Truqap

TRUQAP 160 mg: TRUQAP 160 mg tablets are round, biconvex, beige, film-coated tablets debossed with 'CAV' above '160' on one side and plain on the reverse.
Each film-coated tablet contains 160 mg of capivasertib.
TRUQAP 200 mg: TRUQAP 200 mg are capsule-shaped, biconvex, beige film-coated tablets debossed with 'CAV 200' on one side and plain on the reverse.
Each film-coated tablet contains 200 mg of capivasertib.
Excipients/Inactive Ingredients: Tablet core: Microcrystalline cellulose, Dibasic calcium phosphate, Croscarmellose sodium, Magnesium stearate.
Tablet coating: Hypromellose, Titanium dioxide, Polyethylene glycol 3350, Polydextrose, Copovidone, Medium chain triglycerides, Yellow iron oxide, Red iron oxide, Black iron oxide.

Pharmacotherapeutic group: Antineoplastic agents, other protein kinase inhibitors. ATC code: L01EX27.
Pharmacology: Pharmacodynamics: Mechanism of action: Capivasertib is a potent, selective inhibitor of the kinase activity of all 3 isoforms of serine/threonine kinase 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 tumours is a result of upstream activation from other signalling pathways, mutations of AKT, loss of Phosphatase and Tensin Homolog (PTEN) function and mutations in the catalytic subunit of PI3K (PIK3CA).
Capivasertib inhibits the phosphorylation of downstream AKT substrates such as glycogen synthase kinase 3-β (GSK3β) and proline-rich AKT substrate of 40 kilodaltons (PRAS40). Capivasertib reduces growth of a range of cell lines derived from solid tumours and haematological disease. Multiple breast cancer cell lines were sensitive to capivasertib monotherapy. Within cell lines showing greater sensitivity to capivasertib there was an enrichment of PIK3CA or AKT1 mutations, or loss of PTEN. Some cell lines lacking such mutations were also sensitive to capivasertib.
In vivo, monotherapy capivasertib inhibits growth of human cancer xenograft models representative of different tumour types including estrogen receptor positive (ER⁺) and triple negative breast cancer models with PIK3CA, AKT1 mutations, PTEN loss and HER2 amplification. Combined treatment with capivasertib and fulvestrant demonstrated a greater anti-tumour response in a range of human breast cancer PDX models representative of different breast cancer subsets. This included models without detectable mutations or alterations in PIK3CA, PTEN or AKT, as well as models with mutations or alterations in PIK3CA, PTEN or AKT.
Cardiac Electrophysiology: Based on an exposure-response analysis of data from 180 patients with advanced solid malignancies who received capivasertib doses from 80 to 800 mg, the predicted QTcF prolongation was 3.87 ms at the mean steady state C_max following 400 mg twice daily. No clinically relevant effect of capivasertib on QT prolongation associated with pro-arrhythmic effect was observed at the recommended dose of 400 mg twice daily.
