Date of approval: xxxx xx xx
Please read the instructions carefully and use under the guidance of your physician.
Generic Name: Ibrutinib Capsules
Trade Name: IMBRUVICA®®
English Name: Ibrutinib Capsules
Hanyu Pinyin: Yibutini Jiaonang
[Ingredients]
Active ingredient: Ibrutinib
Chemical name: 1-{(3R)-3-[4-amino-3-(4-phenoxyphenol)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl}propan-2-en-1-one
Chemical structure formula.
Molecular formula: C25H24N6O2
Molecular weight: 440.50
Excipients: microcrystalline cellulose, cross-linked sodium carboxymethylcellulose, sodium dodecyl sulfate, magnesium stearate, gelatin hollow capsule
[Properties]
White opaque hard gelatin capsule with black ink printed with “ibr 140mg” and white or off-white powder content.
[Indications]
This product is indicated as a single agent for the treatment of patients with condylomatous lymphoma who have received at least one prior therapy.
This drug alone is indicated for the treatment of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma who have received at least one prior therapy.
[Specifications]
140 mg.
[Dosage]
Use.
This product should be administered orally once daily at an approximately fixed daily dosing schedule. The entire capsule should be delivered with water. Do not open, break, or chew the capsule.
Dosage
Sleeve Cell Lymphoma (MCL)
The recommended dose of this product for the treatment of MCL is 560 mg (4 capsules of 140 mg) once daily until disease progression or unacceptable toxicity occurs.
Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL)
The recommended dose of this product for CLL/SLL is 420 mg (3 capsules of 140 mg) once daily until disease progression or unacceptable toxicity occurs.
Dose Adjustment in the Event of Adverse Reactions
Treatment with this product should be interrupted in the presence of any ≥ grade 3 non-hematologic toxicity, ≥ grade 3 neutropenia with infection or fever, or grade 4 hematologic toxicity. Treatment may be restarted at the starting dose when symptoms of toxicity subside to Grade 1 or baseline levels (recovery). If this toxicity reoccurs, the dose should be reduced by one capsule (140 mg daily). A further dose reduction of 140 mg may be considered if needed. If the toxicity persists or reoccurs after two dose reductions, the product should be discontinued.
Dose adjustment recommendations are described below.
| RecoveryMCLDose adjustment Starting dose= 560 mg |
RecoveryCLL/SLLDose Adjustment Starting dose= 420 mg |
|
| 1st | Re-dosing at 560 mg per day | Re-dosing at 420 mg per day |
| 2nd | Re-dosing at 420 mg per day | Re-dosing at 280 mg per day |
| 3rd | Re-dosing at 280 mg per day | Re-dosing at 140 mg per day |
| 4th | Discontinue | discontinue |
Dose adjustment when co-administered withP450 3A (CYP3A) enzyme inhibitors
Avoid coadministration with potent or intermediate-acting CYP3A inhibitors and consider alternative drugs with less CYP3A inhibition.
Combination use of potent CYP3A inhibitors requiring long-term dosing (eg, ritonavir, indinavir, nelfinavir, saquinavir, boceprevir, telaprevir, nefazodone) is not recommended. For short-term use (7 days of treatment or less) of potent CYP3A inhibitors (e.g., antifungals and antibiotics), consider interrupting treatment with this product until no further CYP3A inhibitors are needed (see [Drug Interactions]).
If an intermediate-acting CYP3A inhibitor (e.g., fluconazole, darunavir, erythromycin, diltiazem, atazanavir, aripitant, amprenavir, fosamprenavir, crizotinib, imatinib, verapamil, and ciprofloxacin) is necessary, reduce the dose of this product to 140 mg (see [Drug Interactions]).
Patients should be monitored more closely for signs of toxicity with this product when combined with a potent or intermediate-acting CYP3A inhibitor.
Dose Adjustment in Patients With Liver Injury
The recommended dose for patients with mild liver injury (Child-Pugh class A) is 140 mg (1 capsule) per day. This product should be avoided in patients with moderate or severe liver injury (Child-Pugh Class B and C) (see [Dosage] under Special Populations and [Pharmacokinetics]).
missed dose
If you do not take this product at the scheduled time, you may take it as soon as possible on the same day and continue to take it at the normal scheduled time the next day. Do not take additional doses of this product to make up for missed doses.
Medication for Special Populations
Hepatic Injury
Ibrutinib is metabolized in the liver. Data from a liver injury study showed increased exposure to ibrutinib. Patients with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) liver injury had a 2.7-fold, 8.2-fold, and 9.8-fold increase in AUC after a single dose of ibrutinib compared with patients with normal liver function, respectively.
The safety of this product has not been evaluated in patients with Child-Pugh score cancer with mild to severe liver injury.
Monitor patients for signs of toxicity with this product and adjust the dose as needed. This product is not recommended for patients with moderate or severe liver injury (Child-Pugh classes B and C) (see [Pharmacokinetics]).
Females and males of childbearing potential
Pregnancy Trials
Pregnancy status should be confirmed before starting treatment with this product in women of childbearing potential.
Contraception
Females
Women of childbearing potential are advised to avoid pregnancy while taking this product and for 1 month after termination of treatment with this product. Women of childbearing potential must use highly effective contraception while using this product. Women using hormonal methods of contraception must also use an additional barrier method of contraception. If this product is taken during pregnancy or if pregnancy occurs while taking this product, the patient should be clearly informed that this product may cause harm to the fetus. The timing of a safe pregnancy after receiving this product is unknown.
Men
Men are advised to avoid childbirth while taking this product and for 3 months after finishing treatment.
[Adverse Reactions]
For details of the following adverse reactions, please refer to the instructions [Precautions].
- Bleeding
- Infection
- Hematocrit
- Interstitial lung disease
- Atrial fibrillation
- White blood cell stasis
- Hypertension
- Secondary malignancy
- Tumor lysis syndrome
Clinical trial experience
Because clinical trials are conducted under very different conditions, the incidence of adverse events observed in a clinical trial of one drug cannot be directly compared to the incidence of adverse events observed in a clinical trial of another drug and may not reflect the incidence of adverse events observed in practice.
Sleeve Cell Lymphoma
The data described below reflect exposure to this product in Phase 2 clinical trials (PCYC-1104-CA) and Phase 3 clinical trials (MCL-3001) in patients with MCL.
The most frequent adverse reactions (≥20%) in patients with MCL were diarrhea, bleeding (e.g., bruising), fatigue, skeletal muscle pain, nausea, upper respiratory tract infection, cough, and rash.
The most common grade 3 or 4 adverse reactions (≥5%) were neutropenia, thrombocytopenia, infectious pneumonia, and anemia.
Adverse Reactions Leading to Discontinuation and Dose Reduction
Of the 250 patients with MCL treated with this product, 7 (3%) patients discontinued due to adverse reactions. The most common adverse reactions that led to discontinuation included bleeding, infectious pneumonia, and thrombocytopenia. 6% of patients had dose reductions due to adverse reactions.
TrialPCYC-1104-CA
The following data reflect exposure to this product in the clinical trial PCYC-1104-CA, which enrolled 111 patients with MCL who had received at least one prior treatment with 560 mg of this product daily for a median treatment duration of 8.3 months.
