Дозировка и Способ Применения
2 DOSAGE AND ADMINISTRATION BRCA2 m mCSPC: The recommended dosage of AKEEGA is 200 mg niraparib/1,000 mg abiraterone acetate orally once daily in combination with 5 mg prednisone daily until disease progression or unacceptable toxicity. ( 2.2 ) BRCA m mCRPC : The recommended dosage of AKEEGA is 200 mg niraparib/1,000 mg abiraterone acetate orally once daily in combination with 10 mg prednisone daily until disease progression or unacceptable toxicity. ( 2.2 ) Patients receiving AKEEGA should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy. ( 2.2 ) Take AKEEGA on an empty stomach at least one hour before or two hours after food. ( 2.2 ) For adverse reactions, consider interruption of treatment, dose reduction, or dose discontinuation. ( 2.3 ) 2.1 Patient Selection Select patients for the treatment of mCSPC with AKEEGA based on the presence of a BRCA2 gene alteration [see Clinical Studies (14.1) ] . Select patients for the treatment of mCRPC with AKEEGA based on the presence of a BRCA gene alteration [see Clinical Studies (14.2) ] . Information on FDA-approved tests is available at: http://www.fda.gov/CompanionDiagnostics. 2.2 Recommended Dosage BRCA2- mutated ( BRCA2 m) Metastatic Castration-Sensitive Prostate Cancer (mCSPC) The recommended dosage of AKEEGA is 200 mg niraparib/1,000 mg abiraterone acetate orally once daily in combination with 5 mg prednisone once daily until disease progression or unacceptable toxicity. BRCA -mutated ( BRCA m) Metastatic Castration-Resistant Prostate Cancer (mCRPC) The recommended dosage of AKEEGA is 200 mg niraparib/1,000 mg abiraterone acetate orally once daily in combination with 10 mg prednisone once daily until disease progression or unacceptable toxicity. Patients receiving AKEEGA should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy. Take AKEEGA on an empty stomach at least one hour before or two hours after food. Swallow tablets whole with water. Do not break, crush, or chew tablets. If a patient misses a dose, instruct patients to take the dose as soon as possible on the same day and resume their next dose at the normal schedule the following day. 2.3 Dosage Modification for Adverse Reactions The recommended dosage modifications for AKEEGA are provided in Table 1. Treatment with AKEEGA should not be reinitiated until the toxicity has resolved to Grade 1 or baseline. If the toxicity is attributed to one component of AKEEGA, the other component of AKEEGA may be continued as a single agent at the current dose until the adverse reaction resolves and AKEEGA can be resumed (see Table 1 ). Table 1: Dosage Modifications for Adverse Reactions Adverse Reaction Severity Dosage Modification Myelosuppression [see Warnings and Precautions (5.2) ] Hemoglobin <8 g/dL Withhold AKEEGA and monitor blood counts weekly. When hemoglobin returns to ≥9 g/dL, resume at the reduced dose of AKEEGA 100 mg/1,000 mg once daily and monitor blood counts weekly for 28 days and as clinically indicated. Permanently discontinue AKEEGA if hemoglobin has not returned to acceptable levels within 28 days of the dose interruption period or if the patient has already undergone dose reduction to 100 mg/1,000 mg once daily. If myelodysplastic syndrome or acute myeloid leukemia (MDS/AML) is confirmed, discontinue AKEEGA [see Warnings and Precautions (5.1)]. Platelet count <100,000/mcL First occurrence: Withhold AKEEGA for a maximum of 28 days and monitor blood counts weekly until platelet counts return to ≥100,000/mcL. Resume AKEEGA at same or the reduced dose of 100 mg/1,000 mg once daily. If platelet count is <75,000/mcL, resume at the reduced dose of AKEEGA 100 mg/1,000 mg once daily. Second occurrence: Withhold AKEEGA for a maximum of 28 days and monitor blood counts weekly until platelet counts return to ≥100,000/mcL. Resume at the reduced dose of AKEEGA 100 mg/1,000 mg once daily. Permanently discontinue AKEEGA if the platelet count has not returned to acceptable levels within 28 days of the dose interruption period or if the patient has already undergone dose reduction to 100 mg/1,000 mg once daily. Neutrophil <1,000/mcL Withhold AKEEGA and monitor blood counts weekly. When neutrophil counts return to ≥1,500/mcL, resume at the reduced dose of AKEEGA 100 mg/1,000 mg once daily and monitor blood