Clinical efficacy: The efficacy of TRUQAP with fulvestrant was evaluated in CAPItello-291 (NCT04305496), a randomized, double-blind, placebo-controlled, multicenter trial that enrolled 708 adult patients with locally advanced (inoperable) or metastatic HR-positive, HER2-negative (defined as IHC 0 or 1+, or IHC 2+/ISH-) breast cancer of which 289 patients had tumors with eligible PIK3CA/AKT1/PTEN-alterations. Eligible PIK3CA/AKT1 activating mutations or PTEN loss of function alterations were identified in the majority of FFPE tumor specimens using FoundationOne CDx next-generation sequencing (n=686). All patients were required to have progression on an aromatase inhibitor (AI) based treatment in the metastatic setting or recurrence on or within 12 months of completing (neo)adjuvant treatment with an AI. Patients could have received up to two prior lines of endocrine therapy and up to 1 line of chemotherapy for locally advanced (inoperable) or metastatic disease. Patients were excluded if they had clinically significant abnormalities of glucose metabolism (defined as patients with diabetes mellitus Type 1, Type 2, requiring insulin treatment, or HbA1c ≥8% (63.9 mmol/mol)).
Patients were randomized (1:1) to receive either 400 mg of TRUQAP (n=355) or placebo (n=353), given orally twice daily for 4 days followed by 3 days off treatment each week of 28-day treatment cycle. Fulvestrant 500 mg intramuscular injection was administered on cycle 1 days 1 and 15, and then at day 1 of each subsequent 28-day cycle. Patients were treated until disease progression, or unacceptable toxicity. Randomization was stratified by presence of liver metastases (yes vs. no), prior treatment with CDK4/6 inhibitors (yes vs. no) and geographical region (region 1: US, Canada, Western Europe, Australia, and Israel vs region 2: Latin America, Eastern Europe and Russia vs Region 3: Asia).
The major efficacy outcomes were investigator-assessed progression-free survival (PFS) in the overall population, and in the population of patients whose tumors have PIK3CA/AKT1/PTEN-alterations evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Additional efficacy outcome measures were overall survival (OS), investigator assessed objective response rate (ORR) and duration of response (DoR).
A statistically significant difference in PFS was observed in the overall population and the population of patients whose tumors have PIK3CA/AKT1/PTEN-alteration. An exploratory analysis of PFS in the 313 (44%) patients whose tumors did not have a PIK3CA/AKT1/PTEN-alteration showed a HR of 0.79 (95% CI:0.61, 1.02), indicating that the difference in the overall population was primarily attributed to the results seen in the population of patients whose tumors have PIK3CA/AKT1/PTEN-alteration.
Of the 289 patients whose tumors were PIK3CA/AKT1/PTEN-altered, the median age was 59 years (range 34 to 90); female (99%); White (52%), Asian (29%), Black (1%), American Indian/Alaska Native (0.7%), other races (17%) and 9% were Hispanic/Latino. Eastern Cooperative Oncology Group (ECOG) performance status was 0 (66%) or 1 (34%), and 18% were premenopausal or perimenopausal. Seventy-six percent of patients had an alteration in PIK3CA, 13% had an alteration in AKT1, and 17% had an alteration in PTEN. All patients received prior endocrine-based therapy (100% AI based treatment and 44% received tamoxifen). Seventy-one percent of patients were previously treated with a CDK4/6 inhibitor and 18% received prior chemotherapy for locally advanced (inoperable) or metastatic disease.
Efficacy results for PIK3CA/AKT1/PTEN-altered subgroup are presented in Table 1 and figure. Results from the blinded independent review committee (BICR) assessment were consistent with the investigator assessed PFS results. Overall survival results were immature at the time of the PFS analysis (30% of the patients died). (See Table 1 and figure.)