The most frequent adverse reactions (≥20%) were thrombocytopenia, diarrhea, neutropenia, anemia, fatigue, skeletal muscle pain, peripheral edema, upper respiratory tract infection, nausea, bruising, dyspnea, constipation, rash, abdominal pain, vomiting, and decreased appetite (see Tables 1 and 2).
The most common Grade 3 or 4 non-hematologic adverse reactions (≥5%) were infectious pneumonia, abdominal pain, atrial fibrillation, diarrhea, fatigue, and skin infections.
Fatal and severe renal failure events have occurred with treatment with this product. 9% of patients had creatinine levels elevated to 1.5-3 times the upper limit of normal.
Adverse reactions with an incidence of ≥ 10% in trials (N=111) using 560 mg of this product daily as monotherapy for MCL are shown in Table 1.
Table 1: Non-hematologic adverse reactions occurring in ≥ 10% of patients with MCL (N=111)
| Adverse effects | AllLevels (%) | 3levels or4levels (%< strong>) | |
| Gastrointestinal Systemic Disorders | Diarrhea | 51 | 5 |
| Nausea | 31 | 0 | |
| 25 | 0 | ||
| Abdominal pain | 24 | 5 | |
| Vomiting | 23 | 0 | |
| 17 | 1 | ||
| 11 | 0 | ||
| Upper respiratory tract infections | 34 | 0 | |
| Urinary tract infection | 14 | 3 | |
| Infectious pneumonia | 14 | 7 | |
| Skin infections | 14 | 5 | |
| Sinusitis | 13 | 1 | |
| Systemic disease and various reactions at the site of administration |
Fatigue | 41 | 5 |
| 35 | 3 | ||
| 18 | 1 | ||
| 14 | 3 | ||
| Bruising | 30 | 0 | |
| Rash | 25 | 3 | |
| Bruised spots | 11 | 0 | |
| VariousMusculoskeletal and connective tissue disorders | Skeletal muscle pain | 37 | 1 |
| Muscle spasms | 14 | 0 | |
| Joint pain | 11 | 0 | |
| Respiratory, thoracic and mediastinal disease | Hypopnea | 27 | 4 |
| cough | 19 | 0 | |
| Epistaxis | 11 | 0 | |
| Metabolic and nutritionalClassesDiseases | Loss of appetite | 21 | 2 |
| Dehydration | 12 | 4 | |
| Dizziness | 14 | 0 | |
| 13 | 0 |
Table
Table2: MCL Patients with on-treatment* Hemoglobin, platelet, or neutropenia (N = 111)
| Patient Percent Ratio (N = 111 ) | ||
| All levels (%) | 3levels or4levels (%< strong>) | |
| Thrombocytopenia | 57 | 17 |
| 47 | 29 | |
| hemoglobin reduction | 41 | 9 |
* Based on laboratory measurements and adverse effects
Ten patients (9%) in the trial discontinued the drug due to adverse reactions (N=111). The most common adverse reaction leading to discontinuation was subdural hematoma (1.8%). adverse reactions leading to dose reduction occurred in 14% of patients.
Lymphocytosis occurred, and intracranial hemorrhage, sleepiness, unsteady gait and headache were experienced by MCL patients with lymphocyte counts above 400,000/mcL. However, some of these events occurred in the context of disease progression.
Forty percent of patients had elevated uric acid in the study, including 13% with uric acid values above 10 mg/dL. 15% of patients reported hyperuricemia adverse effects.
TrialMCL-3001
The adverse reactions described below reflect exposure to this product in the clinical trial MCL-3001, which enrolled patients with MCL who had received at least one prior therapy for a median duration of treatment of 14.4 months.
| Table 3: Adverse reactions reported in MCL subjects treated with 560 mg of this product – Clinical Trial MCL3001 (N=139) | |||||
| Body System | Adverse effects | This product (n=139) | Temsirolimus(N=139) | ||
| All levels (%) |
3or4 levels (%) |
All Levels (%) |
3or4 levels (%) |
||
| Infectious and Infectious Diseases | Upper respiratory tract infections | 19 | 2 | 12 | 1 |
| Infectious pneumonia* | 14 | 10 | 19 | 12 | |
| Ocular organ disease | Conjunctivitis | 12 | 0 | 5 | 0 |
| Heart organ disease | Atrial fibrillation | 4 | 4 | 2 | 1 |
| Gastrointestinal Disorders | Abdominal pain | 8 | 4 | 8 | 1 |
| Various musculoskeletal and connective tissue disorders | Muscle spasms | 19 | 0 | 3 | 0 |
| * Includes multiple adverse reaction terms. | |||||
Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL)
The data described below reflect exposure to this product in a single-arm, open clinical trial (PCYC-1102-CA) and three randomized, controlled clinical trials (PCYC-1112-CA, PCYC-1115-CA, and CLL-3001) in patients with CLL or SLL (total cases = 1278, of which 668 patients were treated with this product). PCYC-1102-CA included 51 patients with previously treated CLL/SLL, PCYC-1112-CA included 391 patients with previously treated CLL or SLL randomized to ibrutinib or Ofamuxumab monotherapy, and PCYC-1115-CA included 269 patients aged 65 years or older randomized to ibrutinib or azacitidine phenybutyrate monotherapy with CLL or SLL primary patients, and CLL-3001 included 578 previously treated patients with CLL or SLL randomized to receive ibrutinib in combination with bendamustine and rituximab or placebo in combination with bendamustine and rituximab.
The most frequent adverse reactions (≥20%) in patients with CLL or SLL treated with this product in trials PCYC-1102-CA, PCYC-1112-CA, PCYC-1115-CA, and CLL-3001 were neutropenia, thrombocytopenia, anemia, diarrhea, skeletal muscle pain, nausea, rash, bruising, fatigue, fever, and bleeding. Between 4-10% of PCYC-1102-CA, PCYC-1112-CA, PCYC-1115-CA and CLL-3001 patients treated with this product discontinued due to adverse reactions, which included infectious pneumonia, bleeding, atrial fibrillation, rash and neutropenia (1% each). Approximately 6% of patients had a dose reduction due to adverse reactions.
TrialPCYC-1102-CA
The incidence of adverse reactions and abnormal laboratory tests in patients with previously treated CLL or SLL receiving 420 mg of this product daily as monotherapy in the CLL or SLL trial (N=51) with an incidence ≥ 10% (median treatment duration of 15.6 months) is shown in Tables 4 and 5.
Table4:≥ 10% CLL in trialPCYC-1102-CA strong>orSLL patients with non-hematologic adverse reactions (N=51)
| Body systems | Adverse effects | AllLevels (%) | 3levels or4levels (%< strong>) |
| Gastrointestinal Systemic Disorders | Diarrhea | 59 | 4 |
| Constipation | 22 | 2 | |
| disgusting | 20 | 2 | |
| 20 | 0 | ||
| Vomiting | 18 | 2 | |
| 14 | 0 | ||
| Indigestion | 12 | 0 | |
| Infections and Infectious Diseases | Upper respiratory tract infections | 47 | 2 |
| Sinusitis | 22 | 6 | |
| Skin infections | 16 | 6 | |
| Infectious pneumonia | 12 | 10 | |
| Urinary tract infections | 12 | 2 | |
| Systemic disease and various reactions at the site of administration |
Fatigue | 33 | 6 |
| 24 | 2 | ||
| Peripheral edema | 22 | 0 | |
| Lack of energy | 14 | 6 | |
| Chills | 12 | 0 | |
| Bruising | 51 | 2 | |
| Rash | 25 | 0 | |
| Bruised spots | 16 | 0 | |
| Respiratory, thoracic and mediastinal disease | Cough | 22 | 0 |
| Oropharyngeal pain | 14 | 0 | |
| Difficulty breathing | 12 | 0 | |
| Various musculoskeletal and connective tissue disorders | Skeletal muscle pain | 25 | 6 |
| Joint pain | 24 | 0 | |
| Muscle spasms | 18 | 2 | |
| Dizziness | 20 | 0 | |
| Headache | 18 | 2 | |
| Loss of appetite | 16 | 2 | |
| Benign, malignant and tumors of unknown nature | Secondary malignant tumors* | 12 * | 0 |
| Vascular and Lymphatic Vessel-like Diseases | Hypertension | 16 | 8 |
*1 patient died due to histiocytic sarcoma.
