TRUQAP 160mg tablets medication leaflet

TRUQAP 160 mg film-coated tablets

TRUQAP 200 mg film-coated tablets

TRUQAP 160 mg film-coated tablets

Each film-coated tablet contains 160 mg of capivasertib.

TRUQAP 200 mg film-coated tablets

Each film-coated tablet contains 200 mg of capivasertib.

For the full list of excipients, see section 6.1.

Film-coated tablets (tablet).

TRUQAP 160 mg film-coated tablets

Round, biconvex, beige film-coated tablets debossed with ‘CAV’ above ‘160’ on one side and plainon the reverse. Approximate diameter: 10 mm.

TRUQAP 200 mg film-coated tablets

Capsule-shaped, biconvex, beige film-coated tablets debossed with ‘CAV 200’ on one side and plainon the reverse. Approximate size: 14.5 mm (length), 7.25 mm (width).

TRUQAP is indicated in combination with fulvestrant for the treatment of adult patients withoestrogen receptor (ER)-positive, HER2-negative locally advanced or metastatic breast cancer withone or more PIK3CA/AKT1/PTEN-alterations following recurrence or progression on or after anendocrine-based regimen (see section 5.1).

In pre- or perimenopausal women, TRUQAP plus fulvestrant should be combined with a luteinisinghormone releasing hormone (LHRH) agonist.

For men, administration of LHRH agonist according to current clinical practice standards should beconsidered.

Treatment with TRUQAP should be initiated and supervised by a physician experienced in the use ofanticancer medicinal products.

Patients with ER-positive, HER2-negative advanced breast cancer should be selected for treatmentwith TRUQAP based on the presence of one or more PIK3CA/AKT1/PTEN -alterations which shouldbe assessed by a CE-marked IVD with the corresponding intended purpose. If the CE-marked IVD isnot available, an alternative validated test should be used.

The recommended dose of TRUQAP is 400 mg (two 200 mg tablets) twice daily, approximately12 hours apart (total daily dose of 800 mg), for 4 days followed by 3 days off treatment. See Table 1.

Table 1 TRUQAP dosing schedule for each week

Day 1 2 3 4 5* 6* 7*

Morning 2 x 200 mg 2 x 200 mg 2 x 200 mg 2 x 200 mg

Evening 2 x 200 mg 2 x 200 mg 2 x 200 mg 2 x 200 mg

* No dosing on day 5, 6 and 7.

TRUQAP should be co-administered with fulvestrant. The recommended dose of fulvestrant is 500 mgadministered on Days 1, 15, and 29, and once monthly thereafter. Refer to the Summary of Product

Characteristics (SmPC) of fulvestrant for more information.

If a dose of TRUQAP is missed, it can be taken within 4 hours after the time it is usually taken. Aftermore than 4 hours, the dose should be skipped. The next dose of TRUQAP should be taken at theusual time. There should be at least 8 hours between doses.

If the patient vomits, an additional dose should not be taken. The next dose of TRUQAP should betaken at the usual time.

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

Treatment with TRUQAP may be interrupted to manage adverse reactions and dose reduction can beconsidered. Dose reductions for TRUQAP should be carried out as described in Table 2. The dose ofcapivasertib can be reduced up to two times. Dose modification guidance for specific adversereactions is presented in Tables 3-5.

Table 2 TRUQAP dose reduction guidelines for adverse reactions

TRUQAP Dose and schedule Number and strength of tablets

Starting dose 400 mg twice daily for 4 days Two 200 mg tablets twice dailyfollowed by 3 days off treatment

First dose reduction 320 mg twice daily for 4 days Two 160 mg tablets twice dailyfollowed by 3 days off treatment

Second dose reduction 200 mg twice daily for 4 days One 200 mg tablet twice dailyfollowed by 3 days off treatment

Table 3 Recommended dose modification for TRUQAP for hyperglycaemiaa

CTCAE Gradeb and fasting glucose (FG)c Recommendationsdvalues prior to TRUQAP dose

Grade 1 No TRUQAP dose adjustment required.

˃ ULN-160 mg/dL or ˃ ULN-8.9 mmol/L or Consider initiation or intensification of oral

HbA1C ˃ 7% anti-diabetic treatmente.

Grade 2 Withhold TRUQAP and initiate or intensify oral˃ 160-250 mg/dL or ˃ 8.9-13.9 mmol/L anti-diabetic treatment.

If improvement to ≤ 160 mg/dL (or ≤ 8.9 mmol/L)is reached within 28 days, restart TRUQAP at thesame dose level and maintain initiated orintensified anti-diabetic treatment.

If improvement to ≤ 160 mg/dL (or ≤ 8.9 mmol/L)is reached after 28 days, restart TRUQAP at onelower dose level and maintain initiated orintensified anti-diabetic treatment.

Grade 3 Withhold TRUQAP and consult a diabetologist.

˃ 250-500 mg/dL or ˃ 13.9-27.8 mmol/L Initiate or intensify oral anti-diabetic treatment.

Consider additional anti-diabetic medicinalproducts such as insulinf, as clinically indicated.