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Pharmacokinetics: Capivasertib pharmacokinetics have been characterized in healthy subjects and patients with solid tumours. The systemic exposure (AUC and C_max) increased approximately proportionally to the dose over the 80 to 800 mg dose range when given to patients. Following intermittent dosing of capivasertib 400 mg twice daily, 4 days on, 3 days off, steady-state levels are predicted to be attained on every 3^rd and 4^th dosing day 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 C_max).
Absorption: Capivasertib is rapidly absorbed with peak concentration (C_max) observed at approximately 1-2 hours in patients. The mean absolute bioavailability is 29%.
Food Effect: When capivasertib was administered after a high-fat, high-calorie meal (approximately 1000 kcal), the fed to fasted ratio was 1.32 and 1.23, for AUC and C_max, respectively, compared to when given after an overnight fast. When capivasertib was administered after a low-fat, low-calorie (approximately 400 kcal), the exposure was similar to that after fasted administration with fed to fasted ratios of 1.14 and 1.21, for AUC and C_max, respectively. Co-administration with food did not result in clinically relevant changes to the exposure.
Distribution: The mean volume of distribution (V_ss) was 205 L after intravenous administration to healthy subjects. Capivasertib is not extensively bound to plasma protein (percentage unbound 22%) and the plasma to blood ratio is 0.71.
Elimination: The effective half-life after multiple dosing in patients was 8.3 hours. The mean total plasma clearance was 38 L/h after a single intravenous administration to healthy subjects. The mean total oral plasma clearance was 60 L/h after single oral administration and decreased by 8% after repeated dosing of 400 mg twice daily.
Following single oral dose of 400 mg, the mean total recovery of radioactive dose was 45% from urine and 50% from faeces. Renal clearance was 21% of total clearance. Capivasertib is primarily eliminated by metabolism.
Biotransformation: Capivasertib is primarily metabolised by CYP3A4 and UGT2B7 enzymes. The major metabolite in human plasma was an ether glucuronide that accounted for 83% of total drug-related material. A minor oxidative metabolite was quantified at 2% and capivasertib accounted for 15% of total circulating drug-related material. No active metabolites have been identified.
Special populations: Effect of race, age, gender and weight: There were no clinically significant differences in pharmacokinetics of capivasertib based on race/ethnicity (including White and Asian patients), gender or age. There was a statistically 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 on capivasertib exposure was small.
Renal impairment: Based on population pharmacokinetic analyses, AUC and C_max were 1% higher in patients with mild renal impairment (creatinine clearance 60 to 89 mL/min), compared to patients with normal renal function. AUC and C_max were 16% higher in patients with moderate renal impairment (creatinine clearance 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 (creatinine clearance <30 ml/min).
Hepatic impairment: Based on population pharmacokinetic analyses, AUC and C_max were 5% higher in patients with mild hepatic impairment (bilirubin ≤ ULN and AST > ULN, or bilirubin >1 ULN to ≤1.5 ULN), compared to patients with normal hepatic function. No dose adjustment is required for patients with mild hepatic impairment.
Based on limited data the AUC and C_max was 17% and 13% higher respectively 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 moderate hepatic impairment and no data in severe hepatic impairment.
Drug-Drug Interaction: Effects of Other Medicinal Products on capivasertib: In vitro studies have demonstrated that capivasertib is primarily metabolised by CYP3A4 and UGT2B7 enzymes.
In a study in healthy subjects, co-administration of multiple 200 mg doses of the strong CYP3A4 inhibitor itraconazole with a single 80 mg capivasertib dose increased capivasertib AUC and C_max 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 C_max by itraconazole is between 52% and 56%, and between 30% and 35%, respectively, over a dosing cycle.
In a study in patients with prostate cancer, the strong CYP3A4 inducer enzalutamide decreased the capivasertib AUC by approximately 40% to 50% and rifampicin is predicted to decrease capivasertib AUC by approximately 70%.
Co-administration of a single dose of capivasertib 400 mg after repeated dosing of acid-reducing agent rabeprazole 20 mg twice daily for 3 days in healthy subjects did not result in clinically relevant changes of the capivasertib exposure. The capivasertib AUC and C_max decreased by 6% and 27% respectively when administered with and without 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.
Based on physiologically based pharmacokinetic models, the predicted increase in capivasertib AUC by the moderate inhibitors verapamil and erythromycin is approximately 40%, with less impact on C_max. Co-administration with the UGT2B7 inhibitor probenecid is predicted to cause an increase in capivasertib AUC of 23 to 37% over a dosing cycle.
Effects of capivasertib on Other Medicinal Products: Co-administration of TRUQAP at the recommended dose with midazolam (CYP3A substrate), increased the AUC of midazolam by 15% on the 3rd off-dosing day and by 77% on the 4th on-dosing day of capivasertib which shows that capivasertib is a weak CYP3A inhibitor.
Capivasertib inhibited CYP2C9, CYP2D6, CYP3A4 and UGT1A1 metabolizing enzymes and BCRP, OATP1B1, OATP1B3, OAT3, OCT2, MATE1 and MATE2K drug transporters in in vitro studies.
Based on in vitro data and physiologically based modelling, capivasertib was predicted to have no effect on the AUC of CYP2C9, CYP2D6 or UGT1A1 substrates, atorvastatin or rosuvastatin. No meaningful interaction was predicted for metformin (2% to 40% AUC increase, depending on the capivasertib dosing day).
Toxicology: Preclinical safety data: Non-clinical/Repeat-dose toxicity: The major target organs or systems for toxicity were insulin signalling (increased levels of glucose and insulin in rats and dogs), the male reproductive organs (tubular degeneration in in rats and dogs), and the renal 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 cessation of 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).
Mutagenicity and carcinogenicity: 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.
Reproductive toxicity: Embryofetal/Developmental toxicity: In a rat embryo-fetal study, capivasertib caused an increase in post implantation loss, an increase in early embryonic deaths, together with reduced gravid uterine and fetal weights, and minor fetal visceral variations. These effects were seen at a dose level of 150 mg/kg/day which caused maternal toxicity, and where plasma concentrations were approximately 0.8 times the exposure in humans at the recommended dose of 400 mg twice daily (based on total AUC). When capivasertib was administered to pregnant rats at 150 mg/kg/day throughout gestation and through early lactation, there was a reduction in litter and pup weights.
Exposure to capivasertib was confirmed in suckling pups which may indicate the potential for excretion of capivasertib in human milk.
Fertility: Capivasertib had no effect on fertility in male rats. Effects on female fertility have not been studied in animals.