counts weekly for 28 days and as clinically indicated. Permanently discontinue AKEEGA if neutrophils have not returned to acceptable levels within 28 days of the dose interruption period or if the patient has already undergone dose reduction to 100 mg/1,000 mg once daily. Hematologic adverse reaction requiring transfusion Consider platelet transfusion for patients with platelet count ≤10,000/mcL. If there are other risk factors such as coadministration of anticoagulation or antiplatelet drugs, consider interrupting these drugs and/or transfusion at a higher platelet count. Resume at the reduced dose of AKEEGA 100 mg/1,000 mg once daily. Hepatotoxicity [see Warnings and Precautions (5.4) ] ALT and/or AST greater than 5 × ULN or total bilirubin greater than 3 × ULN Withhold AKEEGA and closely monitor liver function. Permanently discontinue AKEEGA if: ALT or AST ≥ 20 times the ULN – OR– ALT > 3 × ULN and total bilirubin > 2 × ULN in the absence of biliary obstruction or other causes responsible for the concurrent elevation -OR- Hepatotoxicity recurs at the reduced dose 100 mg/500 mg. When AST and ALT resolves to less ≤ 2.5 × ULN and total bilirubin ≤ 1.5 × ULN, AKEEGA may be resumed at the reduced dose of 100 mg/500 mg once daily. When resumed, monitor serum transaminases every two weeks for three months, monthly thereafter, and as clinically indicated. Other non-hematological adverse reactions that persist despite medical management [see Warnings and Precautions (5) and Adverse Reactions (6.1) ] Grade 3 or 4 Discontinue AKEEGA in patients who develop hypertensive crisis or other severe cardiovascular adverse reactions [see Warnings and Precautions (5.3)]. Withhold AKEEGA until resolution of adverse reaction or for a maximum of 28 days. If resolves in 28 days or less, AKEEGA may be resumed at the reduced dose. Permanently discontinue AKEEGA if adverse reaction(s) has not resolved after 28 days or Grade 3 or 4 adverse reaction reoccurs after dose reduction.
Side Effects Overview
6 ADVERSE REACTIONS The following adverse reactions are discussed elsewhere in the labeling: Myelodysplastic syndrome/acute myeloid leukemia [see Warnings and Precautions (5.1) ] Myelosuppression [see Warnings and Precautions (5.2) ] Hypokalemia, fluid retention, and cardiovascular adverse reactions [see Warnings and Precautions (5.3) ] Hepatotoxicity [see Warnings and Precautions (5.4) ] Adrenocortical insufficiency [see Warnings and Precautions (5.5) ] Hypoglycemia [see Warnings and Precautions (5.6) ] Increased fractures and mortality in combination with Radium 223 Dichloride [see Warnings and Precautions (5.7) ] Posterior reversible encephalopathy syndrome [see Warnings and Precautions (5.8) ] The most common adverse reactions (≥20%), including laboratory abnormalities, are decreased hemoglobin, decreased lymphocytes, musculoskeletal pain, fatigue, decreased platelets, increased alkaline phosphatase, constipation, hypertension, nausea, decreased neutrophils, increased creatinine, increased potassium, decreased potassium, increased AST, fluid retention/edema, increased bilirubin, respiratory tract infection and arrhythmia. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Janssen Biotech, Inc. at 1-800-526-7736 (1-800-JANSSEN) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial Experience 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 the WARNINGS and PRECAUTIONS reflect exposure to AKEEGA (niraparib 200 mg and abiraterone acetate 1,000 mg) in BRCA2 m patients (N=162) in the AMPLITUDE study and in BRCA m patients in Cohort 1 (N=113) in the MAGNITUDE study unless otherwise specified. BRCA2 -mutated Metastatic Castration-Sensitive Prostate Cancer (mCSPC) The safety of AKEEGA in patients with BRCA2 m mCSPC was evaluated in AMPLITUDE [see Clinical Studies (14.1) ]. Patients were randomized to receive either AKEEGA (niraparib 200 mg and abiraterone acetate 1,000 mg once daily) (n=162), or placebo and abiraterone acetate (n=161) until unacceptable toxicity or progression. Patients in both arms also received prednisone 5 mg daily. The median duration of exposure for AKEEGA was 26 months (range: 0 to 48 months). Serious adverse reactions occurred in 36% of patients who received AKEEGA. Serious adverse reactions reported in >2% of patients included anemia (4.9%), and pneumonia (3.7%). Fatal adverse reactions occurred in 4.9% of patients who received AKEEGA, including sudden death (1.9%), COVID-19 pneumonia (1.2%), pneumocystis jirovecii pneumonia (0.6%), pneumonia (0.6%), and cardio-respiratory arrest (0.6%). Permanent discontinuation of any component of AKEEGA due to an adverse reaction occurred in 13% of patients. Dosage interruptions of any component of AKEEGA due to an adverse reaction occurred in 67% of patients. Adverse reactions which required dosage interruption in >2% of patients included anemia (30%), COVID-19 (10%), hypertension (9%), neutropenia (8%), thrombocytopenia (8%), hypokalemia (7%), vomiting (4.9%), fatigue (4.3%), diarrhea (2.5%), and pneumonia (2.5%). Dose reductions of any component of AKEEGA due to an adverse reaction occurred in 25% of patients. Adverse reactions which required dose reductions in >2% of patients included anemia (17%). The most common adverse reactions (>20%), including laboratory abnormalities, in patients who received AKEEGA were decreased hemoglobin, decreased lymphocyte count, hypertension, decreased neutrophil count, musculoskeletal pain, decreased platelet count, constipation, fatigue, decreased potassium, increase creatinine, nausea, increased alkaline phosphate, increased aspartate aminotransferase, respiratory tract infection, arrhythmia, increased blood bilirubin, and fluid retention/edema. Table 2: Adverse Reactions (>20%) in Patients with BRCA2m mCSPC Who Received AKEEGA (with a Difference of ≥5% Compared to Placebo) in AMPLITUDE Adverse Reaction AKEEGA (N=162) Placebo with Abiraterone Acetate (N=161) All Grades % Grade 3 or 4 % All Grades % Grade 3 or 4 % Vascular disorders Hypertension Grouped terms including multiple similar terms 51 31 36 19 Musculoskeletal and connective tissue disorders Musculoskeletal pain 45 6 58 4.3 Gastrointestinal disorders Constipation 41 0 17 0.6 Nausea 30 0 17 0 General disorders and administration Fatigue 39 4.3 29 3.1 Respiratory, thoracic and mediastinal disorders Respiratory Tract Infection 23 0.6 13 0.6 Cardiac disorders Arrhythmia 23 3.7 9 2.5 Clinically relevant adverse reactions that occurred in ≤20% of patients receiving AKEEGA plus prednisone were hot flush (18%), vomiting (17%), dizziness (17%), abdominal pain (15%), weight decreased (14%), diarrhea (14%), decreased appetite (12%), headache (12%), hemorrhage (12%), dyspnea (10%), urinary tract infection (8%), pneumonia (7%), osteoporosis (4.9%), rash (3.7%), cardiac failure (3.1%), ischemic heart disease (4.9%), acute kidney injury (2.5%), pulmonary embolism (2.5%), and urosepsis (0.6%). The most common select laboratory abnormalities (>20%) that worsened from baseline in patients who received AKEEGA are in Table 3. Table 3: Select Laboratory Abnormalities (>20%) That Worsened from Baseline in Patients with BRCA2m mCSPC Who Received AKEEGA in AMPLITUDE Laboratory Abnormality AKEEGA The denominator used to calculate the rate varied from 160 to 161 for placebo with abiraterone acetate plus prednisone and 159 to 162 for AKEEGA with prednisone based on the number of patients with a baseline value and at least one post-treatment value. (N=162) Placebo with Abiraterone Acetate (N=161) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Hematology Decreased Hemoglobin 74 29 53 1.9 Decreased Lymphocyte Count 59 20 37 13 Decreased Neutrophil Count 49 10 19 3.1 Decreased Platelet Count 41 4.9 23 0.6 Chemistry Decreased Potassium 38 9 29 10 Increased Creatinine 30 1.3 16 2.5 Increased Alkaline Phosphatase 28 0.6 24 3.1 Increased Aspartate Aminotransferase 24 1.3 33 2.5 Increased Blood Bilirubin 22 0 11 0 BRCA -mutated Metastatic Castration-Resistant Prostate Cancer The safety of AKEEGA in patients with BRCA m mCRPC was evaluated in Cohort 1 of MAGNITUDE [see Clinical Studies (14.2) ]. Patients were randomized to receive either AKEEGA (niraparib 200 mg and abiraterone acetate 1,000 mg once daily) (n=113), or placebo and abiraterone acetate (n=112) until unacceptable toxicity or progression. Patients in both arms also received prednisone 10 mg daily. The median duration of exposure for AKEEGA was 18 months (range: 0 to 37 months). Serious adverse reactions occurred in 41% of patients who received AKEEGA. Serious adverse reactions reported in >2% of patients included