Consider intravenous hydration and provideappropriate clinical management as per localguidelines.

If FG decreases to ≤ 160 mg/dL (or ≤ 8.9 mmol/L)within 28 days, restart TRUQAP at one lower doselevel and maintain initiated or intensified anti-diabetic treatment.

If FG does not decrease to ≤ 160 mg/dL (or≤ 8.9 mmol/L) within 28 days followingappropriate treatment permanently discontinue

TRUQAP.

Grade 4 Withhold TRUQAP and consult with a˃ 500 mg/dL or ˃ 27.8 mmol/L diabetologist.

Initiate or intensify appropriate anti-diabetictreatment.

Consider insulinf, (dosing and duration asclinically indicated), intravenous hydration andprovide appropriate clinical management as perlocal guidelines.

If FG decreases to ≤ 500 mg/dL (or≤ 27.8 mmol/L) within 24 hours, then follow theguidance in the table for the relevant grade.

If FG is confirmed at ˃ 500 mg/dL (or˃ 27.8 mmol/L) after 24 hours, permanentlydiscontinue TRUQAP treatment.a For the management of suspected or confirmed diabetic ketoacidosis (DKA) refer to section 4.4.b Grading according to NCI CTCAE Version 4.03.c Considerations should be also given to increases in HbA1C.d See section 4.4 for further recommendations on monitoring of glycaemia and other metabolic parameters.e Consultation with a diabetologist should be considered when selecting the anti-diabetic medicinal product. Apotential for hypoglycaemia with anti-diabetic medicinal product administration on non-TRUQAP dosing daysshould be taken into account. Patients should also consider consultation with a dietician to make lifestylechanges that may reduce hyperglycaemia (see section 4.4).

Metformin is currently the preferred oral antidiabetic recommended for the management of hyperglycaemiaoccurring in patients participating in studies of capivasertib. Dosing and management of patients receiving themetformin and capivasertib combination requires caution. Due to the potential interaction of metformin andcapivasertib (caused by the inhibition of renal transporters [e.g. OCT2] involved in the excretion of metformin),when taking both capivasertib and metformin concurrently, it is recommended weekly monitoring of creatinineafter initiation of metformin, for up to 3 weeks and then on Day 1 of each cycle thereafter.

Metformin should only be given on the days when capivasertib is also administered (the half-life of capivasertibis approximately 8 hours) and should be withdrawn when treatment with capivasertib is withdrawn, unlessotherwise clinically indicated.f There is limited experience in patients receiving insulin when being treated with TRUQAP.

Secondary prophylaxis should be considered in patients with recurrent diarrhoea (see section 4.4).

Table 4 Recommended dose modification for TRUQAP for diarrhoea

CTCAE Gradea Recommendations

Grade 1 No TRUQAP dose adjustment required.

Initiate appropriate anti-diarrhoeal therapy,maximise supportive care and monitor as clinicallyindicated.

Grade 2 Initiate or intensify appropriate anti-diarrhoealtreatment, monitor the patient and if clinicallyindicated interrupt TRUQAP dose for up to28 days until recovery to ≤ Grade 1 and resume

TRUQAP dosing at same dose, or one lower doselevel as clinically indicated.

If Grade 2 diarrhoea is persistent or recurring,maintain appropriate medical therapy and restart

TRUQAP at the next lower dose level, as clinicallyindicated.

Grade 3 Interrupt TRUQAP.

Initiate or intensify appropriate anti-diarrhoealtreatment and monitor as clinically indicated.

If the symptoms improve to ≤ Grade 1 in 28 daysresume TRUQAP at one lower dose level.

If the symptom does not improve to ≤ Grade 1 in28 days permanently discontinue TRUQAP.

Grade 4 P ermanently discontinue TRUQAP.a Grade according to the NCI CTCAE Version 5.0.

Rash and other skin drug reactions

Consultation with a dermatologist for all grades of skin drug reactions regardless of the severityshould be considered. In patients with persistent rash and/or previous occurrence of grade 3 rash,secondary prophylaxis should be considered by continuing oral antihistamines and/or topical steroids(see section 4.4).

Table 5 Recommended dose modification for TRUQAP for rash and other skin drug reactions

CTCAE Gradea Recommendations

Grade 1 No TRUQAP dose adjustment required.

Initiate emollients and consider adding oralnon-sedating antihistamine treatment as clinicallyindicated to manage symptoms.

Grade 2 Initiate or intensify topical steroid treatment andconsider non-sedating oral antihistamines.

If no improvement with treatment, interrupt

TRUQAP.

CTCAE Gradea Recommendations

Resume at the same dose level once the rashbecomes clinically tolerable.

Grade 3 Interrupt TRUQAP.

Initiate appropriate dermatological treatment withtopical steroid of moderate/higher strength,non-sedating oral antihistamines and/or systemicsteroids.

If symptoms improve within 28 days to ≤ Grade 1,restart TRUQAP on one lower dose level.

If the symptoms do not improve to ≤ Grade 1 in28 days discontinue TRUQAP.