Table 5: *Hemoglobin, platelet, or neutropenia during treatment occurring in patients with CLL or SLL in trial PCYC-1102-CA (N = 51)
| Patients Percent Ratio (N = 51< ) | ||
| All levels (%) | 3levels or4levels (%< strong>) | |
| Thrombocytopenia | 69 | 12 |
| 53 | 26 | |
| hemoglobin reduction | 43 | 0 |
* Based on laboratory measurements (based on International Working Group on Chronic Lymphocytic Leukemia [IWCLL] criteria) and adverse effects.
Trial PCYC-1112-CA
Tables 6 and 7 describe adverse reactions and abnormal laboratory tests after treatment with this product in previously treated patients with CLL or SLL in trial PCYC-1112-CA, with a median exposure duration of 8.6 months for this product and 5.3 months for Ofamustab.
Table 6: Adverse reactions reported in ≥ 10% of patients in the treatment arm of this product in trial PCYC-1112-CA and at least 2% higher than in the control arm
| This product (N = 195) |
Ofamuximab (N = 191) |
|||
| All levels (%) | 3levels or4levels (%< strong>) | All levels (%) | 3levels or4levels (%< strong>) | |
| GastrointestinalSystemic Diseases | ||||
| Diarrhea | 48 | 4 | 18 | 2 |
| disgusting | 26 | 2 | 18 | 0 |
| Oral mucositis* | 17 | 1 | 6 | 1 |
| Constipation | 15 | 0 | 9 | 0 |
| Vomiting | 14 | 0 | 6 | 1 |
| Systemic disease and various reactions at the site of administration | ||||
| Fever | 24 | 2 | 15 | 1 |
| Infectious and Infectious Diseases | ||||
| Upper respiratory tract infections | 16 | 1 | 11 | 2 |
| Infectious pneumonia* | 15 | 10 | 13 | 9 |
| Sinusitis* | 11 | 1 | 6 | 0 |
| Urinary tract infection | 10 | 4 | 5 | 1 |
| Dermatologic and subcutaneous tissue disorders | ||||
| Rash* | 24 | 3 | 13 | 0 |
| Silting point | 14 | 0 | 1 | 0 |
| Bruising* | 12 | 0 | 1 | 0 |
| Various musculoskeletal and connective tissue disorders | ||||
| Skeletal Muscle Pain* | 28 | 2 | 18 | 1 |
| Joint pain | 17 | 1 | 7 | 0 |
| All types of neurological disorders | ||||
| Headaches | 14 | 1 | 6 | 0 |
| Dizziness | 11 | 0 | 5 | 0 |
| All types of injuries, poisonings and surgical complications | ||||
| Contusions | 11 | 0 | 3 | 0 |
| Ocular organ disease | ||||
| Blurred vision | 10 | 0 | 3 | 0 |
If subjects had multiple events under an ADR term, they were counted only once under that ADR term.
In this product group, body systems and individual ADR terms are listed in descending order of frequency.
*Multiple ADR terms are included.
Table 7: Occurrence of *hemoglobin, platelet, or neutropenia during treatment in trial PCYC-1112-CA
| This product (N = 195) |
Ofamuximab (N = 191) |
|||
| All levels (%) | 3levels or4levels (%< strong>) | All levels (%) | 3levels or4levels (%< strong>) | |
| Neutropenia | 51 | 23 | 57 | 26 |
| Thrombocytopenia | 52 | 5 | 45 | 10 |
| Decreased hemoglobin | 36 | 0 | 21 | 0 |
* Based on laboratory measurements (based on IWCLL standards)
Test PCYC-1115-CA
Table 8 below describes the adverse effects of treatment with this product in trial PCYC-1115-CA (median exposure duration of 17.4 months). The median duration of exposure for azelaic acid benzoate was 7.1 months.
Table8: The treatment group of this product in trialPCYC-1115-CA was ≥ 10% and at least 10%< strong>and at least 2% higher than the control groupPatient-reported adverse reactions
| Body systems Adverse effects |
This product (N = 135) |
Phenylbutyric acid nitrogen mustard (N = 132) |
||
| All levels (%) | 3levels or4levels (%< strong>) | All levels (%) | 3levels or4levels (%< strong>) | |
| GastrointestinalSystemic Diseases | ||||
| Diarrhea | 42 | 4 | 17 | 0 |
| Oral mucositis* | 14 | 1 | 4 | 1 |
| Various musculoskeletal and connective tissue disorders | ||||
| Skeletal Muscle Pain* | 36 | 4 | 20 | 0 |
| Joint pain | 16 | 1 | 7 | 1 |
| Muscle spasms | 11 | 0 | 5 | 0 |
| Ocular organ disease | ||||
| Dry eye | 17 | 0 | 5 | 0 |
| Tears increase | 13 | 0 | 6 | 0 |
| Blurred vision | 13 | 0 | 8 | 0 |
| Decreased visual acuity | 11 | 0 | 2 | 0 |
| Dermatologic and subcutaneous tissue disorders | ||||
| Rash* | 21 | 4 | 12 | 2 |
| Bruising* | 19 | 0 | 7 | 0 |
| Infectious and Infectious Diseases | ||||
| 15 | 2 | 3 | 1 | |
| Infectious pneumonia* | 14 | 8 | 7 | 4 |
| Urinary tract infection | 10 | 1 | 8 | 1 |
| Respiratory, thoracic and mediastinal disease | ||||
| Cough | 22 | 0 | 15 | 0 |
| Systemic disease and various reactions at the site of administration | ||||
| Peripheral edema | 19 | 1 | 9 | 0 |
| Fever | 17 | 0 | 14 | 2 |
| Vascular and Lymphatic Vascular Disorders | ||||
| Hypertension* | 14 | 4 | 1 | 0 |
| All types of neurological disorders | ||||
| Headaches | 12 | 1 | 10 | 2 |
If subjects had multiple events under an ADR term, they were counted only once under that ADR term.
In this product group, body systems and individual ADR terms are listed in descending order of frequency.
*Multiple ADR terms were included.
Trial CLL-3001
Table 9 describes the ADRs in patients with previously treated CLL or SLL in trial CLL-3001 who received this product in combination with bendamustine and rituximab or placebo in combination with bendamustine and rituximab, with a median duration of exposure of 14.7 months and 12.8 months in the product and placebo groups, respectively.