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 locally advanced or metastatic breast cancer with one or more PIK3CA/AKT1/PTEN-alteration following recurrence or progression on or after an endocrine-based regimen.

Patients with hormone receptor (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 genetic alterations using a validated test.
The recommended dose of TRUQAP in combination with fulvestrant is 400 mg (two 200 mg tablets) taken orally twice daily (approximately 12 hours apart) with or without food, for 4 days followed by 3 days off treatment. See Table 2.
The recommended dose of fulvestrant is 500 mg administered on Days 1, 15, and 29, and once monthly thereafter. Refer to the approved Prescribing Information of fulvestrant for more information.
In pre/peri-menopausal women, TRUQAP plus fulvestrant should be combined with a luteinizing hormone releasing hormone (LHRH) agonist. Refer to the approved Prescribing Information 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. After more than 4 hours, 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. (See Table 2.)

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Duration of treatment: Treatment with TRUQAP should continue until disease progression or unacceptable toxicity occurs.
Dose adjustments: For Adverse Reactions: Treatment with TRUQAP may be interrupted to manage adverse reactions and dose reduction can be considered. If dose reduction is considered, the dose reduction guidelines are described in Table 3. The dose of TRUQAP can be reduced up to two times. Dose modification guidance for specific adverse reactions is presented in Tables 4-6. (See Table 3.)

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Hyperglycaemia: Consider a consult with diabetologist/endocrinologist when selecting the antidiabetic medicinal product, a potential for hypoglycaemia with antidiabetic medication administration on non-TRUQAP dosing days should be taken in account. (See Table 4.)

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Diarrhoea: Consider secondary prophylaxis in patients with recurrent diarrhoea. (See Table 5.)

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Rash and other Skin 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. (See Table 6.)

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Other toxicities: (See Table 7.)