In patients with reoccurrence of intolerable≥ Grade 3 rash, consider permanentdiscontinuation of TRUQAP.

Grade 4 Permanently discontinue TRUQAP.a Grading according to CTCAE Version 5.0.

Other toxicities

Table 6 Recommended dose modification and management for other toxicities (excludinghyperglycaemia, diarrhoea, rash and other skin drug reactions)

CTCAE Gradea Recommendations

Grade 1 No TRUQAP dose adjustment required, initiateappropriate medical therapy and monitor asclinically indicated.

Grade 2 Interrupt TRUQAP until symptoms improve to≤ Grade 1.

Grade 3 Interrupt TRUQAP until symptoms improve to≤ Grade 1. If symptoms improve, restart

TRUQAP at same dose or one lower dose levelas clinically appropriate.

Grade 4 Permanently discontinue TRUQAP.a Grading according to CTCAE Version 5.0.

Co-administration with strong and moderate CYP3A4 inhibitors

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

TRUQAP 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 strong or moderate CYP3A4 inhibitor, TRUQAP dosage (after 3 to 5half-lives of the inhibitor) that was taken prior to initiating the strong or moderate CYP3A4 inhibitorshould be resumed.

See section 4.5 for further information.

No dose adjustment is required for elderly patients (see section 5.2). There are limited data in patientsaged ≥ 75 years.

No dose adjustment is required for patients with mild or moderate renal impairment. TRUQAP is notrecommended for patients with severe renal impairment, as safety and pharmacokinetics have not beenstudied in these patients (see section 5.2).

No dose adjustment is required for patients with mild hepatic impairment. Limited data are availablefor patients with moderate hepatic impairment; TRUQAP should be administered to patients withmoderate hepatic impairment only if the benefit outweighs the risk and these patients should bemonitored closely for signs of toxicity. TRUQAP is not recommended for patients with severe hepaticimpairment, as safety and pharmacokinetics have not been studied in these patients (see section 5.2).

The safety and efficacy of TRUQAP in children aged 0-18 years of age has not been established. Nodata are available.

TRUQAP is for oral use. The tablets can be taken with or without food (see section 5.2). They shouldbe swallowed whole with water and not chewed, crushed, dissolved, or divided. No tablet should beingested if it is broken, cracked, or otherwise not intact because these methods have not been studiedin clinical trials.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

The safety and efficacy of TRUQAP in patients with pre-existing Type 1 diabetes or Type 2 diabetesrequiring insulin and/or in patients with HbA1C ˃ 8.0% (63.9 mmol/mol) has not been studied as thesepatients 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 inpatients with a baseline HbA1C ≥ 6.5% (28.6% of patients) than those with a baseline HbA1C < 6.5%(15.4%). Severe hyperglycaemia, associated with diabetic ketoacidosis (DKA) and with fataloutcomes occurred in patients treated with TRUQAP (see section 4.8). DKA can occur at any timeduring TRUQAP treatment. In some reported cases, DKA developed in less than 10 days. Patientswith history of diabetes mellitus may require intensified anti-diabetic treatment and should be closelymonitored. Consultation with a diabetologist or a healthcare professional experienced in the treatmentof hyperglycaemia is recommended for patients with diabetes.

Before initiating treatment with TRUQAP, patients should be informed about TRUQAP’s potential tocause hyperglycaemia (see section 4.8) and requested to immediately contact their healthcareprofessional if hyperglycaemia symptoms (e.g. excessive thirst, urinating more often than usual orgreater amount of urine than usual, or increased appetite with weight loss) occur. In a setting ofadditional co-morbidities and treatments (e.g. dehydration, malnourishment, concurrentchemotherapy/steroids, sepsis), the risk of hyperglycaemia progressing to diabetic ketoacidosis may behigher. DKA should be considered as one of the differential diagnoses in the event of additionalnonspecific symptoms such as nausea, vomiting, abdominal pain, difficulty breathing, fruity odour onbreath, confusion, unusual fatigue, or sleepiness. In patients where DKA is suspected, TRUQAPtreatment should be interrupted immediately. If DKA is confirmed, then TRUQAP should bepermanently discontinued.

Patients must be tested for fasting blood glucose (FG) levels and HbA1C prior to start of treatmentwith TRUQAP and in accordance with the intervals stated in Table 7. Based on the severity ofhyperglycaemia, TRUQAP dosing may be interrupted, reduced, or permanently discontinued (seesection 4.2, Table 3).

More frequent blood glucose monitoring is recommended in patients that develop hyperglycaemiaduring treatment, those with baseline risk factors for DKA (including but not exclusive to diabetesmellitus, pre-diabetes, those receiving regular oral steroids) and in those that develop risk factors for

DKA during treatment (e.g. infection, sepsis, raised HbA1c) (see Table 7). In addition to FG,monitoring of ketones (preferably in blood) and other metabolic parameters (as indicated) isrecommended when a patient experiences hyperglycaemia.

In addition to the recommended management of hyperglycaemia described in Section 4.2 Table 3,counselling on lifestyle changes is recommended for patients with baseline risk factors and those thatdevelop hyperglycaemia during treatment with TRUQAP.

