4.1. Therapeutic indications

Truqap is indicated in combination with fulvestrant for the treatment of adult patients with hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) negative (defined as IHC 0 or 1+, or IHC 2+/ISH-) locally advanced or metastatic breast cancer with one or more PIK3CA/AKT1/PTEN-alterations following recurrence or progression on or after an endocrine based regimen (see section 5.1).

4.2. Posology and method of administration

Treatment with Truqap should be initiated and supervised by a physician experienced in the use of anticancer medicinal products.

Patients with HR-positive, HER2-negative advanced breast cancer should be selected for treatment with Truqap based on the presence of one or more PIK3CA/AKT1/PTEN‑alterations using a validated test.

Posology

The recommended dose of Truqap in combination with fulvestrant is 400 mg (two 200 mg tablets) taken orally twice daily approximately 12 hours apart (total daily dose of 800 mg) with or without food, 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 mg administered intramuscularly on Days 1, 15, and 29, and once monthly thereafter. Refer to the approved Summary of Product Characteristics (SmPC) of fulvestrant for more information.

In pre/perimenopausal women, Truqap plus fulvestrant should be combined with a luteinizing hormone releasing hormone (LHRH) agonist. For men, consider administering a LHRH agonist according to current clinical practice standards. Refer to the approved 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. If a dose is missed and more than 4 hours have passed, the dose should be skipped. The next dose of Truqap should be taken at the usual 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 be taken at the usual time.

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

Dose adjustments

Treatment with Truqap may be interrupted to manage adverse reactions and dose reduction can be considered. Dose reductions for capivasertib should be carried out as described in Table 2. The dose of capivasertib can be reduced up to two times. Dose modification guidance for specific adverse reactions is presented in Tables 3‑5.

Table 2 Truqap dose reduction guidelines for adverse reactions

Truqap

Dose and Schedule

Number and Strength of Tablets

First dose reduction

320 mg twice daily for 4 days followed by 3 days off treatment.

Two 160 mg tablets

Second dose reduction

200 mg twice daily for 4 days followed by 3 days off treatment.

One 200 mg tablet

Hyperglycaemia

Table 3 Recommended dose modification for Truqap for hyperglycaemiaa

CTCAE Gradeb and Fasting Glucose (FG)c values prior to Truqap dose

Recommendationsd

Grade 1

> ULN‑160 mg/dL or > ULN‑8.9 mmol/L or HbA1C > 7%

No Truqap dose adjustment required.

Consider initiation or intensification of oral anti-diabetic treatmente.

Grade 2

> 160‑250 mg/dL or > 8.9‑13.9 mmol/L

Initiate or intensify oral anti-diabetic treatment.

Withhold Truqap until fasting glucose (FG) level decrease to ≤ 160 mg/dl (or ≤ 8.9 mmol/L).

If recovery occurs in ≤28 days, resume Truqap at the same dose and maintain initiated or intensified anti-diabetic treatment.

If improvement to ≤ 160 mg/dL (or ≤ 8.9 mmol/L) is reached in more than 28 days restart at one lower dose level and maintain initiated or intensified anti-diabetic treatment.

Grade 3

> 250‑500 mg/dL or > 13.9‑27.8 mmol/L

Withhold Truqap until fasting glucose (FG) level decrease to ≤ 160 mg/dl (or ≤ 8.9 mmol/L) and consult a diabetologist.

Initiate or intensify oral anti-diabetic treatment. Consider additional anti-diabetic medicinal products such as insulinf, as clinically indicated.

Consider intravenous hydration and provide appropriate clinical management as per local guidelines.

If FG decreases to ≤ 160 mg/dL (or ≤ 8.9 mmol/L) within 28 days, restart Truqap at one lower dose level 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 following appropriate treatment permanently discontinue Truqap.

Grade 4

> 500 mg/dL or > 27.8 mmol/L)

Withhold Truqap and consult with a diabetologist.

