TRUQAP Film-coated tablet Ref.[107254] Active ingredients: Capivasertib

5.1 Hyperglycemia

Severe hyperglycemia, associated with ketoacidosis, occurred in patients treated with TRUQAP. The safety of TRUQAP has not been established in patients with Type I diabetes or diabetes requiring insulin. Patients with insulin dependent diabetes were excluded from CAPItello-291.

Hyperglycemia occurred in 18% of patients treated with TRUQAP. Grade 3 (insulin therapy initiated; hospitalization indicated) or Grade 4 (life-threatening consequences; urgent intervention indicated) hyperglycemia occurred in 2.8% of patients. Diabetic ketoacidosis occurred in 0.3% of patients and diabetic metabolic decompensation in 0.6% of patients. Dose reduction for hyperglycemia was required in 0.6% of patients and permanent discontinuation was required in 0.6% of patients. The median time to first occurrence of hyperglycemia was 15 days (range: 1 to 367).

In the 65 patients with hyperglycemia, 45% required treatment with anti-hyperglycemic medication (insulin in 15%, and metformin in 29%). Of the 29 patients who required anti-hyperglycemic medication during treatment with TRUQAP, 66% (19/29) remained on these medications at treatment discontinuation or last follow up.

Evaluate fasting blood glucose (FG) and hemoglobin A1C (HbA1c) and optimize blood glucose prior to treatment. Before initiating TRUQAP, inform patients about TRUQAP’s potential to cause hyperglycemia and to immediately contact their healthcare professional if hyperglycemia symptoms occur (e.g., excessive thirst, urinating more often than usual or greater amount of urine than usual, increased appetite with weight loss). Evaluate FG at least every two weeks during the first month and at least once a month starting from the second month, prior to the scheduled dose of TRUQAP. Monitor HbA1c every three months. Monitor FG more frequently during treatment with TRUQAP in patients with a medical history of diabetes mellitus and in patients with risk factors for hyperglycemia such as obesity (BMI ≥30), elevated FG of >160 mg/dL (>8.9 mmol/L), HbA1c at or above the upper limit of normal, use of concomitant systemic corticosteroids, or intercurrent infections.

If a patient experiences hyperglycemia after initiating treatment with TRUQAP, monitor FG as clinically indicated, and at least twice weekly until FG decreases to normal levels. During treatment with anti-hyperglycemic medication, continue monitoring FG at least once a week for 8 weeks, followed by once every 2 weeks and as clinically indicated. Consider consultation with a healthcare practitioner with expertise in the treatment of hyperglycemia and counsel patients on lifestyle changes.

Withhold, reduce dose, or permanently discontinue TRUQAP based on severity [see Dosage and Administration (2.4)].

5.2 Diarrhea

Severe diarrhea associated with dehydration occurred in patients who received TRUQAP.

Diarrhea occurred in 72% of patients. Grade 3 or 4 diarrhea occurred in 9% of patients. The median time to first occurrence was 8 days (range 1 to 519). In the 257 patients with diarrhea, 59% required anti-diarrheal medications to manage symptoms. Dose reductions were required in 8% of patients, and 2% of patients permanently discontinued TRUQAP due to diarrhea. In patients with Grade ≥ 2 diarrhea (n=93) with at least 1 grade improvement (n=89), median time to improvement from the first event was 4 days (range: 1 to 154).

Monitor patients for signs and symptoms of diarrhea. Advise patients to increase oral fluids and start antidiarrheal treatment at the first sign of diarrhea while taking TRUQAP. Withhold, reduce dose, or permanently discontinue TRUQAP based on severity [see Dosage and Administration (2.4)].

5.3 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.

Cutaneous adverse reactions occurred in 58% of patients. Grade 3 or 4 cutaneous adverse reactions occurred in 17% of patients receiving TRUQAP. EM occurred in 1.7% of patients and DRESS occurred in 0.3% of patients. Dose reduction was required in 7% of patients and 7% of patients permanently discontinued TRUQAP due to cutaneous adverse reactions.

The median time to onset of cutaneous adverse reactions was 13 days (range 1 to 575 days). Among the 204 patients with cutaneous adverse reactions, 44% (90/204) required corticosteroid treatment. Of these, 37% (76/204) were treated with topical corticosteroids and 19% (39/204) with systemic corticosteroids. In patients with Grade ≥ 2 cutaneous adverse reaction (n=116) with at least 1 grade improvement (n=104), median time to improvement from the first event was 12 days (range 2 to 544).

Monitor patients for signs and symptoms of cutaneous adverse reactions. Early consultation with a dermatologist is recommended. Withhold, reduce dose, or permanently discontinue TRUQAP based on severity [see Dosage and Administration (2.4)].