Table 7 Schedule of monitoring of fasting glucose and HbA1c levels in patients treated with

TRUQAP

Recommended schedule for the Recommended schedule ofmonitoring of fasting glucose and monitoring of fasting glucose and

HbA1c levels in all patients treated HbA1c levels in patients withwith TRUQAP diabetes and treated with TRUQAP1

At screening, before Test for fasting blood glucose (FG) levels, HbA1c, and optimise the patient’sinitiating treatment level of blood glucose (see Table 3).with TRUQAP

After initiating Monitor fasting glucose at weeks 1, 2, 4, 6 and 8 after treatment start andtreatment with monthly thereafter.

TRUQAP

It is recommended to test FG pre-dose at Day 3 or 4 of the dosing week.

HbA1c should be monitored every 3 months.

Monitor/self-monitor fasting glucose Monitor/self-monitor fasting glucoseregularly, more frequently in the first daily for the first 2 weeks of treatment.

4 weeks and especially within the first Then continue to monitor fasting2 weeks of treatment, according to the glucose as frequently as needed toinstructions of a healthcare manage hyperglycaemia according toprofessional*. the instructions of a healthcareprofessional*.

Additional HbA1c testing isrecommended at week 4 with diabetes,pre-diabetes, or hyperglycaemia atbaseline.

If hyperglycaemia Monitor fasting glucose as clinically indicated (at least twice weekly, i.e. ondevelops after days on and off capivasertib treatment) until FG decreases to baseline levels2.

initiating treatmentwith TRUQAP Consultation with a healthcare practitioner with expertise in the treatment ofhyperglycaemia should be considered.

Based on the severity of hyperglycaemia, TRUQAP dosing may beinterrupted, reduced, or permanently discontinued (see section 4.2, Table 3).

During treatment with anti-diabetic medication, FG should be monitored for atleast once a week for 2 months, followed by once every 2 weeks or as clinicallyindicated2.

Recommended schedule for the Recommended schedule ofmonitoring of fasting glucose and monitoring of fasting glucose and

HbA1c levels in all patients treated HbA1c levels in patients withwith TRUQAP diabetes and treated with TRUQAP1

* 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 withoutprior 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 conditionswhich may require intensified glycaemia management to prevent worsening of impaired glucose metabolismand potential complications, namely diabetic ketoacidosis.

2 It is recommended to test FG pre-dose at Day 3 or 4 of the dosing week.

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 reportedduring treatment with TRUQAP. Based on the severity of diarrhoea, TRUQAP dosing may beinterrupted, reduced, or permanently discontinued (see section 4.2, Table 4). Advise patients to startanti-diarrhoeal treatment at the first sign of diarrhoea, increase oral fluids if diarrhoea symptoms occurwhile taking TRUQAP. Maintenance of normovolaemia and electrolyte balance is required in patientswith 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, werereported in patients receiving TRUQAP (see section 4.8). Patients should be monitored for signs andsymptoms of rash or dermatitis and based on severity of skin drug reactions, the dosing may beinterrupted, reduced, or permanently discontinued (section 4.2, Table 5). Early consultation with adermatologist 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 symptomaticvisceral 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 eventsor risk of cardiac function impairment, or patients with pre-existing Type 1 diabetes and Type 2diabetes 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 increasedcapivasertib 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 decreasedcapivasertib exposure. Concomitant administration of strong and moderate CYP3A4 inducers and

TRUQAP should be avoided.

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 aweak, 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 inhibitorsshould 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 beavoided, TRUQAP dose should be reduced (see section 4.2). Co-administration of multiple 200 mgdoses of the strong CYP3A4 inhibitor itraconazole increased capivasertib total exposure (AUCinf) andthe peak concentration (Cmax) by 95% and 70%, respectively, relative to capivasertib given alone.

Moderate CYP3A4 inhibitors

Co-administration of TRUQAP with moderate CYP3A4 inhibitors increases capivasertibconcentration, which may increase the risk of TRUQAP toxicity. TRUQAP dose should be reducedwhen 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

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 CYP3A4inducer 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 theconcentration of capivasertib. This may reduce the efficacy of TRUQAP. Co-administration ofmoderate 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 mayincrease when co-administered with TRUQAP which may then lead to increased toxicity dependingon their therapeutic window. Capivasertib increased the midazolam AUC by 15% to 77% and istherefore a weak CYP3A inhibitor (see section 5.2). Dose adjustment may be required for medicinalproducts that are primarily eliminated via CYP3A metabolism and have narrow therapeutic window(e.g. carbamazepine, cyclosporine, fentanyl, pimozide, simvastatin, tacrolimus).The SmPC of the othermedicinal products should be consulted for the recommendations regarding co-administration withweak CYP3A4 inhibitors.