Initiate or intensify appropriate anti-diabetic treatment.

Consider insulinf, (dosing and duration as clinically indicated), intravenous hydration and provide appropriate clinical management as per local guidelines.

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

If FG is confirmed at > 500 mg/dl (or ≥ 27.8 mmol/l) after 24 hours, permanently discontinue 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. A potential for hypoglycaemia with anti-diabetic medicinal product administration on non‑Truqap dosing days should be taken into account. Patients should also consider consultation with a dietician to make lifestyle changes that may reduce hyperglycaemia (see section 4.4).

f There is limited experience in patients receiving insulin when being treated with Truqap.

Diarrhoea

Consider secondary prophylaxis 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 clinically indicated.

Grade 2

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

Withhold Truqap dose for up to 28 days until recovery to ≤ Grade 1 and resume Truqap dosing at same dose or one lower dose level as clinically indicated.

If Grade 2 diarrhoea is persistent or recurring, maintain appropriate medical therapy and restart Truqap at one lower dose level, as clinically indicated.

Grade 3

Withhold Truqap until recovery to ≤ Grade 1.

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

If recovery occurs in ≤ 28 days, resume Truqap at one lower dose level.

If recovery to ≤ Grade 1 in > 28 days, permanently discontinue Truqap.

Grade 4

Permanently discontinue Truqap.

a Grade according to the NCI CTCAE Version 5.0.

Cutaneous adverse drug reactions

Consider consultation with a dermatologist for all grades of skin drug reactions regardless of the severity. In patients with persistent rash and/or previous occurrence of grade 3 rash, consider secondary prophylaxis by continuing oral antihistamines and/or topical steroids.

Table 5 Recommended dose modification for Truqap for cutaneous adverse drug reactions

CTCAE Gradea

Recommendations

Grade 1

No Truqap dose adjustment required.

Initiate emollients and consider adding oral non -sedating antihistamine treatment as clinically indicated to manage symptoms.

Grade 2

Withhold Truqap until recovery to ≤ Grade 1.

Initiate or intensify topical steroid treatment and consider non-sedating oral antihistamines.

If recovery occurs in ≤ 28 days, resume Truqap at the same dose level.

If persistent or recurrent: restart Truqap by one dose level.

Grade 3

Withhold Truqap until recovery to ≤ Grade 1.

Initiate appropriate dermatological treatment with topical steroid of moderate/higher strength, non-sedating oral antihistamines and/or systemic steroids.

If recovery occurs in ≤ 28 days, restart Truqap on one lower dose level.

If the symptoms do not improve to ≤ Grade 1 within 28 days discontinue Truqap.

In patients with reoccurrence of intolerable Grade 3 rash, permanently discontinue Truqap.

Grade 4

Permanently discontinue Truqap.

a Grading according to CTCAE Version 5.0.

Other toxicities

Table 6 Dose modification and management for other toxicities (excluding hyperglycaemia, diarrhoea and, cutaneous adverse drug reactions)

CTCAE Gradea

Recommendations

Grade 1

No Truqap dose adjustment required, initiate appropriate medical therapy and monitor as clinically indicated.

Grade 2

Withhold Truqap until symptoms improve to ≤ Grade 1.

Grade 3

Withhold Truqap until symptoms improve to ≤ Grade 1. If symptoms improve, restart Truqap at same dose or one lower dose level as clinically appropriate.

Grade 4

Permanently discontinue Truqap.

a Grading according to CTCAE Version 5.0

Co-administration with strong and moderate CYP3A4 inhibitors

The dose of Truqap should be reduced to 320 mg twice daily, 4 days on, 3 days off when concomitantly used with strong or moderate CYP3A4 inhibitors (see section 4.5).