COVID-19 (7%), anemia (4.4%), pneumonia (3.5%), and hemorrhage (3.5%). Fatal adverse reactions occurred in 9% of patients who received AKEEGA, including COVID-19 (5%), cardiopulmonary arrest (1%), dyspnea (1%), pneumonia (1%), and septic shock (1%). Permanent discontinuation of any component of AKEEGA due to an adverse reaction occurred in 15% of patients. Adverse reactions which resulted in permanent discontinuation of AKEEGA in > 2% of patients included COVID-19 (4.4%), anemia (2.7%), asthenia (2.7%), and vomiting (2.7%). Dosage interruptions of any component of AKEEGA due to an adverse reaction occurred in 50% of patients. Adverse reactions which required dosage interruption in > 2% of patients included anemia (23%), thrombocytopenia (12%), neutropenia (7%), COVID-19 (6%), fatigue (3.5%), asthenia (3.5%), nausea (3.5%), pneumonia (2.7%), hematuria (2.7%), and vomiting (2.7%). Dose reductions of any component of AKEEGA due to an adverse reaction occurred in 28% of patients. Adverse reactions which required dose reductions in > 2% of patients included anemia (12%), thrombocytopenia (4.4%), and fatigue (2.7%). The most common adverse reactions (>20%), including laboratory abnormalities, in patients who received AKEEGA were hemoglobin decreased, lymphocyte decreased, musculoskeletal pain, fatigue, platelets decreased, constipation, alkaline phosphatase increased, hypertension, nausea, neutrophils decreased, creatinine increased, potassium increased, potassium decreased, and aspartate aminotransferase increased. Tables 4 and 5 summarize adverse reactions and laboratory abnormalities for patients with BRCA m mCRPC in MAGNITUDE, respectively. Table 4: Adverse Reactions (>10%) in Patients with BRCAm mCRPC Who Received AKEEGA in MAGNITUDE AKEEGA (N=113) Placebo with Abiraterone Acetate (N=112) Adverse Reaction All Grades % Grade 3 or 4 % All Grades % Grade 3 or 4 % Musculoskeletal and connective tissue disorders Musculoskeletal pain Grouped terms including multiple similar terms. 44 4 42 5 General disorders and administration site conditions Fatigue 43 5 30 4 Edema 17 0 9 0 Pyrexia 10 2 6 0 Gastrointestinal disorders Constipation 34 1 20 0 Vomiting 15 0 7 1 Nausea 33 1 21 0 Abdominal pain 12 2 12 1 Vascular disorders Hypertension 33 14 27 17 Hemorrhage 12 2 8 1 Respiratory, thoracic and mediastinal disorders Dyspnea 15 1 8 3 Cough 12 0 6 0 Metabolism and nutrition disorders Decreased appetite 15 2 8 0 Nervous system disorders Dizziness 14 0 10 0 Headache 12 1 9 0 Infections and infestations COVID-19 13 7 9 4 Urinary tract infection 12 3 9 1 Psychiatric disorders Insomnia 12 0 4 0 Investigations Weight decreased 10 1 4 1 Cardiac disorders Arrhythmia 10 2 4 1 Injury, poisoning and procedural complications Fall 10 1 13 4 Clinically relevant adverse events that occurred in <10% of patients receiving AKEEGA plus prednisone were rash (7%), alanine aminotransferase increased (5%), aspartate aminotransferase increased (5%), cerebrovascular accident (4.4%), pulmonary embolism (2.7%), deep vein thrombosis (2.7%), and acute kidney injury (2.7%). Table 5: Select Laboratory Abnormalities (>20%) That Worsened from Baseline in Patients with BRCAm mCRPC Who Received AKEEGA in MAGNITUDE AKEEGA The denominator used to calculate the rate varied from 111 to 112 for placebo with abiraterone acetate plus prednisone and 113 for AKEEGA with prednisone based on the number of patients with a baseline value and at least one post-treatment value. (N=113) Placebo with Abiraterone Acetate (N=112) Laboratory Abnormality All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Hematology Hemoglobin decreased 67 26 53 7 Lymphocyte decreased 55 22 32 13 Platelets decreased 37 8 22 1.8 Neutrophils decreased 32 7 16 2.7 Chemistry Alkaline Phosphatase increased 34 1.8 29 1.8 Creatinine increased 30 0 13 1.8 Potassium increased 25 0.9 21 3.6 Potassium decreased 20 5 20 5 Aspartate Aminotransferase increased 20 1.8 25 2.7 Other Clinical Trial Experience The following adverse reactions have been reported with the individual components of AKEEGA but were not observed in AMPLITUDE or MAGNITUDE Cohort 1: myopathy, rhabdomyolysis, adrenal insufficiency, allergic alveolitis, febrile neutropenia, anaphylactic reaction, posterior reversible encephalopathy (PRES), and hypertensive crisis.