5.4 Embryo-Fetal Toxicity

Based on findings from animals and mechanism of action, TRUQAP can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. In an animal reproduction study, oral administration of capivasertib to pregnant rats during the period of organogenesis caused adverse developmental outcomes, including embryo-fetal mortality, and reduced fetal weights at maternal exposures 0.7 times the human exposure (AUC) at the recommended dosage of 400 mg twice daily.

Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TRUQAP and for 1 month after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with TRUQAP and for 4 months after the last dose [see Use in Specific Populations (8.1, 8.3)].

TRUQAP is used in combination with fulvestrant. Refer to the Full Prescribing Information of fulvestrant for pregnancy and contraception information.

The following adverse reactions are also discussed in greater details in other sections of the labeling:

• Hyperglycemia [see Warnings and Precautions (5.1)]
• Diarrhea [see Warnings and Precautions (5.2)]
• Cutaneous Adverse Reactions [see Warnings and Precautions (5.3)]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety population described in WARNINGS and PRECAUTIONS reflects exposure to TRUQAP 400 mg orally, twice a day for 4 days followed by 3 days off, in combination with fulvestrant, in 355 patients in CAPItello-291 until disease progression or unacceptable toxicity. Among the 355 patients who received TRUQAP, 52% were exposed for 6 months or longer, and 27% were exposed for greater than one year. In this safety population, the most common (≥20%) adverse reactions including laboratory abnormalities were diarrhea (72%), cutaneous adverse reactions (58%), increased random glucose (57%), decreased lymphocytes (47%), decreased hemoglobin (45%), increased fasting glucose (37%), nausea and fatigue (35% each), decreased leukocytes (32%), increased triglycerides (27%), decreased neutrophils (23%), increased creatinine (22%), vomiting (21%), and stomatitis (20%).

CAPItello-291

The safety of TRUQAP was evaluated in CAPItello-291, a clinical trial including 288 adult patients (155 patients in TRUQAP with fulvestrant arm and 133 patients in placebo with fulvestrant arm) whose breast cancer had one or more PIK3CA/AKT1/PTEN-alterations [see Clinical Studies (14)]. Among patients who received TRUQAP, 61% were exposed for 6 months or longer and 30% were exposed for greater than one year.

Of the 155 patients who received TRUQAP with fulvestrant, the median age was 58 years (range 36 to 84); female (99%); White (48%), Asian (31%), Black (1.3%), American Indian/Alaska Native (0.6%), and other races (19%).

Serious adverse reactions occurred in 18% of patients receiving TRUQAP with fulvestrant. The most common serious adverse reactions (≥1%) were cutaneous adverse reaction (3.9%), diarrhea and pneumonia (2.6% each), vomiting and pyrexia (1.9% each), hyperglycemia, hypersensitivity, fatigue, renal injury and second malignancy (1.3% each).

Fatal adverse reactions occurred in 1.3% of patients who received TRUQAP with fulvestrant, including sepsis (0.6%), and acute myocardial infarction (0.6%).

Permanent TRUQAP discontinuation due to an adverse reaction occurred in 10% of patients. The most common adverse reaction (≥2%) leading to permanent discontinuation of TRUQAP was cutaneous adverse reactions (6%). Dosage interruptions of TRUQAP due to an adverse reaction occurred in 39% of patients. Adverse reactions leading to dosage interruption in ≥2% of patients included cutaneous adverse reactions (14%), diarrhea (10%), pyrexia (4.5%), vomiting and nausea (3.2% each), and fatigue (2.6%).

Dose reductions of TRUQAP due to adverse reactions occurred in 21% of patients receiving TRUQAP with fulvestrant. Adverse reactions leading to TRUQAP dose reductions in ≥2% of patients were diarrhea and cutaneous adverse reactions (8% each).

The most common (≥20%) adverse reactions including laboratory abnormalities were diarrhea (77%), increased random glucose (58%), cutaneous adverse reaction (56%), decreased lymphocytes (49%), decreased hemoglobin (47%), fatigue (38%), increased fasting glucose (37%), nausea and decreased leukocytes (35% each), increased triglycerides (30%), stomatitis (25%), decreased neutrophils (25%), and vomiting (21%). Adverse reactions and laboratory abnormalities are listed in Table 4 and Table 5, respectively.

Table 4. Adverse Reactions ≥10% in Patients who Received TRUQAP with Fulvestrant [with a Difference Between Arms of ≥3%] in CAPItello-291:

^* Includes other related terms.
^† Cutaneous adverse reaction includes butterfly rash, dermatitis, allergic dermatitis, dry skin, eczema, erythema multiforme, hand dermatitis, palmar-plantar erythrodysesthesia syndrome, pruritus, rash, erythematous rash, maculo-papular rash, papular rash, skin discoloration, skin fissures, skin reaction, skin ulcer, urticaria, purpura, erythema and drug eruption.
^‡ Hyperglycemia includes hyperglycemia, blood glucose increased, glycosylated hemoglobin increased, glucose tolerance impaired and diabetes mellitus.
^§ Renal injury includes acute kidney injury, renal failure, renal impairment, glomerular filtration rate decreased, increased creatinine and proteinuria.