Special populations

Elderly population

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

Renal impairment

No dose adjustment is required for patients with mild (creatinine clearance 60 to 89 mL/min) or moderate (creatinine clearance 30 to 59 mL/min) renal impairment. Truqap is not recommended for patients with severe renal impairment (creatinine clearance <30 mL/min), as safety and pharmacokinetics have not been studied in these patients (see section 5.2).

Hepatic impairment

No dose adjustment is required for patients with mild hepatic impairment (bilirubin ≤ULN and AST > ULN or bilirubin >1.0x - 1.5xULN). Limited data are available for patients with moderate hepatic impairment (bilirubin >1.5x - 3.0x ULN); Truqap should be administered to patients with moderate hepatic impairment only if the benefit outweighs the risk and these patients should be monitored closely for adverse effects due to potential increase in capivasertib exposure. Truqap is not recommended for patients with severe hepatic impairment (bilirubin >3.0x ULN), as safety and pharmacokinetics have not been studied in these patients (see section 5.2).

Paediatric population

The safety and efficacy of Truqap in children aged 0-18 years of age has not been established.

Method of administration

Truqap tablets should be swallowed whole with water and not chewed, crushed dissolved, or divided. No tablets should be ingested if it is broken, cracked, or otherwise not intact.

4.3. Contraindications

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

4.4. Special warnings and precautions for use

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% (33.3% of patients) than those with a baseline HbA1C < 6.5% (16.0%). Severe hyperglycaemia, associated with diabetic ketoacidosis (DKA) and with fatal outcomes occurred in patients treated with Truqap (see section 4.8). DKA can occur at any time during Truqap treatment. In some reported cases, DKA developed in less than 10 days. 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 requested 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. In a setting of additional co‑morbidities and treatments (e.g. dehydration, malnourishment, concurrent chemotherapy/steroids, sepsis), the risk of hyperglycaemia progressing to diabetic ketoacidosis may be higher. DKA should be considered as one of the differential diagnoses in the event of additional nonspecific symptoms such as nausea, vomiting, abdominal pain, difficulty breathing, fruity odour on breath, confusion, unusual fatigue, or sleepiness. In patients where DKA is suspected, Truqap treatment should be interrupted immediately. If DKA is confirmed, then Truqap should be permanently discontinued.

Patients must be tested for fasting blood glucose (FG) levels and HbA1C prior to the start and during treatment with Truqap, in accordance with the intervals recommended in Table 7. Based on the severity of hyperglycaemia, Truqap dosing may be interrupted, reduced, or permanently discontinued (see section 4.2, Table 3).

More frequent blood glucose monitoring is recommended in patients that develop hyperglycaemia during treatment, those with baseline risk factors for DKA (including but not exclusive to diabetes mellitus, 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) is recommended 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 that develop 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 monitoring of fasting glucose and HbA1c levels in all patients treated with Truqap

Recommended schedule of monitoring of fasting glucose and HbA1c levels in patients with diabetes and treated with Truqap1

At screening, before initiating treatment with Truqap

Test for fasting blood glucose (FG) levels, HbA1c, and optimise the patient's level of blood glucose (see Table 3).

After initiating treatment with Truqap

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

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 regularly, more frequently in the first 4 weeks and especially within the first 2 weeks of treatment, according to the instructions of a healthcare professional*.

Monitor/self-monitor fasting glucose daily for the first 2 weeks of treatment. Then continue to monitor fasting glucose as frequently as needed to manage hyperglycaemia according to the instructions of a healthcare professional*.

Additional HbA1c testing is recommended at week 4 with diabetes, pre-diabetes, or hyperglycaemia at baseline.

If hyperglycaemia develops after initiating treatment with Truqap

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

Consultation with a healthcare practitioner with expertise in the treatment of hyperglycaemia should be considered.

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

During treatment with anti-diabetic medication, FG should be monitored for at least once a week for 2 months, followed by once every 2 weeks or as clinically indicated2.

* 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 patients 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.