CYP2D6 substrates with a narrow therapeutic index

In vitro evaluations indicated that capivasertib has a potential to inhibit the activities of CYP2D6enzymes. Capivasertib should be used with caution in combination with sensitive substrates of

CYP2D6 enzymes which exhibit a narrow therapeutic index because capivasertib may increase thesystemic 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 CYP2B6enzymes. 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 maydecrease 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 UGT1A1enzymes. Capivasertib should be used with caution in combination with sensitive substrates of

UGT1A1 enzymes which exhibit a narrow therapeutic index (e.g. irinotecan) because capivasertibmay 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 berequired for medicinal products that are sensitive to inhibition of BCRP, OATP1B1 and/or OATP1B3if they are metabolised by CYP3A4 (e.g. simvastatin). The SmPC of the other medicinal productsshould 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 thatare sensitive to inhibition of MATE1, MATE2K and OCT2 (e.g. dofetilide, procainamide). The SmPCof the other medicinal products should be consulted for the recommendations regardingco-administration with MATE1, MATE2K and/or OCT2 inhibitors. Transient serum creatinineincreases may be observed during treatment with TRUQAP due to inhibition of OCT2, MATE1 and

MATE2K by capivasertib.

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 toinitiating 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 thefollowing periods after completion of treatment with TRUQAP: at least 4 weeks for females and 16weeks for males.

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

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

There are no clinical data on fertility. In animal studies, no adverse effect on female reproductiveorgans was observed, but the effect on female fertility in rats was not studied. Capivasertib hasresulted in testicular toxicity and may impair fertility in males of reproductive potential (see section5.3).

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).

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 tocapivasertib 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%) anddecreased 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. Mostcommon serious adverse reactions reported in patients receiving TRUQAP plus fulvestrant includedrash (2.3%), diarrhoea (1.7%) and vomiting (1.1%).

Dose reductions due to adverse reactions were reported in 17.7% of patients. The most commonadverse 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 commonadverse reactions leading to treatment discontinuation were rash (4.5%), diarrhoea (2%) and vomiting(2%).

Table 8 lists the adverse reactions based on pooled data from patients treated with TRUQAP plusfulvestrant 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

MedDRA SOC MedDRA term Any grade (%)

Infections and Urinary tract infection1 Very commoninfestations

MedDRA SOC MedDRA term Any grade (%)

Blood and lymphatic Anaemia Very commonsystem disorders

Immune system Hypersensitivity2 Commondisorders

Metabolism and Hyperglycaemia2 Very commonnutrition disorders

Decreased appetite Very common

Hypokalaemia Common

Diabetic ketoacidosis3 Uncommon

Nervous system Headache Very commondisorders

Dysgeusia Common

Dizziness Common

Syncope Common

Renal and urinary Acute kidney injury Commondisorders

Gastrointestinal Dry Mouth Commondisorder

Abdominal pain Common

Diarrhoea2 Very common

Nausea Very common

Vomiting Very common

Stomatitis4 Very common

Dyspepsia Common

Skin and subcutaneous Rash5 Very commontissue disorders

Pruritis Very common

Dry skin Common

Erythema multiforme Common

Drug eruption Uncommon

Dermatitis Uncommon

MedDRA SOC MedDRA term Any grade (%)

Dermatitis exfoliative Uncommongeneralised

Toxic skin eruption Uncommon

General disorders and Fatigue6 Very commonadministration site

Commonconditions Mucosal inflammation

Pyrexia Common

Investigations Blood creatinine increased Common

Glycosylated haemoglobin Commonincreased1 Urinary tract infection includes urinary tract infection and cystitis.2 Includes other related terms.3 Diabetic ketoacidosis includes ketoacidosis.4 Stomatitis includes stomatitis, aphthous ulcer and mouth ulceration.5 Rash includes erythema, rash, rash erythematous, rash macular, rash maculo-papular, rash papular and rashpruritic.6 Fatigue includes fatigue and asthenia.

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%) patientdiscontinued 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 section4.4.

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

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 rashwas 12 days (range 1-226). Grade 3 and/or 4 occurred in 44 (12.4%) of patients who receivedcapivasertib. Erythema multiforme occurred in 6 (1.7%) patients and the highest grade was grade 3 in3 (0.8%) of the patients. Dermatitis exfoliative generalised occurred in 2 (0.6%) patients, these eventswere grade 3 in severity. Dose reduction was required in 16 (4.5%) patients and 16 (4.5%) patientsdiscontinued TRUQAP due to rash.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is currently no specific treatment in the event of an overdose with TRUQAP. Higher than theindicated dosing of capivasertib can increase risk of capivasertib adverse reactions, includingdiarrhoea. Physicians should follow general supportive measures and patients should be treatedsymptomatically.

Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents, ATC code: L01EX27.

Capivasertib is a potent, selective inhibitor of the kinase activity of all 3 isoforms of serine/threoninekinase AKT (AKT1, AKT2 and AKT3). AKT is a pivotal node in the phosphatidylinositol 3-kinase(PI3K) signalling cascade regulating multiple cellular processes including cellular survival,proliferation, cell cycle, metabolism, gene transcription and cell migration. AKT activation in tumoursis a result of upstream activation from other signalling pathways, mutations of AKT1, loss of

Phosphatase and Tensin Homolog (PTEN) function and mutations in the catalytic subunit of PI3K(PIK3CA).