Table9: The treatment group of this product in trialCLL-3001 was ≥ 10% and at least 2% higher than the control group Patient-reported adverse reactions
| Body systems Adverse effects |
This product+BR (N = 287) |
Placebo +BR (N = 287) |
||
| All levels (%) |
3levels or 4levels (%) |
All levels (%) |
3levels or 4levels (%) |
|
| Diseases of the blood and lymphatic system | ||||
| 66 | 61 | 60 | 55 | |
| Thrombocytopenia | 34 | 16 | 26 | 16 |
| Dermatologic and subcutaneous tissue disorders | ||||
| 32 | 4 | 25 | 1 | |
| Bruising* | 20 | <1 | 8 | <1 |
| GastrointestinalSystemic Disorders | ||||
| 36 | 2 | 23 | 1 | |
| Abdominal pain | 12 | 1 | 8 | <1 |
| Various musculoskeletal and connective tissue disorders | ||||
| 29 | 2 | 20 | 0 | |
| Muscle spasms | 12 | <1 | 5 | 0 |
| Systemic disease and various reactions at the site of administration | ||||
| 25 | 4 | 22 | 2 | |
| Vascular and Lymphatic Vessel Disease | ||||
| 19 | 2 | 9 | 1 | |
| High blood pressure* | 11 | 5 | 5 | 2 |
| Infectious and Infectious Diseases | ||||
| 13 | 2 | 10 | 3 | |
| skin infection* | 10 | 3 | 6 | 2 |
| Metabolic and nutritional disorders | ||||
| 10 | 2 | 6 | 0 | |
BR: bendamustine and rituximab
Body systems and individual ADR terms in this treatment group are listed in descending order of frequency.
*Multiple ADR terms were included.
For frequencies greater than 0 and less than 0.5% use <1 to indicate.
Various grades of atrial fibrillation occurred in 7% and 2% of patients treated with this product in combination with bendamustine and rituximab or placebo in combination with bendamustine and rituximab, respectively, with the incidence of grade 3 and 4 atrial fibrillation being 3% and 1%, respectively.
Other important adverse reactions
Diarrhea
The incidence of diarrhea (any grade) in patients treated with this product was 43% (range: 36-59%). Grade 2 and grade 3 diarrhea occurred in 9% (range: 3-14%) and 3% (range: 0-5%) of patients treated with this product, respectively. The median time to first occurrence of diarrhea (of any grade) was 10 days (range: 0-627 days), and the median time to first occurrence of grade 2 and 3 diarrhea was 39 days (range: 1-719 days) and 74 days (range: 3-627 days), respectively. At the time of analysis, 82% of patients who reported diarrhea were cured, 1% were partially improved, and 17% had not reported improvement. The median time from onset to recovery or improvement for diarrhea (any grade) was 5 days (range: 1-418 days), and was similar for grades 2 and 3 diarrhea. Less than 1% of patients discontinued treatment with this product because of diarrhea.
Visual disturbances
Blurred vision and reduced visual acuity occurred in approximately 10% of patients treated with this product (any grade; grade 1 9%, grade 2 2%). The median time to the first of these events was 85 days (range: 1-414 days). As of the time of analysis, 61% of patients with visual impairment had healed and 38% had not reported improvement. The median time from event to healing or improvement was 29 days (range: 1-335 days).
Clinical Study Experience in Chinese Patients
A randomized, multicenter, open, phase III study comparing this product with rituximab (PCI-32765CLL3002) was conducted in 160 previously treated patients with CLL or SLL (including 36 patients with 17p-deficient CLL). Patients were randomly assigned to receive either this product or rituximab in a 2:1 ratio, with 82% of patients enrolled in China.
Adverse reactions and laboratory abnormalities described in Tables 10 and 11 below reflect safety data from 128 Chinese patients in study PCI-32765CLL3002 with a median duration of dosing of 12.6 and 4.6 months for this product and rituximab, respectively.
Table10: Trial PCI-32765CLL3002 in the treatment arm of this product ≥10%and at least 5% higher than the control group of Chinese subjects reported adverse reactions
| This product | Rituximab | ||||
| (N = 86) | (N = 42) | ||||
| All levels | Level 3 orLevel 4 | All Levels | Level 3 orLevel 4 | ||
| (%) | (%) | (%) | (%) | ||
| 25 (29.1) | 2 (2.3) | 3 (7.1) | 0 | ||
| 14 (16.3) | 1 (1.2) | 1 (2.4) | 0 | ||
| 22 (25.6) | 17 (19.8) | 7 (16.7) | 4 (9.5) | ||
| Upper respiratory tract infection | 20 (23.3) | 6 (7.0) | 4 (9.5) | 1 (2.4) | |
| 20 (23.3) | 1 (1.2) | 4 (9.5) | 0 | ||
| 19 (22.1) | 1 (1.2) | 2 (4.8) | 0 | ||
| 15 (17.4) | 5 (5.8) | 1 (2.4) | 0 | ||
| 12 (14.0) | 12 (14.0) | 0 | 0 | ||
| Systemic disease and various reactions at the site of administration | |||||
| 13 (15.1) | 0 | 3 (7.1) | 0 | ||
| 13 (15.1) | 0 | 0 | 0 | ||
| All types of checks | |||||
| 10 (11.6) | 8 (9.3) | 0 | 0 | ||
| Elevated blood lactate dehydrogenase | 9 (10.5) | 2 (2.3) | 1 (2.4) | 0 | |
| 9 (10.5) | 0 | 0 | 0 | ||
| If subjects had multiple events under a given ADR term, they were counted only once under that ADR term. In this product group, body systems and individual ADR terms are listed in descending order of frequency. *Multiple ADR terms were included. |
|||||
Table11: Trial PCI-32765CLL3002 in Chinese subjects during *hemoglobin, platelet, or neutropenia during treatment
| This product(N=86) | Rituximab(N=42) | |||
| All levels (%) | 3levels or4levels (%< strong>) | All levels (%) | 3levels or4levels (%< strong>) | |
| Neutropenia | 62.8 | 37.2 | 54.8 | 33.3 |
| Thrombocytopenia | 65.1 | 15.1 | 45.2 | 9.5 |
| Decreased hemoglobin | 46.5 | 1.2 | 26.2 | 0 |
* Based on laboratory measurements (based on IWCLL standards).
Postmarketing Experience
The following adverse reactions were identified during post-approval dosing of this product. Given that this adverse reaction originated from a spontaneous report and the size of the reporting population is unknown, it is not possible to reliably estimate its frequency or to determine the causal relationship between the adverse reaction and drug exposure.
Hepatobiliary system disorders: hepatic failure (includes multiple terms)
Respiratory system disorders: interstitial lung disease (including events with fatal outcomes) (includes multiple terms)
Metabolic and nutritional disorders: tumor lysis syndrome (see [Caution])
Immune system disorders: tachyphylaxis, angioedema, urticaria
Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome (SJS), brittle nail
[Contraindications]
This product is contraindicated in patients who have been hypersensitized to ibrutinib or excipients (e.g., tachyphylaxis and tachyphylaxis-like reactions).
[Precautions]
Bleeding
Fatal bleeding events have occurred in patients treated with this product. Up to 6% of patients have had ≥ grade 3 bleeding events (intracranial hemorrhage [including subdural hematoma], gastrointestinal hemorrhage, hematuria, and postoperative hemorrhage). Bleeding events of various grades, including bruising and bruising, occurred in approximately half of the patients treated with this product.