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Co-administration with strong CYP3A4 inhibitors: Avoid concomitant use with strong CYP3A inhibitors. If concomitant use with a strong CYP3A inhibitor cannot be avoided, the dose of TRUQAP should be reduced to 320 mg twice daily (equivalent to a total daily dose of 640 mg) for 4 days followed by 3 days off (see Interactions).
When concomitantly used with a moderate CYP3A inhibitor, reduce the dosage of TRUQAP to 320 mg orally twice daily for 4 days followed by 3 days off.
After discontinuation of a strong or moderate CYP3A inhibitor, resume the TRUQAP dosage (after 3 to 5 half-lives of the inhibitor) that was taken prior to initiating the strong or moderate CYP3A inhibitor.
Special populations: Elderly: No dose adjustment is required for elderly patients (see Pharmacology: Pharmacokinetics under Actions). There are limited data in patients aged ≥75 years.
Renal impairment: No dose adjustment is required for patients with mild or moderate renal impairment. TRUQAP is not recommended for patients with severe renal impairment, as safety and pharmacokinetics have not been studied in these patients (see Pharmacology: Pharmacokinetics under Actions).
Hepatic impairment: No dose adjustment is required for patients with mild hepatic impairment. Limited data are available for patients with moderate hepatic impairment; 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 signs of toxicity. TRUQAP is not recommended for patients with severe hepatic impairment, as safety and pharmacokinetics have not been studied in these patients (see Pharmacology: Pharmacokinetics under Actions).
Paediatric population: TRUQAP is not indicated for use in paediatric patients, as safety and efficacy of TRUQAP in children and adolescents have not been established.
Method of administration: TRUQAP tablets should be swallowed whole with water and not chewed, crushed, dissolved, or divided. TRUQAP should not be ingested if it is broken, cracked, or otherwise not intact.

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.

Prior severe hypersensitivity to the active substance or to any of the excipients listed in Description.

Hyperglycaemia: Severe hyperglycaemia, associated with diabetic ketoacidosis (DKA) and ketoacidosis, was reported in patients treated with TRUQAP (see Adverse Reactions). Some cases of DKA have been reported with fatal outcomes. DKA can occur at any time during TRUQAP treatment. In some reported cases, DKA developed in less than 10 days.
Hyperglycaemia of any grade occurred in 60 (16.9%) patients and grade 3 or 4 occurred in 8 (2.3%) patients receiving TRUQAP. In the study, dose reduction was required in 2 (0.6%) patients and 1 (0.3%) 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 10 (16.7%) patients).
Before initiating treatment with TRUQAP, inform patients about TRUQAP's potential to cause hyperglycaemia and request for them 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, 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 non-specific 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 start of treatment with TRUQAP and in accordance with the intervals stated in Table 8. Based on the severity of hyperglycaemia, TRUQAP dosing may be interrupted, reduced, or permanently discontinued (see Table 4 under Dosage & Administration).
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 8). 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 Table 4 under Dosage & Administration, counselling on lifestyle changes is recommended for patients with baseline risk factors and those that develop hyperglycaemia during treatment with TRUQAP.
The safety of TRUQAP in patients with Type 1 and Type 2 diabetes requiring insulin has not been studied as these patients were excluded from the clinical study. Patients with history of diabetes mellitus may require intensified diabetic treatment and should be closely monitored. (See Table 8.)

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Diarrhoea: Severe diarrhoea associated with dehydration occurred in patients who received TRUQAP.
Diarrhoea occurred in 257 (72.4%) patients receiving TRUQAP. Grade 3 and/or 4 diarrhoea occurred in 33 (9.3%) patients. Dose reduction was required in 28 (7.9%) patients and 7 (2.0%) patients discontinued TRUQAP due to diarrhoea. In the 257 patients with diarrhoea, antidiarrheal medication was required in 59% (151/257) of patients to manage diarrhoea symptoms.
Based on the severity of diarrhoea, TRUQAP dosing may be interrupted, reduced, or permanently discontinued (see Table 5 under Dosage & Administration). Advise patients to start anti-diarrheal 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 hypovolaemia and low electrolyte levels.
Cutaneous Adverse Reactions: Cutaneous adverse reactions, which can be severe, including erythema multiforme (EM), palmar-plantar erythrodysesthesia, and drug reaction with eosinophilia and systemic symptoms (DRESS), occurred in patients who received TRUQAP.
Rash (including erythema, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, and rash pruritic) was reported in 143 (40.3%) patients. Grade 3 and/or 4 occurred in 44 (12.4%) of patients who received capivasertib. Dose reduction was required in 16 (4.5%) patients and 16 (4.5%) patients discontinued TRUQAP due to rash.
Patients should be monitored for signs and symptoms of rash or dermatitis and based on severity of skin drug reactions the dosing may be interrupted, reduced, or permanently discontinued (see Table 6 under Dosage & Administration). Early consultation with a dermatologist is recommended to ensure greater diagnostic accuracy and appropriate management.
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 operating machinery.