Clinically relevant adverse reactions occurring in <10% of patients treated with TRUQAP included anemia, hypersensitivity (including anaphylactic reaction), dysgeusia, dyspepsia, pneumonia and pyrexia.

Table 5. Laboratory Abnormalities (≥10%) in Patients who Received TRUQAP with Fulvestrant [With a Difference Between Arms ≥3%] in CAPItello-291:

^* The denominator used to calculate the rate varied from 129 to 155 based on the number of patients with a baseline value and at least one post-treatment value.
^† The denominator used to calculate the rate varied from 109 to 131 based on the number of patients with a baseline value and at least one post-treatment value.

7.1 Effects of Other Drugs on TRUQAP

Table 6 describes drug interactions where concomitant use of another drug affects TRUQAP.

Table 6. Drug Interactions with TRUQAP:

Risk Summary

TRUQAP is used in combination with fulvestrant. Refer to the Full Prescribing Information of fulvestrant for pregnancy information.

Based on findings in animals and mechanism of action, TRUQAP can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on the use of TRUQAP in pregnant women. In an animal reproduction study, oral administration of capivasertib to pregnant rats during the period of organogenesis caused adverse developmental outcomes, including embryo-fetal mortality and reduced fetal weights at maternal exposures 0.7 times the human exposure (AUC) at the recommended dose of 400 mg twice daily (see Data). Advise pregnant women and females of reproductive potential of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies in the U.S. general population.

Data

Animal Data

In an embryo-fetal development study, pregnant rats received oral doses of capivasertib up to 150 mg/kg/day during the period of organogenesis. Administration of capivasertib resulted in maternal toxicities (reduced body weight gain and food consumption, increased blood glucose) and adverse developmental outcomes, including embryo-fetal deaths (post-implantation loss), reduced fetal weights, and minor fetal visceral variations at a dose of 150 mg/kg/day (0.7 times the human exposure at the recommended dose of 400 mg twice daily based on AUC).

In a pre- and post-natal assessment, pregnant rats received oral doses of capivasertib up to 150 mg/kg/day from gestation day 6 through at least lactation day 6. Administration of 150 mg/kg/day resulted in reduced litter and pup weights.

Risk Summary

TRUQAP is used in combination with fulvestrant. Refer to the Full Prescribing Information of fulvestrant for lactation information.

There are no data on the presence of capivasertib or its metabolites in human milk or their effects on milk production or the breastfed child. Capivasertib was detected in the plasma of suckling rat pups (see Data). Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with TRUQAP.

Data

Animal Data

In a pre- and post-natal assessment, when capivasertib was administered to maternal rats during the lactation period, capivasertib was detected in plasma of suckling rat pups on lactation day 7 to 8 [see Use in Specific Populations (8.1)]. Plasma concentrations in pups were up to 0.6% of concentrations in maternal plasma in the 150 mg/kg/day group.

TRUQAP is used in combination with fulvestrant. Refer to the Full Prescribing Information of fulvestrant for contraception and infertility information.

TRUQAP can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)].

Pregnancy Testing

Verify pregnancy status of females of reproductive potential prior to initiating TRUQAP [see Use in Specific Populations (8.1)].

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with TRUQAP and for 1 month after the last dose.

Males

Advise male patients with female partners of reproductive potential to use effective contraception during treatment with TRUQAP and for 4 months after the last dose.

The safety and effectiveness of TRUQAP have not been established in pediatric patients.

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 reactions (57% versus 36%), dosage reductions (30% versus 15%), dose interruptions (57% versus 30%), and permanent discontinuations (23% versus 8%), respectively.

No dosage modification is recommended for patients with mild to moderate (creatinine clearance (CLcr) 30 to 89 mL/min) renal impairment [see Clinical Pharmacology (12.3)].

TRUQAP has not been studied in patients with severe (CLcr 15 to 29 mL/min) renal impairment.

No dosage modification is recommended for patients with mild hepatic impairment (bilirubin ≤ upper limit of normal (ULN) and AST > ULN or bilirubin >1 to 1.5x ULN and any AST) [see Clinical Pharmacology (12.3)].

Monitor patients with moderate (bilirubin >1.5 to 3x ULN and any AST) hepatic impairment for adverse reactions due to potential increased capivasertib exposure [see Warnings and Precautions (5.1, 5.2, 5.3)].

TRUQAP has not been studied in patients with severe (bilirubin >3x ULN and any AST) hepatic impairment.