Capivasertib reduces growth of cell lines derived from solid tumours and haematological disease,including breast cancer cell lines with and without PIK3CA or AKT1 mutations, or PTEN alterations.

Treatment with capivasertib and fulvestrant demonstrated anti-tumour response in a range of ER+human breast cancer PDX models representative of different breast cancer subsets. This includedmodels with and without detectable mutations or alterations in PIK3CA, PTEN or AKT1.

Based on an exposure-response analysis of data from 180 patients with advanced solid malignancieswho received capivasertib doses from 80 to 800 mg, the predicted QTcF prolongation was 3.87 ms atthe mean steady state Cmax following 400 mg twice daily.

CAPItello-291 was a randomised, double-blind, placebo-controlled study that enrolled 708 patients,designed to study the efficacy and safety of TRUQAP in combination with fulvestrant in adultfemales, pre- or post-menopausal, and adult males with locally advanced (inoperable) or metastatic

ER-positive and HER2-negative (defined as IHC 0 or 1+, or IHC 2+/ISH-) breast cancer of which289 patients had tumors with one or more eligible PIK3CA/AKT1/PTEN alterations followingrecurrence or progression on or after aromatase inhibitor (AI)-based treatment.

Patients were excluded if they had more than 2 lines of endocrine therapy for locally advanced(inoperable) or metastatic disease, more than 1 line of chemotherapy for locally advanced (inoperable)or metastatic disease, prior treatment with AKT, PI3K, mTOR inhibitors, fulvestrant and/or other

SERDs, clinically significant abnormalities of glucose metabolism (defined as patients with diabetesmellitus Type 1 or Type 2 requiring insulin treatment, and/or HbA1c ˃ 8.0% (63.9 mmol/mol)),history of clinically significant cardiac disease, and symptomatic visceral disease or any diseaseburden that makes the patient ineligible for endocrine therapy.

Patients were randomised 1:1 to receive either 400 mg of TRUQAP (N=355) or placebo (N=353)given twice daily for 4 days followed by 3 days off treatment each week of 28-day treatment cycle.

Fulvestrant 500 mg was administered on cycle 1 days 1 and 15 and then at day 1 of a 28-day cycle.

Pre- or perimenopausal women were treated with an LHRH agonist. Randomisation was stratified bypresence of liver metastases, prior treatment with CDK4/6 inhibitors and geographical region.

Treatment was administered until disease progression, death, withdrawal of consent, or unacceptabletoxicity. A tumour sample was collected prior to randomisation to determine PIK3CA/AKT1/PTENalteration status retrospectively by central testing.

Demographic and baseline characteristics were well balanced between arms. Of the 708 patients, themedian age was 58 years (range 26 to 90 and 30.7% were over 65 years of age); female (99%); White(57.5%), Asian (26.7%), Black (1.1%); Eastern Cooperative Oncology Group (ECOG) performancestatus 0 (65.7%), 1 (34.2%), 21.8% were pre- or perimenopausal. All patients received priorendocrine-based therapy (100% AI-based treatment and 44.1% received tamoxifen). Prior treatmentwith CDK4/6 inhibitor was reported in 70.1% of patients. Chemotherapy for locally advanced(inoperable) or metastatic disease was reported in 18.2% of patients. Patient demographics for those inthe PIK3CA/AKT1/PTEN-altered subgroup were generally representative of the overall studypopulation.

The dual primary endpoints were investigator assessed progression free survival (PFS) in the overallpopulation and PFS in the PIK3CA/AKT1/PTEN-altered subgroup per Response Evaluation Criteria in

Solid Tumours (RECIST) v1.1.

At the data cutoff date (DCO) of 15 August 2022, the study showed statistically significantimprovement in PFS for patients receiving TRUQAP plus fulvestrant compared to patients receivingplacebo plus fulvestrant, in both the overall population and the PIK3CA/AKT1/PTEN-altered subgroup(see table 9). An exploratory analysis of PFS in the 313 (44%) patients whose tumours did not have a

PIK3CA/AKT1/PTEN alterations showed a HR of 0.79 (95% CI: 0.61, 1.02), indicating that thedifference in the overall population was primarily attributed to the results seen in the population ofpatients whose tumours have PIK3CA/AKT1/PTEN alteration. PFS results by investigator assessmentwere supported by consistent results from a blinded independent central review (BICR) assessment.

The investigator-assessed ORR in patients receiving TRUQAP plus fulvestrant and placebo plusfulvestrant was 22.9% and 12.2%, respectively, in the overall population and 28.8% and 9.7%,respectively, in the altered subgroup.

A prespecified interim analysis of OS (DCO 15 April 2024, 59% of patients had died) showed a HR of0.88 (95% CI: 0.65, 1.19) in the PIK3CA/AKT1/PTEN-altered subgroup.

Efficacy results are presented in Table 9 and Figure 1.