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 prior to initiating treatment, and re-testing considered throughout treatment.
Patients should be advised to use effective contraception during treatment with TRUQAP and for the following periods after completion of treatment with TRUQAP: at least 4 weeks for females and 16 weeks for males.
Pregnancy: There are no data from the use of TRUQAP in pregnant women. Studies in animals have shown reproductive toxicity (see Pharmacology: Toxicology: Preclinical safety data under Actions). 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 suckling child cannot be excluded (see Pharmacology: Toxicology: Preclinical safety data under Actions). 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 Pharmacology: Toxicology: Preclinical safety data under Actions).
Refer to Use in Pregnancy & Lactation of the prescribing information for fulvestrant.

Overall summary of the 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%), rash (40.3%), nausea (34.6%), fatigue (20.8%) and vomiting (20.6%). The most common grade 3 or 4 adverse reactions (reported at frequency ≥2%) were rash (12.4%), diarrhoea (9.3%), hyperglycaemia (2.3%), anaemia (2.0%), and stomatitis (2.0%).
Serious adverse reactions (SARs) were seen in 23 (6.5%) patients receiving TRUQAP plus fulvestrant. Serious adverse reactions reported in ≥1% of patients receiving TRUQAP plus fulvestrant included rash 8 (2.3%), diarrhoea 6 (1.7%), and vomiting 4 (1.1%).
Dose reductions due to adverse reactions were reported in 62 (17.5%) patients. The most common adverse reactions (reported at frequency ≥2%) leading to dose reduction of TRUQAP were diarrhoea (7.9%) and rash (4.5%).
Treatment discontinuation due to adverse reactions occurred in 33 (9.3%) patients. The most common adverse reactions (reported at frequency ≥2%) leading to treatment discontinuation were rash (4.5%), diarrhoea (2.0%), and vomiting (2.0%).
Adverse Drug Reactions: 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 <1/1000); very rare (<1/10,000) and not known (cannot be estimated from available data). (See Table 9.)

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Description of selected adverse reaction: Hyperglycaemia: Hyperglycaemia of any grade occurred in 60 (16.9%) patients and grade 3 or 4 occurred in 8 (2.3%) patients receiving TRUQAP. In the study, dose reduction was required in 2 (0.6%) patients and 1 (0.3%) 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 10 (16.7%) patients).
Diarrhoea: Diarrhoea occurred in 257 (72.4%) patients receiving TRUQAP. Grade 3 and/or 4 diarrhoea occurred in 33 (9.3%) patients. Dose reduction was required in 28 (7.9%) patients and 7 (2.0%) patients discontinued TRUQAP due to diarrhoea. In the 257 patients with diarrhoea, anti-diarrheal medication was required in 59% (151/257) of patients to manage diarrhoea symptoms.
Rash: Rash (including erythema, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, and rash pruritic) was reported in 143 (40.3%) patients. Grade 3 and/or 4 occurred in 44 (12.4%) of patients who received capivasertib. Dose reduction was required in 16 (4.5%) patients and 16 (4.5%) patients discontinued TRUQAP due to rash.

The mechanism of drug-drug clinical interactions and study results are described in Pharmacology: Pharmacokinetics under Actions.
Effect of Other Drugs on TRUQAP: (See Table 10.)

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Effect of TRUQAP on Other Drugs: (See Table 11.)

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Incompatibilities: Not applicable.
Instructions for use, handling and disposal: TRUQAP: Any unused product or waste material should be disposed of in accordance with local requirements.

Store in original package at or below 30°C.

Targeted Cancer Therapy

L01EX27 - capivasertib ; Belongs to the class of other protein kinase inhibitors. Used in the treatment of cancer.

POM