The mechanisms of bleeding events are not fully understood.
This product may increase the risk of bleeding in patients receiving antiplatelet or anticoagulant therapy, and patients should be monitored for signs of bleeding. Phase 2 and 3 studies of this product excluded patients who required treatment with warfarin or other vitamin K antagonists. Warfarin or other vitamin K antagonists should not be used in combination with this product. Avoid supplements, such as fish oil and vitamin E preparations, if possible. In an in vitro platelet function study, inhibition of collagen-induced platelet aggregation by ibrutinib was observed.
Depending on the type of surgery and bleeding risk, this product should be withheld for at least 3-7 days pre- and post-operatively (see [Clinical Trials]).
Infection
Fatal and non-fatal infections have occurred with treatment with this product. 14-29% of patients developed ≥ grade 3 infections (see [Adverse Reactions]). Prophylaxis based on standard therapy should be considered for patients at increased risk for opportunistic infections. Progressive multifocal leukoencephalopathy (PML) and Pneumocystis carinii pneumonia (PJP) have occurred in patients treated with this product. Assess the patient for fever and infection and treat appropriately.
Hemocytopenia
Patients receiving monotherapy with this product have experienced grade 3 or 4 hematocrit reduction during treatment, including neutropenia (range: 13-29%), thrombocytopenia (range: 5-17%), and anemia (range: 0-13%), based on laboratory testing.
Monitor a complete blood count once a month.
Interstitial Lung Disease
Interstitial lung disease has been reported in patients treated with this product. Monitor patients for pulmonary symptoms suggestive of interstitial lung disease. If symptoms occur, suspend treatment with this product for appropriate treatment of interstitial lung disease. If symptoms persist, consider the risk of benefit from treatment with this product and make appropriate dose adjustments.
Cardiac Arrhythmias
Atrial fibrillation, atrial flutter, and ventricular tachycardia have been reported in clinical trials and postmarketing observations with ibrutinib (0.7%), particularly in patients with cardiac risk factors, hypertension, acute infection, and a prior history of atrial fibrillation. Cases with ventricular tachycardia adverse events had confounding factors that may have contributed to the event, such as a history of cardiac disease, combined medications, or other risk factors. There is no positive evidence that ibrutinib may cause sudden unexplained death. All patients should be monitored clinically for the occurrence of arrhythmias on a regular basis. Patients presenting with symptoms of arrhythmia or new onset of dyspnea, dizziness, or syncope should be evaluated clinically and an electrocardiogram (ECG) should be performed as indicated.
Patients presenting with signs and/or symptoms of ventricular tachycardia should have this product suspended and a full clinical benefit/risk assessment should be performed before possible restart of therapy.
Patients with pre-existing atrial fibrillation requiring anticoagulation should be considered for treatment with CLL other than this product. Patients who develop atrial fibrillation during treatment with this product should be fully assessed for risk of thromboembolic disease. Anticoagulant therapy under strict monitoring should be considered for patients assessed as being at high risk and not suitable for treatment other than this product.
White Blood Cell Stasis
Isolated cases of leukocyte stasis have been reported in patients treated with this product. High circulating lymphocyte counts (>400,000/mcL) may increase the risk. Consider withholding this product. Patients should be monitored closely. Give supportive therapy including hydration and/or leukocyte debridement depending on clinical presentation.
Hypertension
Patients treated with this product had hypertension (range: 6-17%) with a median time to onset of 4.6 months (range: 0.03-22 months). Monitor patients for new-onset hypertension or hypertension that is not adequately controlled after initiation of this product. Adjust existing antihypertensive medication and/or initiate antihypertensive therapy as appropriate.
Secondary malignancy
Patients treated with this product have had other malignancies (range: 3-16%), including non-skin cancers (range: 1-4%). The most common secondary malignancy was non-melanoma skin cancer (range: 2-13%). According to the pooled analysis of randomized controlled phase 3 clinical trials (PCYC-1112-CA, PCYC-1115-CA, CLL-3001 and MCL-3001), the incidence of non-melanoma skin cancer was 6% in the treatment arm of the product and 3% in the control arm.
Tumor lysis syndrome
A small number of tumor lysis syndromes have been reported with treatment with this product. Baseline risk (e.g., high tumor load) should be assessed and appropriate precautions taken. Monitor patients closely and treat appropriately.
Hepatitis B virus reactivation
Cases of hepatitis B reactivation were reported in clinical trials and post-marketing observations of ibrutinib. The occurrence of hepatitis B virus reactivation was occasional (0.2%) in company-sponsored clinical trials. In these clinical trials, patients with active hepatitis B were excluded. Therefore, the effect of ibrutinib on hepatitis B virus reactivation is uncertain at this time. Hepatitis B virus (HBV) status should be determined prior to initiating treatment with this product. If a patient tests positive for HBV infection, consultation with a physician with expertise in the field of hepatitis B treatment is recommended. If the patient has a positive serologic test result for hepatitis B, a hepatologist should be consulted prior to initiating treatment and the patient’s condition should be monitored and controlled according to local medical standards to prevent recurrence of hepatitis B.
Effects on the ability to drive and operate machinery
Fatigue, dizziness, and malaise have been reported in some patients using this product and should be considered when assessing a patient’s ability to drive or operate machinery.
Keep out of the reach of children.
[For Pregnant and Lactating Women]
Pregnancy andEmbryonic–Fetal Toxicity
The results of studies in animal testing indicate that this product, as a kinase inhibitor, can cause fetal harm. In animal reproduction studies, pregnant rats and rabbits received ibrutinib administration during the organogenesis phase, causing embryo-fetal toxicity, including malformations, when exposure reached 2-20 times the clinical dose (420-560 mg daily). Female patients are advised to avoid pregnancy while taking this product and for 1 month after termination of therapy. If this product is used during pregnancy or if the patient becomes pregnant while taking this product, the patient should be informed of the potential hazards to the fetus (see [DOSAGE AND ADMINISTRATION] for use in special populations).
Background risk estimates for major birth defects and miscarriage in the indicated population are not known.
Lactation
There is no information regarding whether ibrutinib and its metabolites are secreted through human milk and whether they may have an effect on breastfed infants or lactation.
Because many drugs can be secreted into breast milk and because this product may cause serious adverse reactions in nursing infants, breastfeeding should be discontinued during treatment with this product.
[Pediatric Use]
The safety and efficacy of this product in pediatric patients have not been established.
[For use in the elderly]
A total of 905 patients were enrolled in clinical studies of this product, 62% of whom were ≥65 years of age and 21% of whom were ≥75 years of age. No differences in efficacy were observed overall between older patients and younger patients. Anemia (all grades) and grade ≥3 infectious pneumonia occurred more frequently in older patients treated with this product.
[Drug Interactions]
CYP3A inhibitor
Ibrutinib is primarily metabolized by the cytochrome P450 3A (CYP3A) enzyme.
In healthy subjects, the Cmax and AUC of ibrutinib were elevated 29-fold and 24-fold, respectively, when coadministered with the potent CYP3A inhibitor ketoconazole. The highest dose of ibrutinib in the clinical trial was 12.5 mg/kg (actual dose 840 – 1400 mg) administered for 28 days. The AUC for a single dose was 1445 ± 869 ng ⋅ hr/mL, which was approximately 50% higher than the steady-state AUC at the highest indicated dose (560 mg).