Предупреждения и Меры Предосторожности
5 WARNINGS AND PRECAUTIONS Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML) : MDS/AML, including a case with fatal outcome, has been observed in patients treated with AKEEGA. Monitor patients for hematological toxicity and discontinue if MDS/AML is confirmed. ( 5.1 ) Myelosuppression: Test complete blood counts weekly for the first month, every two weeks for the next two months, monthly for the remainder of the first year, then every other month, and as clinically indicated. ( 2.3 , 5.2 ) Hypokalemia, Fluid Retention, and Cardiovascular Adverse Reactions: Monitor patients for hypertension, hypokalemia, and fluid retention at least weekly for the first two months, then once a month. Closely monitor patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia, or fluid retention. Control hypertension and correct hypokalemia before and during treatment with AKEEGA. ( 5.3 ) Hepatotoxicity: Can be severe and fatal. Monitor liver function and modify, interrupt, or discontinue treatment as recommended. ( 2.3 , 5.4 ) Adrenocortical insufficiency : Monitor for symptoms and signs of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations. ( 5.5 ) Hypoglycemia: Severe hypoglycemia has been reported when abiraterone acetate, a component of AKEEGA, was administered to patients receiving medications containing thiazolidinediones (including pioglitazone) or repaglinide. Monitor blood glucose in patients with diabetes during and assess if antidiabetic agent dose modifications are required. ( 5.6 ) Increased fractures and mortality in combination with radium Ra 223 dichloride : Use of AKEEGA plus prednisone in combination with radium Ra 223 dichloride is not recommended. ( 5.7 ) Posterior Reversible Encephalopathy Syndrome (PRES): PRES has been observed in patients treated with niraparib, a component of AKEEGA. Discontinue AKEEGA if PRES is confirmed. ( 5.8 ) Embryo-Fetal Toxicity: AKEEGA can cause fetal harm. Advise males with female partners of reproductive potential to use effective contraception. ( 5.9 , 8.1 , 8.3 ) 5.1 Myelodysplastic Syndrome/Acute Myeloid Leukemia AKEEGA may cause myelodysplastic syndrome/acute myeloid leukemia (MDS/AML). In the individual AMPLITUDE and MAGNITUDE studies, MDS or AML, including cases with fatal outcomes, were reported in 0.6% (2/347) and 0.5% (1/212) of patients treated with AKEEGA plus prednisone, respectively. All patients in other tumor types treated with niraparib, a component of AKEEGA, who developed secondary MDS/cancer-therapy-related AML had received previous chemotherapy with platinum agents and/or other DNA-damaging agents, including radiotherapy. For suspected MDS/AML or prolonged hematological toxicities, refer the patient to a hematologist for further evaluation. Discontinue AKEEGA if MDS/AML is confirmed. 5.2 Myelosuppression AKEEGA may cause myelosuppression (anemia, thrombocytopenia, or neutropenia). In AMPLITUDE, Grade 3–4 anemia, neutropenia, and thrombocytopenia were reported, respectively in 29%, 10%, and 4.9% of patients receiving AKEEGA. Overall, 25% of patients with anemia required a red blood cell transfusion, including 15% who required more than one transfusion. Discontinuation due to anemia occurred in 1.2% of patients. In MAGNITUDE Cohort 1, Grade 3–4 anemia, thrombocytopenia, and neutropenia were reported, respectively in 28%, 8%, and 7% of patients receiving AKEEGA. Overall, 27% of patients with anemia required a red blood cell transfusion, including 19.5% who required more than one transfusion. Discontinuation due to anemia occurred in 3% of patients. Monitor complete blood counts weekly during the first month of AKEEGA treatment, every two weeks for the next two months, monthly for the remainder of the first year and then every other month, and as clinically indicated. Do not start AKEEGA until patients have adequately recovered from hematologic toxicity caused by previous therapy. If hematologic toxicities do not resolve within 28 days following interruption, discontinue AKEEGA and refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics [see Dosage and Administration (2.3) ] . 