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

Diarrhoea

Diarrhoea has been frequently reported in patients treated with Truqap (see section 4.8), including severe diarrhoea associated with dehydration and Grade ≥ 3 hypokalaemia. 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 normovolaemia and electrolyte balance is required in patients with diarrhoea to avoid complications related to hypovolemia and low electrolyte levels.

Cutaneous adverse drug reactions

Cutaneous adverse drug reactions, including erythema multiforme and dermatitis exfoliative generalised have been reported in patients receiving Truqap. Patients should be advised of the risk of severe skin reactions and should be monitored for signs and symptoms of rash or dermatitis. Based on severity of skin drug reactions, Truqap 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 receiving bisphosphonates or RANK-ligand inhibitors

Patients with metastatic cancer receiving bisphosphonates or RANK-ligand inhibitors prior to or during treatment with capivasertib should be closely monitored for signs or symptoms of jaw osteonecrosis. Patients should be advised to promptly report any new or worsening oral symptoms including dental mobility, pain or swelling, non-healing of mouth sores or discharge. In patients who develop osteonecrosis of the jaw, standard medical management should be initiated.

Sodium content

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

4.5. Interaction with other medicinal products and other forms of interaction

Medicinal products that may increase capivasertib plasma concentrations

Strong CYP3A4 inhibitors

Co-administration of multiple 200 mg doses of the strong CYP3A4 inhibitor itraconazole with a single 80 mg capivasertib dose increased capivasertib total exposure (AUCinf) and the peak concentration (Cmax) by 95% and 70%, respectively, relative to a single 80 mg capivasertib dose given alone. At the therapeutic dose regimen, the predicted increase in capivasertib AUC and Cmax by itraconazole is 52‑56% and 30‑35%, respectively. Co‑administration of Truqap with strong CYP3A4 inhibitors increases capivasertib concentration, which may increase the risk of Truqap toxicity. Reduce the dose of Truqap when co‑administered with strong CYP3A4 inhibitors (e.g., Boceprevir, ceritinib, clarithromycin, cobicistat, conivaptan, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, mibefradil, mifepristone, nefazodone, nelfinavir, posaconazole, ribociclib, ritonavir, saquinavir, ritonavir, telaprevir, telithromycin, troleandomycin, tucatinib, voriconazole, grapefruit or grapefruit juice) (see section 4.2).

Moderate CYP3A4 inhibitors

Co-administration of Truqap with moderate CYP3A4 inhibitors is predicted to increase capivasertib concentration, which may increase the risk of Truqap toxicity. Reduce the dose of Truqap when coadministered with moderate CYP3A4 inhibitors (e.g., aprepitant, ciprofloxacin, cyclosporine, diltiazem, erythromycin, fluconazole fluvoxamine, tofisopam, verapamil) (see section 4.2).

UGTB27 inhibitors

Coadministration of Truqap with UGT2B7 inhibitors (e.g. probenecid, valproic acid) has the potential to increase capivasertib concentration, which may increase the risk of Truqap toxicity.

Medicinal products that may decrease capivasertib plasma concentrations

Strong CYP3A4 inducers

Co‑administration of capivasertib with strong CYP3A4 inducer enzalutamide decreased the capivasertib AUC by approximately 40% to 50% and rifampicin is predicted to decrease capivasertib AUC by 70%. Co‑administration of Truqap with strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampicin, St. John's wort) is not recommended.

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 Truqap with moderate CYP3A4 inducers is not recommended (e.g., bosentan, cenobamate, dabrafenib, elagolix, etravirine, lersivirine, lesinurad, lopinavir, lorlatinib, metamizole, mitapivat, modafinil, nafcillin, pexidartinib, phenobarbital, rifabutin, semagacestat, sotorasib, talviraline, telotristat ethyl, thioridazine).

UGT2B7 inducers

Coadministration of Truqap with UGT2B7 inducers (e.g. rifampicin) has the potential to decrease capivasertib concentration. This may potentially reduce the efficacy of Truqap.