Avoid combining this product with potent or moderately potent inhibitors of CYP3A. For short-term use of potent CYP3A inhibitors (e.g., antifungals and antibiotics [e.g., ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin] given for 7 days or less), consider interrupting treatment with this product during the use of the inhibitor. Avoid combination use of potent CYP3A inhibitors that require long-term dosing. If an intermediate-acting CYP3A inhibitor must be used, reduce the dose of this product to 140 mg for the duration of the inhibitor. signs of toxicity should be monitored more closely when combining with a potent or intermediate-acting CYP3A4 inhibitor (see [DOSAGE]). No dose adjustment is required when combined with mild inhibitors.
Avoid consumption of grapefruit and Seville oranges, which contain components of intermediate-acting CYP3A inhibitors, during treatment with this product (see [Dosage] and [Pharmacokinetics]).
CYP3A Inducer
The Cmax and AUC values of ibrutinib were reduced approximately 13-fold and 10-fold, respectively, when this product was administered concomitantly with the potent CYP3A inducer rifampin.
Avoid coadministration with potent CYP3A-inducing agents (e.g., carbamazepine, rifampin, phenytoin, and onychomycin). Consider alternative drugs that are less CYP3A-inducing (see [Pharmacokinetics]).
Drugs that may alter plasma concentrations due to ibrutinib
To minimize the potential for interactions in the gastrointestinal tract, P-gp or BCRP substrates with narrow therapeutic indices (eg, digoxin or methotrexate) should not be used for at least 6 hours before or after administration of this product. Ibrutinib may also systemically inhibit BCRP and increase exposure to BCRP-mediated hepatic efflux of metabolized drugs, such as resupristatin.
[Drug overdose]
There is no specific experience in the management of ibrutinib overdose. 1 healthy subject developed reversible grade 4 liver enzyme elevations (AST and ALT) after administration of 1680 mg of this product. Patients who have taken more than the recommended dose of this product are monitored closely and given appropriate supportive therapy.
[Clinical Trials]
Sleeve Cell Lymphoma
Trial PCYC-1104-CA
The safety and efficacy of this product was evaluated in an open, multicenter, single-arm trial (PCYC-1104-CA) treating 111 patients with MCL treated with at least one prior therapy. The median age of the patients was 68 years (range: 40-84 years), 77% were male, and 92% were Caucasian. At baseline, 89% of patients had a baseline ECOG physical status score of 0 or 1. The median time since diagnosis was 42 months, and the median number of prior treatments was 3 (range: 1-5 treatments), with 11% of patients having received prior stem cell transplantation. At baseline, 39% of patients had at least one tumor ≥ 5 cm, 49% had bone marrow infiltration, and 54% had extra-nodal infiltration at screening.
Patients received 560 mg of this product orally once daily until disease progression or intolerable toxicity occurred. Tumor remission was assessed according to the revised International Working Group (IWG) criteria for non-Hodgkin’s lymphoma (NHL). The primary endpoint in this study was the investigator-assessed overall remission rate (ORR). The remissions after administration of this product are shown in Table 12.
Table 12: Overall remission rate (ORR) and duration of remission (DOR) in patients with MCL as assessed by the investigators
| Total(N=111) | |
| Overall remission rate (%) | 65.8 |
| 95% Confidence Interval (%) | (56.2, 74.5) |
| 17.1 | |
| Partial remission (%) | 48.6 |
| 17.5 (15.8, not met) |
The imaging scans were independently reviewed and interpreted by an independent review committee (IRC).The IRC review showed an ORR of 69%.
The median time to remission was 1.9 months.
Lymphocytosis
In the MCL study, 33% of patients had a temporary increase in lymphocyte count (ie, ≥ 50% from baseline and above an absolute lymphocyte count of 5000/mcL) after initiation of this product. Patients experienced lymphocytosis only in the first few weeks of treatment with this product, and the median time to regression was 8 weeks.
TrialMCL-3001
A randomized, phase III, open, multicenter clinical trial, MCL-3001, evaluated the safety and efficacy of this product in patients with MCL who had received at least one prior therapy, enrolling 280 subjects. Subjects were randomized in a 1:1 ratio to receive either 560 mg orally once daily for 21 days or Temsirolimus 175 mg intravenously on days 1, 8, and 15 of cycle 1, followed by 75 mg intravenously on days 1, 8, and 15 of each 21-day cycle. Treatment continued in both groups until disease progression or intolerable toxicity developed. The median age was 68 years (range: 34-88), of which 74% were male and 87% were Caucasian. The median time since diagnosis was 43 months, and the median number of prior treatments was 2 (range: 1-9), including 51% prior high-dose chemotherapy, 18% prior bortezomib, 5% prior lenalidomide, and 24% prior stem cell transplantation. At baseline, 53% of subjects presented with large tumors (≥5 cm), 21% had a simplified MIPI score of high risk, and at screening, 60% had extralymph node disease and 54% had bone marrow infiltration.
Progression-free survival (PFS) was assessed by the IRC according to the revised International Working Group (IWG) criteria for non-Hodgkin’s lymphoma (NHL). The efficacy results of study MCL3001 are shown in Table 13, and the Kaplan-Meier curve for PFS is shown in Figure 1.
| Table13: Efficacy results in relapsed or refractoryMCL subjects (trialMCL3001) | |||
| Endpoints | This product N = 139 |
Temsirolimus N = 141 |
|
| Progression-free survivala | |||
| Median Progression-Free Survival (95% CI) (months) | 14.6 (10.4, NE) | 6.2 (4.2, 7.9) | |
| HR = 0.43 [95% CI:0.32, 0.58] | |||
| 71.9 | 40.4 | ||
| p-value | p <0.0001 | ||
Only a small proportion of subjects treated with this product experienced clinically meaningful worsening of lymphoma symptoms compared to temsirolimus (27% vs 52%), and this product was slower to worsen symptoms compared to temsirolimus (HR 0.27, p<0.0001).
Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL)
One uncontrolled trial and three randomized, controlled trials confirmed the safety and efficacy of this product in treating patients with CLL/SLL.
TrialPCYC-1102-CA
An open, multicenter trial was conducted in 48 patients with treated CLL. The median age of the patients was 67 years (range: 37-82 years), of whom 71% were male and 94% were Caucasian. All patients had a baseline ECOG physical status score of 0 or 1. The median time since diagnosis was 80 months, and the median number of prior treatments was 4 (range: 1-12). At baseline, 46% of patients had at least one tumor ≥5 cm.
420 mg of this product was administered orally once daily until disease progression or intolerable toxicity occurred. The ORR and DOR were assessed by an independent review committee according to the revised IWG CLL criteria. 58.3% (95% CI: 43.2%, 72.4%) ORR was achieved, both in partial remission. No patients achieved complete remission. the range of DOR was 5.6-24.2+ months. Median DOR was not achieved.
