate CYP3A4 inhibitors.

After discontinuation of a moderate CYP3A4 inhibitor, capivasertib dosage (after 3 to 5 half-lives of the inhibitor) that was taken prior to initiating the moderate CYP3A4 inhibitor should be resumed.

Co-administration of capivasertib 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%.

Capivasertib is not recommended for patients with severe renal impairment, as safety and pharmacokinetics have not been studied in these patients.

Limited data are available for patients with moderate hepatic impairment; capivasertib should be administered to patients with moderate hepatic impairment only if the benefit outweighs the risk and these patients should be monitored closely for signs of toxicity. Capivasertib is not recommended for patients with severe hepatic impairment, as safety and pharmacokinetics have not been studied in these patients.

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.

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.

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.

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 were excluded from CAPItello-291. This should be considered if capivasertib is prescribed in these patients.

The efficacy and safety of this medicinal product have not been studied in patients with symptomatic visceral disease. This should be considered if capivasertib is prescribed in these patients.

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

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. Breast-feeding should be discontinued during treatment with capivasertib.

Women of childbearing potential/Contraception in males and females

Women of childbearing potential should be advised to avoid becoming pregnant while receiving capivasertib. 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 capivasertib and for the following periods after completion of treatment with capivasertib: at least 4 weeks for females and 16 weeks for males.

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.

Capivasertib 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.

Summary of safety profile

The summary of safety profile of capivasertib is based on data from 355 patients who received capivasertib 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 capivasertib plus fulvestrant. Most common serious adverse reactions reported in patients receiving capivasertib 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 capivasertib 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

The table below lists the adverse reactions based on pooled data from patients treated with capivasertib 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).

Adverse drug reactions observed in patients treated with capivasertib:

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 capivasertib. 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%).

Diarrhoea

Diarrhoea occurred in 257 (72.4%) patients receiving capivasertib. 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 capivasertib 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 capivasertib due to rash.