Interaction with acid reducing agents

Co-administration of a single dose of capivasertib 400 mg after repeated dosing of acid-reducing agent rabeprazole 20 mg BID for 3 days in healthy subjects did not result in clinically relevant changes of the capivasertib exposure. The capivasertib AUC and Cmax decreased by 6% and 27% respectively when co‑administered with rabeprazole. In addition, a population pharmacokinetic analysis showed no significant impact of co‑administration of acid‑reducing agents on the pharmacokinetics of capivasertib in patients. Capivasertib can be taken with acid reducing agents.

In vitro studies

In vitro studies have demonstrated that capivasertib is primarily metabolised by CYP3A4 and UGT2B7 enzymes. Based on physiologically based pharmacokinetic models, the predicted increase in capivasertib AUC by the moderate inhibitors verapamil and erythromycin is 40%, with less impact on Cmax. Co-administration with the UGT2B7 inhibitor probenecid is predicted to cause an increase in capivasertib AUC of 37% over a dosing cycle.

Medicinal products whose plasma concentrations may be altered by capivasertib

Substrates of CYP3A

Concentration of drugs 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 drugs that are primarily eliminated via CYP3A metabolism and have narrow therapeutic window (e.g., carbamazepine, cyclosporine, fentanyl, pimozide, simvastatin, tacrolimus). Refer to specific guidance in the prescribing information for these drugs.

Substrates of CYP2B6

Concentration of drugs that are substrates of CYP2B6 may decrease when co-administered with Truqap (e.g., bupropion).

Substrates of UGT1A1

Concentration of drugs that are sensitive substrates of UGT1A1 may increase when co-administered with Truqap. Dose adjustment may be needed for drugs that are sensitive substrates of UGT1A1 (e.g., bictegravir, irinotecan).

Interactions with hepatic transporters (OATP1B1, OATP1B3)

The exposure of drugs that are sensitive to inhibition of 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 drugs that are sensitive to inhibition of OATP1B1 and/or OATP1B3 (e.g., simvastatin), if they are metabolised by CYP3A4. Refer to specific guidance in the prescribing information for these drugs.

Interactions with renal transporters (MATE1, MATE2K, OCT2)

The exposure of drugs that are sensitive to inhibition of MATE1, MATE2K and/or OCT2 may increase by co‑administration with Truqap. This may lead to increased toxicity. Transient serum creatinine increases may be observed during treatment with Truqap. due to inhibition of OCT2, MATE1 and MATE2K by capivasertib. Depending on their therapeutic window, dose adjustment may be needed for drugs that are sensitive to inhibition of MATE1, MATE2K, OCT2 (e.g., dofetilide, procainamide). Refer to specific guidance in the prescribing information for these drugs.

In vitro studies

Capivasertib inhibited CYP2C9, CYP2D6, CYP3A4 and UGT1A1 metabolizing enzymes and OATP1B1, OATP1B3, OAT3, OCT2, MATE1 and MATE2K drug transporters in in vitro studies.

Based on in vitro and physiologically based modelling, capivasertib was predicted to have no effect on the AUC of CYP2C9 or CYP2D6 substrates, atorvastatin or rosuvastatin. No meaningful interaction was predicted for metformin (2% to 40% AUC increase, depending on the dosing day).

4.6. Fertility, pregnancy, and lactation

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, and re-testing 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 after the last dose for women and 16 weeks after the last dose for men.

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, capivasertib resulted in tubular degeneration in male reproductive organs in mice, rats and dogs but had no effects on fertility in male rats. The effect on female fertility in rats has not been studied (see section 5.3).

Truqap is given with fulvestrant. Please refer to section 4.6 of the Summary of Product Characteristics (SmPC) for fulvestrant.

4.7. Effects on ability to drive and use machines

Truqap has no influence on the ability to drive and use machines. However, during treatment with capivasertib, fatigue has been reported and those patients who experience this symptom should be advised to observe caution when driving or using machinery.