TrialPCYC-1112-CA
A randomized, multicenter, open phase III trial of this product versus ovalbumin control was conducted in patients with treated CLL or SLL. Patients (n = 391) were randomized in a 1:1 ratio to two groups, one of which was given this product at a daily dose of 420 mg until disease progression or intolerance to toxicity, and the other group was given offalumab at an initial dose of 300 mg, followed by a weekly dose of 2000 mg for 7 doses after 1 week of administration, followed by 4 doses every 4 weeks for a total of 4 doses. 57 patients randomly assigned to the The patients in the Ofamustab group crossed over to receive this product after disease progression. The median age of the patients was 67 years (range: 30-88 years), of whom 68% were male and 90% were Caucasian. All patients had a baseline ECOG physical status score of 0 or 1. 373 patients with CLL and 18 patients with SLL were enrolled in the trial. The median time since diagnosis was 91 months and the median number of prior treatments was 2 (range: 1-13). At baseline, 58% of patients had at least one tumor ≥ 5 cm. 32% of patients had 17p deletion.
The efficacy results of trial PCYC-1112-CA are shown in Table 14, and the Kaplan-Meier curves for PFS and OS as assessed by the Independent Review Committee (IRC) according to the IWCLL criteria are shown in Figures 2 and 3, respectively.
Table 14: Efficacy results of the trial PCYC-1112-CA
| This product group N=195 |
OfamuximabGroup N = 196 |
|
| Progression-free survivalperiodb | ||
| Number of events (%) | 35 (17.9) | 111 (56.6) |
| 26 | 93 | |
| 9 | 18 | |
| Not met | 8.1 (7.2, 8.3) | |
| Risk ratio (95% confidence interval) | 0.22 (0.15, 0.32) | |
| Deaths (%) | 16 (8.2) | 33 (16.8) |
| Risk ratio (95% confidence interval) | 0.43 (0.24, 0.79) | |
| 42.6% | 4.1% | |
a Neither group reached median OS
b as assessed by IRC. All patients achieved partial remission; no patients have yet achieved complete remission.
Figure2:Progression-free survival in the trialPCYC-1112-CA Progression-free survival< strong>period(ITTpopulation) of theKaplan-Meier Curve
| Month |
| Ofamuximab |
| Ibrutinib capsules |
Figure3: Overall survival in the trialPCYC-1112-CA (ITT< strong>population)Kaplan-Meier curves
| Month |
| Ofamuximab |
| Ibrutinib capsules |
TrialPCYC-1112-CAwith17pDeficientCLL/SLL >
The trial PCYC-1112-CA enrolled 127 patients with CLL/SLL with 17p deletion. The median age of the patients was 67 years (range: 30-84 years), of whom 62% were male and 88% were Caucasian. All patients had a baseline ECOG physical status score of 0 or 1. PFS and ORR were assessed by IRC.17 The outcome of patients with CLL/SLL with p deletion is shown in Table 15.
Table15: TrialPCYC-1112-CA in17p strong>DeficientCLL/SLL patient outcomes
| This product group N=63 |
OfamuximabGroup N = 64 |
|
| Progression-free survival period | ||
| Number of events (%) | 16 (25.4) | 38 (59.4) |
| Disease progression | 12 | 31 |
| Fatalities | 4 | 7 |
| Not met | 5.8 (5.3, 7.9) | |
| 0.25 (0.14, 0.45) | ||
| 47.6% | 4.7% | |
a Assessed by IRC. All patients achieved partial remission; no patients have yet achieved complete remission.
A randomized, multicenter, double-blind phase 3 study of this product in combination with bendamustine and rituximab (BR) versus placebo in combination with BR was conducted in patients with previously treated CLL/SLL. Patients (n = 578) were randomized in a 1:1 ratio to receive either this product (420 mg per day) or placebo in combination with BR until disease progression, or unacceptable toxicity developed. All patients received BR for a maximum of 6 cycles (28 days per cycle). Bendamustine was administered as a 70 mg / m2 dose by intravenous infusion over 30 minutes on days 2 and 3 for cycle 1 and days 1 and 2 for cycles 2 – 6. Rituximab was administered at a dose of 375 mg/m2 on day 1 of the first cycle and at a dose of 500 mg / m2 on day 1 of the 2nd through 6th cycles.
The median age of the patients was 64 years (range: 31 – 86 years), 66% were male, and 91% were white. All patients had a baseline ECOG physical status score of 0 or 1. The median time since diagnosis was 5.9 years, and the median number of treatments before treatment was 2 (range: 1 – 11). At baseline, 56% of patients had at least one tumor > 5 cm and 26% had an 11q deletion.
The efficacy results of the trial CLL-3001 are shown in Table 16. kaplan meier curves for PFS are shown in Figure 4.
Table16: Efficacy results of trialCLL-3001
| Endpoints | This product+BRGroup N=289 |
Placebo+BRGroup N=289 |
| Progression-free survivala | ||
| Number of events (%) | 56 (19.4) | 183 (63.3) |
| Median (95% CI) | Not reached | 13.3 (11.3, 13.9) |
| 0.20 (0.15, 0.28) | ||
| 82.7% | 67.8% | |
a Complete remission was achieved in 24 subjects (8.3%) in the Benzedrine + BR group and in 6 subjects (2.1%) in the placebo + BR group as assessed by IRC.
BR = bendamustine versus rituximab; CI = confidence interval; HR = hazard ratio.
Figure4: Progression-free survival in the trialCLL-3001 (ITT< strong>population)Kaplan-Meier curves
Lymphocytosis
In the CLL study, 66% of patients on this product experienced elevated lymphocyte counts (i.e., ≥ 50% increase from baseline and above an absolute lymphocyte count of 5,000/mcL). Lymphocytosis occurred only within the first month of treatment, with a median regression time of 14 weeks (range: 0.1-104 weeks). When this product was administered in combination with chemotherapy, the incidence of lymphocytosis was 7% and 6% for this product in combination with bendamustine and rituximab versus placebo in combination with bendamustine and rituximab, respectively.
Asia Pacific Clinical StudyPCI-32765CLL3002
A randomized, multicenter, open, phase III study comparing this product with rituximab in patients with previously treated CLL or SLL. Patients (N = 160) were randomly assigned in a 2:1 ratio to receive either this product (420 mg once daily until disease progression or development of intolerable toxicity) or rituximab (starting dose of 375 mg/m2, with dose adjustment to 500 mg/m2 after 1 week of dosing and 3 doses every 2 weeks, followed by 4 doses every 4 weeks (1 dose was administered 4 times). Sixteen patients (30%) in the rituximab group crossed over to receive this product after disease progression. The median age was 66 years (range: 21-87 years), 71% were male, and 85% were Chinese patients. All patients had a baseline ECOG physical status score of 0 or 1. A total of 151 patients with CLL and 9 patients with SLL were enrolled in the trial. The median time since diagnosis was 41 months, and the median number of prior treatments was 2 (range: 1-14). At baseline, 43.8% of patients had at least 1 tumor ≥5 cm. 22.5% of patients (36 patients, including 26 Chinese patients) had 17p deletion.
The investigators evaluated progression-free survival (PFS) according to IWCLL criteria and showed an approximately 80% reduction in the risk of death or progression. Despite crossover treatment, overall survival (OS) analysis showed a trend toward superiority in the native group (hazard ratio [HR] = 0.45). See Table 17 for the efficacy results of this study.