Table 9 Progression-free survival, by investigator assessment in PIK3CA/AKT1/PTEN-alteredsubgroup

PIK3CA/AKT1/PTEN-altered subgroup

N = 289

TRUQAP plus fulvestrant Placebo plus fulvestrant

N = 155 N = 134

Number of PFS events - n (%) 121 (78.1) 115 (85.8)

Median PFS months (95% CI) 7.3 (5.5, 9.0) 3.1 (2.0, 3.7)

Hazard ratio (95% CI)a 0.50 (0.38, 0.65)p-valueb < 0.001a Stratified Cox proportional hazards model. A hazard ratio < 1 favours capivasertib + fulvestrant. For the

Overall population, log-rank test and Cox model stratified by presence of liver metastases (yes vs no), prior useof CDK4/6 inhibitors (yes vs no) and geographic region (Region 1: United States, Canada, Western Europe,

Australia, and Israel, Region 2: Latin America, Eastern Europe and Russia vs Region 3: Asia). For the alteredpopulation, the log rank test and Cox model stratified by presence of liver metastases (yes vs no), and prior useof CDK4/6 inhibitors (yes vs no).b Stratified log-rank test.

Figure 1 - Kaplan-Meier plot of progression-free survival - CAPItello-291 (investigatorassessment, PIK3CA/AKT1/PTEN-altered subgroup)

Median PFS in months (95% CI)

- ------------- TRUQAP plus Fulvestrant: 7.3 (5.5, 9.0)

- ------------- Placebo plus Fulvestrant: 3.1 (2.0, 3.7)

HR (95% CI): 0.50 (0.38, 0.65)

Log-rank P-value < 0.001

Time from randomisation (months)

Number of patients at risk

TRUQAP plus Fulvestrant

Placebo plus Fulvestrant

The European Medicines Agency has waived the obligation to submit the results of studies with

TRUQAP in all subsets of the paediatric population in breast cancer (see section 4.2 for informationon paediatric use).

Capivasertib pharmacokinetics have been characterised in healthy subjects and patients with solidtumours. The systemic exposure (AUC and Cmax) increased proportionally over the dose range of 80 to800 mg range after single dose administration in patients. After multiple-dose administration of 80 to600 mg twice daily, the AUC increased slightly more than dose proportional. Following intermittentdosing of capivasertib 400 mg twice daily, 4 days on and 3 days off, the capivasertib steady-stateconcentrations with AUC of 8 069 hng/mL (37%) and Cmax of 1 371 ng/mL (30%) are predicted to beattained on the 3rd and 4th dosing day of each week, starting from week 2. During the off-dosing days,the plasma concentrations are low (approximately 0.5% to 15% of the steady state Cmax).

Capivasertib is rapidly absorbed with peak concentration (Cmax) observed at approximately 1-2 hoursin patients. The mean absolute bioavailability is 29%.

When capivasertib was administered after a high-fat, high-calorie meal (approximately 1000 kcal), thefed to fasted ratio was 1.32 and 1.23, for AUC and Cmax, respectively, compared to when given after anovernight fast. When capivasertib was administered after a low-fat, low-calorie meal (approximately400 kcal), the exposure was similar to that after fasted administration with fed to fasted ratios of 1.14and 1.21, for AUC and Cmax, respectively. Co-administration with food did not result in clinicallyrelevant changes to the exposure.

Probability of progression free survival

The mean volume of distribution was 2.6 L/Kg after intravenous administration to healthy subjects.

Capivasertib is not extensively bound to plasma protein (percentage unbound 22%) and the plasma toblood ratio is 0.71.

Capivasertib is primarily metabolised by CYP3A4 and UGT2B7 enzymes. The major metabolite inhuman plasma was an ether glucuronide that accounted for 83% of total drug-related material. Aminor oxidative metabolite was quantified at 2% and capivasertib accounted for 15% of totalcirculating drug-related material. No active metabolites have been identified.

The effective half-life after multiple dosing in patients was 8.3 h. The mean total plasma clearance was38 L/h after a single IV administration to healthy subjects. The mean total oral plasma clearance was60 L/h after single oral administration and decreased by 8% after repeated dosing of 400 mg twicedaily.

Following single oral dose of 400 mg, the mean total recovery of radioactive dose was 45% from urineand 50% from faeces. Renal clearance was 21% of total clearance. Capivasertib is primarilyeliminated by metabolism.

Effect of race, age, gender and weight

Based on population pharmacokinetic analysis, AUC and Cmax showed that race (including White and

Japanese patients), gender or age did not significantly impact the capivasertib exposure. There was astatistically significant correlation of apparent oral clearance of capivasertib to body weight.

Compared to a patient with a body weight of 66 kg, a 47 kg patient is predicted to have 12% higher

AUC. There is no basis for dose modification based on body weight as the predicted effect oncapivasertib exposure was small.

Based on population pharmacokinetic analyses, AUC and Cmax were 1% higher in patients with mildrenal impairment (creatinine clearance 60 to 89 mL/min), compared to patients with normal renalfunction. AUC and Cmax were 16% higher in patients with moderate renal impairment (creatinineclearance 30 to 59 mL/min), compared to patients with normal renal function.