4.8. Undesirable effects

Summary of safety profile

The safety profile of Truqap is based on data from 355 patients who received Truqap plus fulvestrant in CAPItello‑291.

The most common adverse reactions (reported at a frequency of ≥ 20%), were diarrhoea (72.4%), cutaneous adverse drug reactions (46.5%), nausea (34.6%), fatigue (34.6%), and vomiting (20.6%).

The most common grade 3 or 4 adverse reactions (reported at frequency ≥ 2%) were cutaneous adverse drug reactions (14.9%), diarrhoea (9.3%), hyperglycaemia (2.5%), hypokalaemia (2.3%), anaemia (2.0%), and stomatitis (2.0%).

Serious adverse reactions were seen in 26 (7.3%) patients receiving Truqap plus fulvestrant. Serious adverse reactions reported in ≥ 1% of patients receiving Truqap plus fulvestrant included cutaneous adverse drug reactions in 12 (3.4%), diarrhoea in 6 (1.7%), hyperglycaemia in 4 (1.1%), to include diabetic metabolic decompensation in 1 (0.3%), and vomiting in 4 (1.1%) patients.

Dose reductions due to adverse reactions were reported in 64 (18%) patients. The most common adverse reactions (reported at frequency ≥ 2%) leading to dose reduction of Truqap were diarrhoea (7.9%) and cutaneous adverse drug reactions (5.9%).

Treatment discontinuation due to adverse reactions occurred in 36 (10.1%) patients. The most common adverse reactions (reported at frequency ≥ 2%) leading to treatment discontinuation were cutaneous adverse drug reactions (5.4%), diarrhoea (2.0%), and vomiting (2.0%).

Tabulated list of adverse reactions

Adverse drug reactions 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 <1/1000); very rare (<1/10,000) and not known (cannot be estimated from available data).

Table 8 Adverse Drug Reactions observed in CAPItello‑291 study

MedDRA SOC

MedDRA Term

Any Grade (%)

Grade 3 or 4 (%)

Infections and infestations

Urinary Tract Infection1

Very Common

49 (13.8)

6 (1.7)

Blood and lymphatic system disorders

Anaemia

Very Common

37 (10.4)

7 (2.0)

Immune system disorders

Hypersensitivity2

Common

4 (1.1)

1 (0.3)

Metabolism and nutrition disorders

Hyperglycaemia3

Very Common

63 (17.7)

9 (2.5)

Decreased appetite

Very Common

59 (16.6)

1 (0.3)

Hypokalaemia4

Common

16 (4.5)

8 (2.3)

Diabetic Ketoacidosis5

Uncommon

1 (0.3)

1 (0.3)

Nervous system disorders

Dysgeusia

Common

21 (5.9)

0

Gastrointestinal disorders

Diarrhoea6

Very Common

257 (72.4)

33 (9.3)

Nausea

Very Common

123 (34.6)

3 (0.8)

Vomiting

Very Common

73 (20.6)

6 (1.7)

Stomatitis7

Very Common

61 (17.2)

7 (2.0)

Dyspepsia

Common

18 (5.1)

0

Skin and subcutaneous tissue disorders

Cutaneous adverse drug reactions8

Very Common

165 (46.5)

53 (14.9)

Pruritus

Very Common

44 (12.4)

2 (0.6)

Dry skin

Common

25 (7.0)

0

General disorders and administration site conditions

Fatigue9

Very Common

123 (34.6)

6 (1.7)

Pyrexia10

Common

34 (9.6)

2 (0.6)

Mucosal inflammation

Common

11 (3.1)

1 (0.3)

Investigations

Blood creatinine increased

Common

16 (4.5)

1 (0.3)

Weight decreased

Common

12 (3.4)

0

Glycosylated haemoglobin increased

Common

5 (1.4)

0

1 Urinary Tract Infection includes urinary tract infection, pyuria, and cystitis.

2 Hypersensitivity includes hypersensitivity, drug hypersensitivity and anaphylactic reaction.

3 Hyperglycaemia includes hyperglycaemia, blood glucose increased, diabetes mellitus, type 2 diabetes mellitus and diabetic metabolic decompensation.