Table17:Efficacy Results in PCI32765CLL3002
| Endpoints | This product N = 106 |
Rituximab N = 54 |
| 20 (18.9) | 28 (51.9) | |
| Risk Ratio (95% Confidence Interval) | 0.197 (0.107, 0.364) | |
| 12 (11.3) | 9 (16.7) | |
| HR (95% confidence interval) | 0.453 (0.183, 1.124) | |
| 45.3% | 5.6% | |
| Overall remission rate (including partial remission with lymphocytosis) | 56.6% | 5.6% |
PFS results showed prolonged PFS in all subgroup analyses (including age, sex, Rai stage at screening, purine therapy resistance, 17p deletion, baseline ECOG score, number of prior lines of therapy, and 11q deletion) consistent with the overall population analysis: the ibrutinib-treated group had prolonged PFS compared with the rituximab group.
[Pharmacology and Toxicology]
Pharmacological effects
Ibrutinib is a small molecule BTK (Bruton tyrosine kinase) inhibitor. Ibrutinib inhibits the enzymatic activity of BTK by forming covalent bonds with cysteine residues at the active site of BTK, a signaling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways.BTK is an essential pathway for B-cell migration, chemotaxis, and adhesion through the signaling pathway activated by B-cell surface receptors. Results from non-clinical studies have shown that ibrutinib inhibits malignant B-cell proliferation and survival in vivo and cell migration and basal adhesion in vitro.
In patients with recurrent B-cell lymphoma, binding of the BTK active site in peripheral blood monocytes was above 90% within 24 hours of administration of ibrutinib at doses above 2.5 mg/kg/day (≥175 mg/day at a mean body weight of 70 kg or more).
In healthy subjects, given at 3 times the maximum recommended dose (1680 mg), ibrutinib did not cause clinically relevant QT prolongation.
Toxicology Studies
Carcinogenicity studies with ibrutinib have not been performed.
Genotoxicity
The results of the ibrutinib Ames test, the CHO cell chromosome aberration test, and the mouse bone marrow micronucleus test (at doses up to 2000 mg/kg) were negative.
Reproductive toxicity
Ibrutinib (100 mg/kg/day) was administered orally for 4 consecutive weeks before and during mating in male rats and for 2 consecutive weeks before and during mating in female rats, and was administered to the end of the test in males and to day 7 of conception (GD7) in females, showing no effect on male and The results showed no effect on fertility or reproductive capacity in male and female rats at doses up to 100 mg/kg (equivalent to 16 mg/kg in humans).
Oral administration of ibrutinib (10, 40, and 80 mg/kg/day) to pregnant rats during fetal organogenesis showed that ibrutinib (80 mg/kg/day) caused cardiac and major vascular malformations and increased embryonic resorption and post-arrival loss in rats. The exposure of ibrutinib (80 mg/kg/day) in rats was approximately 14 times greater than the in vivo exposure of patients with mantle cell lymphoma (MCL) at a dose of 560 mg/day and 20 times greater than the in vivo exposure of patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) or patients with Warf’s macroglobulinemia (WM) at a dose of 420 mg/day. Ibrutinib (40 mg/kg/day and higher doses) caused weight loss in rat fetal litters. The exposure of ibrutinib (40 mg/kg/day) in rats was approximately 6 times greater than the in vivo exposure of patients with mantle cell lymphoma (MCL) at a dose of 560 mg/day. Ibrutinib (5, 15, 45 mg/kg/day) was administered orally to pregnant rabbits during the organogenesis period of the fetal litter. Ibrutinib (15 mg/kg/day and above) caused sternal fusion in rabbit fetuses. Ibrutinib (45mg/kg/day) caused an increased rate of embryonic resorption and post-implantation loss in rabbits. The exposure of ibrutinib (15 mg/kg/day) in rabbits was approximately 2 times the in vivo exposure of patients with mantle cell lymphoma (MCL) at a dose of 560 mg/day and 2.8 times the in vivo exposure of patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) or patients with Warf’s macroglobulinemia (WM) at a dose of 420 mg/day. [Pharmacokinetics]
Absorption
The median Tmax for oral absorption of ibrutinib is 1-2 hours. Exposure increases as the dose is increased to 840 mg. The steady-state AUC (mean ± standard deviation) was 953 ± 705 ng⋅h/mL for patients administered at 560 mg and 680 ± 517 ng⋅h/mL for patients administered at 420 mg. The absolute bioavailability of oral absorption was 2.9% (90% CI=2.1- 3.9) for patients in the fasted state (n=8) and 3.9 for patients in the fed state. 3.9), doubling the absorption in the fed state. The maximum blood concentration (Cmax) of ibrutinib was increased by approximately 2-4-fold and the AUC value was increased by approximately 2-fold when administered with food compared with that given after an overnight fast.
Distribution
The reversible binding of ibrutinib to human plasma proteins in vitro was 97.3%, with no concentration dependence in the range of 50-1000 ng/mL. The volume of distribution (Vd) was 683 L, and the steady-state apparent volume of distribution (Vd,ss/F) was approximately 10,000 L.
Metabolism
Metabolism is the primary pathway of ibrutinib elimination. Ibrutinib is metabolized primarily by cytochrome P450 CYP3A to a variety of metabolites, with a small portion metabolized by CYP2D6. The active metabolite, PCI-45227, is a dihydrodiol compound with approximately 1/15 the inhibitory activity of ibrutinib against BTK. The ratio of the major metabolite, PCI-45227, to the prototype drug at steady state ranges from 1-2.8.
Elimination
Intravenous clearance was 62 L/h and 76 L/h in the fasted and fed states, respectively. apparent oral clearance was approximately 2000 L/h and 1000 L/h in the fasted and fed states, respectively, which is consistent with a higher first-pass effect. The drug half-life of ibrutinib is 4-6 hours.
Ibrutinib (mostly in the form of metabolites) is mainly eliminated via feces. Following a single oral dose of radiolabeled [14C]-ibutinib in healthy subjects, approximately 90% of the radioactive dose was excreted within 168 hours, with the majority (80%) excreted in the feces and less than 10% excreted in the urine. Prototype ibrutinib in the feces accounts for about 1% of the radiolabeled excretion, and there is no prototype ibrutinib in the urine; the rest is metabolites.
Age.
In older patients (67-81 years), expected ibrutinib exposure was 14% higher. No dose adjustment based on age is required.
Gender
Gender had no effect on the systemic clearance of ibrutinib.
Race
The pharmacokinetic properties of 20 Chinese subjects with relapsed or refractory CLL or SLL in the Asia-Pacific study PCI-32765CLL3002 were evaluated. The exposure parameters for this product in Chinese subjects were within the range of other populations compared to other populations.
Renal damage
Ibrutinib is not primarily cleared by the kidneys; metabolite excretion via urine is less than 10% of the dose. Creatinine clearance (CrCL)> 25 mL/min had no effect on exposure to this product. No data are available on patients with severe renal impairment (CrCL < 25 mL/min) or on dialysis patients.
Liver injury
Ibrutinib is metabolized in the liver. In the liver injury trial, non-cancerous subjects received 140 mg of this product as a single dose. Patients with mild (n=6), moderate (n=10), and severe (n=8) liver injury received a 2.7-fold, 8.2-fold, and 9.8-fold increase in AUC values after receiving this product compared with subjects with normal liver function, respectively. Compared with subjects with normal liver function, Cmax increased 5.2-fold, 8.8-fold, and 7.0-fold in patients with mild, moderate, and severe liver injury, respectively, after receiving this product (see [DOSAGE AND ADMINISTRATION] for special population dosing).