5.3 Hypokalemia, Fluid Retention, and Cardiovascular Adverse Reactions AKEEGA may cause hypokalemia and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Clinical Pharmacology (12.1) ] . In post-marketing experience, QT prolongation and Torsades de Pointes have been observed in patients who develop hypokalemia while taking abiraterone acetate, a component of AKEEGA. Hypertension and hypertensive crisis have also been reported in patients treated with niraparib, a component of AKEEGA. In AMPLITUDE, which used prednisone 5 mg daily in combination with AKEEGA, Grades 3–4 hypokalemia was detected in 9% of patients on the AKEEGA arm, and Grades 3–4 hypertension was observed in 30% of patients on the AKEEGA arm. In MAGNITUDE Cohort 1, which used prednisone 10 mg daily in combination with AKEEGA, Grade 3–4 hypokalemia was detected in 2.7% of patients on the AKEEGA arm and Grade 3–4 hypertension was observed in 14% of patients on the AKEEGA arm. Monitor patients for hypertension, hypokalemia, and fluid retention at least weekly for the first two months, then once a month. Closely monitor patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia, or fluid retention, such as those with heart failure, recent myocardial infarction, cardiovascular disease, or ventricular arrhythmia. Control hypertension and correct hypokalemia before and during treatment with AKEEGA. Discontinue AKEEGA in patients who develop hypertensive crisis or other severe cardiovascular adverse reactions. The safety of AKEEGA in patients with New York Heart Association (NYHA) Class II to IV heart failure has not been established because these patients were excluded from AMPLITUDE and MAGNITUDE. 5.4 Hepatotoxicity AKEEGA may cause hepatotoxicity. Hepatotoxicity in patients receiving abiraterone acetate, a component of AKEEGA, has been reported in clinical trials. In post-marketing experience, there have been abiraterone acetate-associated severe hepatic toxicity, including fulminant hepatitis, acute liver failure, and deaths. In AMPLITUDE, Grade 3–4 ALT or AST increases (at least 5 × ULN) were reported in 1.9% and 1.3% of patients, respectively. In MAGNITUDE Cohort 1, Grade 3–4 ALT or AST increases (at least 5 × ULN) were reported in 1.8% and 0.9% of patients, respectively. The safety of AKEEGA in patients with moderate or severe hepatic impairment has not been established as these patients were excluded from AMPLITUDE and MAGNITUDE. Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with AKEEGA, every two weeks for the first three months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient's baseline should prompt more frequent monitoring and may require dosage modifications [see Dosage and Administration (2.3) ]. Permanently discontinue AKEEGA for patients who develop a concurrent elevation of ALT greater than 3 × ULN and total bilirubin greater than 2 × ULN in the absence of biliary obstruction or other causes responsible for the concurrent elevation, or in patients who develop ALT or AST ≥20 × ULN at any time after receiving AKEEGA. 5.5 Adrenocortical Insufficiency AKEEGA may cause adrenal insufficiency. Adrenocortical insufficiency has been reported in clinical trials in patients receiving abiraterone acetate, a component of AKEEGA, in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Monitor patients for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with abiraterone acetate. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased doses of corticosteroids may be indicated before, during, and after stressful situations. 5.6 Hypoglycemia AKEEGA may cause hypoglycemia in patients being treated with other medications for diabetes. Severe hypoglycemia has been reported when abiraterone acetate, a component of AKEEGA, was administered to patients receiving medications containing thiazolidinediones (including pioglitazone) or repaglinide [see Drug Interactions (7.2) ] . Monitor blood glucose in patients with diabetes during and after discontinuation of treatment with AKEEGA. Assess if antidiabetic drug dosage needs to be adjusted to minimize the risk of hypoglycemia. 