4 Hypokalaemia includes blood potassium decreased and hypokalaemia.

5 Diabetic Ketoacidosis includes ketoacidosis.

6 Diarrhoea includes diarrhoea and frequent bowel movements.

7 Stomatitis includes stomatitis, aphthous ulcer and mouth ulceration.

8 Cutaneous adverse drug reactions include butterfly rash, dermatitis, dermatitis exfoliative generalised, drug eruption, drug reaction with eosinophilia and systemic symptoms (DRESS), erythema, erythema multiforme, papule, rash, rash erythematous, rash follicular, rash macular, rash maculo-papular, rash papular, rash pruritic, skin reaction, toxic skin eruption.

9 Fatigue includes asthenia, fatigue and malaise.

10 Pyrexia includes body temperature increased and pyrexia.

Description of selected adverse reactions (see section 4.4)

Hyperglycaemia

Hyperglycaemia of any grade occurred in 63 (17.7%) patients and grade 3 or 4 occurred in 9 (2.5%) patients receiving Truqap. In the 63 patients with hyperglycaemia, 30 (47.6%) patients were treated using anti-hyperglycaemic medication including metformin (30.1%) and insulin (17.4%). Out of the 63 patients with hyperglycaemia, dose reduction was required in 2 (3.1%) patients, dose interruption was required in 11 (17.4%) patients, and 1 (1.5%) patient discontinued treatment due to hyperglycaemia.

Diarrhoea

Diarrhoea occurred in 257 (72.4%) patients receiving Truqap. Grade 3 or 4 diarrhoea occurred in 33 (9.3%) patients. The median time to first occurrence was 8 days (1 to 519). In the 257 patients with diarrhoea, anti-diarrheal medication was required in 59% (151/257) of patients to manage diarrhoea symptoms. Out of 257 with diarrhoea, dose reduction was required in 28 (10.9%) patients, dose interruption was required in 35 (13.6%) and 7 (2.7%) patients discontinued Truqap due to diarrhoea. There was a higher incidence of diarrhoea in patients who were on metformin (88.6%) in comparison to that in patients who did not receive metformin in the study (70.1%).

Rash and other cutaneous adverse drug reactions

Cutaneous adverse drug reactions were reported in 165 (46.5%) patients. The median time to first occurrence was 12 days (1-377). Grade 3 or 4 occurred in 53 (14.9%) of patients who received capivasertib. Among the 165 patients with cutaneous adverse drug reactions, 44.8% (74/165) were treated with topical corticosteroids and 21.2% (35/165) with systemic corticosteroids. Out of 165 patients with cutaneous adverse drug reactions, dose reduction was required in 21 (12.7%) patients, dose interruption was required in 51 (30.9%) patients and 19 (11.5%) patients discontinued Truqap due to cutaneous adverse drug reactions.

Elderly

Of the 355 patients who received Truqap in CAPItello-291, 115 (32%) patients were ≥ 65 years of age and 24 (7%) patients were ≥ 75 years of age. No overall differences in the efficacy of Truqap were observed between patients ≥ 65 years of age and younger patients. Analysis of the safety of Truqap comparing patients ≥ 65 years of age to younger patients suggest a higher incidence of Grade 3 to 5 adverse events (57% versus 36%), dose reductions (30% versus 15%), dose interruptions (57% versus 30%), and permanent discontinuations (23% versus 8%), respectively.

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:

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

There is currently no specific treatment in the event of an overdose with Truqap and possible symptoms of overdose are not established. Physicians should follow general supportive measures and patients should be treated symptomatically.