There is no data in severe renal impairment or end-stage renal disease (creatinineclearance < 30 ml/min).

Based on population pharmacokinetic analyses, AUC and Cmax were 5% higher in patients with mildhepatic impairment (bilirubin ≤ ULN and AST > ULN, or bilirubin > 1 ULN to ≤ 1.5 ULN), comparedto patients with normal hepatic function (bilirubin ≤ ULN and AST ≤ ULN). AUC was 17% and Cmaxwas 13% higher in patients with moderate hepatic impairment (bilirubin > 1.5 ULN to ≤ 3 ULN),compared to patients with normal hepatic function. There is limited data in patients with moderatehepatic impairment and no data in severe hepatic impairment.

Co-administration of a single dose of capivasertib 400 mg after repeated dosing of acid-reducing agentrabeprazole 20 mg BID for 3 days in healthy subjects did not result in clinically relevant changes ofthe capivasertib exposure.

In vitro studies have demonstrated that capivasertib is primarily metabolised by CYP3A4 and

UGT2B7 enzymes. Results of clinical drug-drug interaction (DDI) studies investigating potential DDIbased on CYP3A4 interactions (itraconazole and enzalutamide) are included in section 4.5 above.

Clinical DDI studies investigating potential DDIs based on UGT2B7 interactions have not beenperformed.

Capivasertib inhibited CYP2C9, CYP2D6, CYP3A4 and UGT1A1 and induced CYP1A2, CYP2B6and CYP3A4 metabolising enzymes in in vitro studies. It also inhibited BCRP, OATP1B1, OATP1B3,

OAT3, OCT2, MATE1 and MATE2K drug transporters in vitro. Results of clinical DDI studyinvestigating potential DDIs based on CYP3A4 interactions (midazolam) are included in section 4.5above. Clinical DDI studies investigating potential DDIs based on CYP1A2, CYP2B6, CYP2C9,

CYP2D6, UGT1A1, BCRP, OATP1B1, OATP1B3, OAT3, OCT2, MATE1 and MATE2Kinteractions have not been performed.

Non-clinical/Repeat-dose toxicity

The major target organs or systems for toxicity were insulin signalling (increased levels of glucose andinsulin in rats and dogs), the male reproductive organs (tubular degeneration in rats and dogs), and therenal system in rats (polyuria, decreased tubular epithelial cell size, decreased kidney size and weight).

The findings present following 1 month of dosing were largely reversible within 1 month of cessationof dosing. Findings occurred at plasma concentrations lower or similar to those in humans(approximately 0.14 to 2 times) at the recommended dose of 400 mg twice daily (based on total AUC).

Cardiovascular effects (QTc interval prolongation, increased cardiac contractility, and decreased bloodpressure) were seen in dogs at plasma concentrations approximately 1.4 to 2.7 times the expectedclinical exposure in humans at the recommended dose of 400 mg twice daily (based on unbound

Cmax).

Capivasertib showed no mutagenic or genotoxic potential in vitro. When dosed orally to rats,capivasertib induced micronuclei in the bone marrow via an aneugenic mode of action.

Carcinogenicity studies have not been conducted with capivasertib.

Embryofoetal/Developmental toxicity

In a rat embryofoetal study, capivasertib caused an increase in post implantation loss, an increase inearly embryonic deaths, together with reduced gravid uterine and foetal weights, and minor foetalvisceral variations. These effects were seen at a dose level of 150 mg/kg/day which caused maternaltoxicity, and where plasma concentrations were approximately 0.8 times the exposure in humans at therecommended dose of 400 mg twice daily (based on total AUC). When capivasertib was administeredto pregnant rats at 150 mg/kg/day throughout gestation and through early lactation, there was areduction in litter and pup weights.

Exposure to capivasertib was confirmed in suckling pups which may indicate the potential forexcretion of capivasertib in human milk.

Capivasertib has resulted in testicular toxicity and may impair fertility in males of reproductivepotential. Effects on female fertility have not been studied in animals. In females, repeat-dose toxicitystudies have reported some weight changes of the uterus in rats which were attributed to estrous cyclechanges. Histopathological examination conducted in rat and dog studies did not show any treatment-related effects on female reproductive organs, which may be indicative of an adverse effect on femalefertility.

Microcrystalline cellulose (E460i)

Calcium hydrogen phosphate

Croscarmellose sodium (E468)

Magnesium stearate (E470b)

Hypromellose

Titanium dioxide (E171)

Macrogol 3350

Polydextrose

Copovidone

Triglycerides, medium chain

Black iron oxide (E172)

Red iron oxide (E172)

Yellow iron oxide (E172)

Not applicable.

4 years.

The medicinal product does not require any special storage conditions.

Aluminium/Aluminium blister containing 16 film-coated tablets. Pack of 64 tablets (4 blisters).

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

AstraZeneca AB

SE-151 85 Södertälje

Sweden

EU/1/24/1820/001 160 mg tablets

EU/1/24/1820/002 200 mg tablets

Date of first authorisation: 17 June 2024

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.