5.7 Increased Fractures and Mortality in Combination with Radium 223 Dichloride AKEEGA with prednisone is not recommended for use in combination with Ra-223 dichloride outside of clinical trials. The clinical efficacy and safety of concurrent initiation of abiraterone acetate plus prednisone/prednisolone and radium Ra 223 dichloride was assessed in a randomized, placebo-controlled multicenter study (ERA-223 trial) in 806 patients with asymptomatic or mildly symptomatic castration-resistant prostate cancer with bone metastases. The study was unblinded early based on an Independent Data Monitoring Committee recommendation. At the primary analysis, increased incidences of fractures (29% vs 11%) and deaths (39% vs 36%) have been observed in patients who received abiraterone acetate plus prednisone/prednisolone in combination with radium Ra 223 dichloride compared to patients who received placebo in combination with abiraterone acetate plus prednisone. It is recommended that subsequent treatment with Ra-223 not be initiated for at least five days after the last administration of AKEEGA, in combination with prednisone. 5.8 Posterior Reversible Encephalopathy Syndrome AKEEGA may cause Posterior Reversible Encephalopathy Syndrome (PRES). PRES has been observed in patients treated with niraparib as a single agent at higher than the recommended dose of niraparib included in AKEEGA. Monitor all patients treated with AKEEGA for signs and symptoms of PRES. If PRES is suspected, promptly discontinue AKEEGA and administer appropriate treatment. The safety of reinitiating AKEEGA in patients previously experiencing PRES is not known. 5.9 Embryo-Fetal Toxicity The safety and efficacy of AKEEGA have not been established in females. Based on animal reproductive studies and mechanism of action, AKEEGA can cause fetal harm and loss of pregnancy when administered to a pregnant female [see Clinical Pharmacology (12.1) ] . Niraparib has the potential to cause teratogenicity and/or embryo-fetal death since niraparib is genotoxic and targets actively dividing cells in animals and patients (e.g., bone marrow) [see Warnings and Precautions (5.2) and Nonclinical Toxicology (13.1) ] . In animal reproduction studies, oral administration of abiraterone acetate to pregnant rats during organogenesis caused adverse developmental effects at maternal exposures approximately ≥ 0.03 times the human exposure (AUC) at the recommended dose. Advise males with female partners of reproductive potential to use effective contraception during treatment and for 4 months after the last dose of AKEEGA [see Use in Specific Populations (8.1 , 8.3) ] . Females who are or may become pregnant should handle AKEEGA with protection, e.g., gloves [see How Supplied/Storage and Handling (16) ].
Фармакокинетика
12.3 Pharmacokinetics Niraparib Following the administration of AKEEGA, the mean (coefficient of variation [CV%]) C max, ss was 831 ng/mL (32%) and AUC 0–24h, ss was 13,616 ng∙h/mL (36%). The accumulation ratio following daily administration of AKEEGA was 3.5-, and 2.6-fold for niraparib AUC 0–24h and C max . Niraparib exhibits dose proportional increase in C max and AUC in the dose range of 30 mg (0.15 times the recommended dosage) to 400 mg (2 times the recommended dosage). Abiraterone Acetate Following the administration of AKEEGA, the mean (CV%) C max,ss was 151 ng/mL (59%) and AUC 0–24h,ss was 707 ng∙h/mL (59%) for abiraterone. The accumulation ratio following daily administration of AKEEGA was 2-, and 1.8-fold for abiraterone AUC 0–24h and C max . No major deviation from dose proportionality was observed for abiraterone acetate in the dose range of 250 mg (0.25 times the recommended dosage) to 1,000 mg (the recommended dosage). Absorption Niraparib The median T max was 3 hours after dosing. The absolute bioavailability of niraparib is approximately 73%. Abiraterone Acetate The median T max of abiraterone was 1.5 hours after dosing. Administration of abiraterone acetate with food, compared with administration in a fasted state, results in up to a 10-fold (AUC) and up to a 17-fold (C max ) increase in mean systemic exposure of abiraterone, depending on the fat content of the meal. Given the normal variation in the content and composition of meals, taking abiraterone acetate with meals has the potential to result in increased and highly variable exposures. Distribution Niraparib The apparent volume of distribution of niraparib was 1,117 L. Niraparib is 83% bound to human plasma proteins. Abiraterone Acetate The apparent volume of distribution of abiraterone was 25,774 L. Abiraterone is highly bound (>99%) to the human plasma proteins, albumin and alpha-1 acid glycoprotein. Elimination Niraparib The mean t ½ of niraparib when given in combination was approximately 62 hours (CV%: 42%) and apparent CL/F was 16.7 L/h (CV%: 27%). Abiraterone Acetate The mean t ½ of abiraterone when given in combination was approximately 20 hours (CV%: 7.8%) and apparent CL/F was 1673 L/h (CV%: 24%). Metabolism Niraparib Niraparib is metabolized by carboxylesterases. Abiraterone Acetate Abiraterone acetate is rapidly converted in vivo to abiraterone. CYP3A4 and SULT2A1 are the enzymes involved in the metabolism of abiraterone. Excretion Niraparib About 48% (33% to 60%) of the radiolabeled dose was recovered in urine and 39% (28% to 47%) in feces. Unchanged niraparib accounted for 11% and 19% of the administered dose recovered in urine and feces, respectively. Abiraterone Acetate Approximately 88% of the radiolabeled dose is recovered in feces and 5% in urine. Unchanged abiraterone acetate and abiraterone accounted for 55% and 22% of the administered dose recovered in the feces, respectively. Specific Populations No clinically significant effects on the PK of niraparib and abiraterone were observed based on body weight (43.3–165 kg for niraparib and 46–165 kg for abiraterone), age (45–90 years for niraparib and 43–90 years for abiraterone), race/ethnicity (White, Asian, and Hispanic) and mild to moderate renal impairment (CLcr: 30–90 mL/min). Severe renal impairment (CLcr: 15–30 mL/min) has not been studied. Hepatic Impairment Niraparib Mild hepatic impairment did not affect the exposure of niraparib. Moderate hepatic impairment (Total bilirubin > 1.5 to 3 × ULN and any aspartate aminotransferase value) increased niraparib AUC by 56% compared to that of patients with normal hepatic function. Abiraterone Acetate Mild (Child-Pugh score of 5 to 6; Child-Turcotte-Pugh Class A) hepatic impairment increased abiraterone (AUC) by 1.1-fold and moderate (Child-Pugh score of 7 to 9; Child-Turcotte-Pugh Class B) hepatic impairment increased abiraterone (AUC) by 3.6-fold compared to subjects with normal hepatic function. Severe (Child-Pugh score of 10 to 15; Child-Turcotte-Pugh Class C) hepatic impairment increased abiraterone AUC by 7-fold and the fraction of free drug increased by 2-fold in subjects compared to subjects with normal hepatic function. Drug Interactions Studies Niraparib In Vitro Studies Inhibition of Cytochrome P450 ( CYP) Enzymes: Niraparib is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Induction of CYP Enzymes: Niraparib is not a CYP3A4 inducer. Niraparib induces CYP1A2 in vitro . Inhibition of Uridine 5'-Diphospho-Glucuronosyltransferases (UGTs): Niraparib did not inhibit UGT1A1, UGT1A4, UGT1A9, and UGT2B7. Inhibition of Transporter Systems: Niraparib inhibits BCRP, but does not inhibit P-gp, BSEP, or MRP2. Niraparib inhibits MATE 1 and 2. Substrate of Transporter Systems: Niraparib is a substrate of P-gp and BCRP. Niraparib is not a substrate of BSEP, MRP2, or MATE1 or 2. Abiraterone Acetate Clinical Studies Effect of Strong CYP3A4 Inducers on Abiraterone: Coadministration of rifampin (strong CYP3A4 inhibitor) decreased abiraterone mean AUC by 55%. Effect of Strong CYP3A4 Inhibitors on Abiraterone: Coadministration of ketoconazole (strong CYP3A4 inhibitor) had no clinically meaningful effect on the pharmacokinetics of abiraterone. Effect of Abiraterone Acetate on CYP2D6 Substrates: The C max and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively when dextromethorphan 30 mg was given with abiraterone acetate 1,000 mg daily (plus prednisone). The AUC for dextrorphan, the active metabolite of dextromethorphan, increased approximately 1.3-fold. Effect of Abiraterone Acetate on CYP1A2 Substrates: When abiraterone acetate (plus prednisone) was given with a single dose of 100 mg theophylline (CYP1A2 substrate), no increase in systemic exposure of theophylline was observed. Effect of Abiraterone Acetate on CYP2C8 Substrates: The AUC of pioglitazone (CYP2C8 substrate) was increased by 46% when pioglitazone was given to healthy subjects with a single dose of abiraterone acetate. In vitro Studies Cytochrome P450 (CYP) Enzymes: Abiraterone is a substrate of CYP3A4 and has the potential to inhibit CYP1A2, CYP2D6, CYP2C8 and to a lesser extent CYP2C9, CYP2C19 and CYP3A4/5. Transporter Systems: Abiraterone acetate and abiraterone are not substrates of P-gp. Abiraterone acetate is an inhibitor of P-gp. Abiraterone and its major metabolites were inhibitors of OATP1B1.