Approval Date.
Cetapenem tablets instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name]
Generic Name: Cetapenemide Tablets
Trade name: Epidaza® (Epidaza®)
English name: Chidamide Tablets
Hanyu Pinyin: Xidaben’an Pian
Ingredients
The main ingredient of this product is Chidaben’an Pian.
Chemical name: N-(2-amino-4-fluorophenyl)-4-[N-[(E)-3-(3-pyridyl)acryloyl]aminomethyl]benzamide
Chemical structure formula.
Molecular formula: C22H19FN4O2
Molecular weight: 390.42
Properties
This product is an off-white tablet.
Indications】
Cetapenemide tablets are indicated for patients with relapsed or refractory peripheral T-cell lymphoma (PTCL) who have received at least one prior systemic chemotherapy. This indication was granted conditional approval based on objective remission rate results from a single-arm clinical trial. Benefit in terms of long-term survival following administration of this product has not been demonstrated and confirmatory clinical trials in a randomized controlled design are ongoing.
Specification
5mg
Dosage]
This product should be used under the supervision of an experienced physician.
Medication Information
Cetapenem tablets are for oral use and the recommended dose for adults is 30 mg (6 tablets) twice a week, with no less than 3 days between doses (e.g., Monday and Thursday, Tuesday and Friday, Wednesday and Saturday, etc.), taken 30 minutes after breakfast. Continued dosing is recommended if the disease has not progressed or if no intolerable adverse effects have occurred.
Monitoring and dose adjustment
Prior to the use of this product, routine blood tests should be performed and the relevant indicators should meet the following conditions before starting the drug: absolute neutrophil value ≥ 1.5×109/L, platelets ≥ 75×109/L, hemoglobin ≥ 9.0 g/dL. Regular blood tests (usually once a week) are required during the drug administration.
The physician should adjust the medication according to the adverse reactions during the course of administration, including suspension and symptomatic management, dose reduction or discontinuation of the treatment. The principles of dose adjustment for hematologic and non-hematologic adverse reactions are described below.
Management of hematologic adverse reactions and dose adjustment
Suspend the drug in case of grade 3 or 4 neutropenia (neutrophil count <1.0×109/L). If grade 3 neutropenia with temperature above 38.5°C or grade 4 neutropenia occurs, cytokine therapy such as G-CSF should be administered. Blood tests should be performed regularly (every other day or at least twice a week), and when the absolute neutrophil value is restored to ≥1.5×109/L and confirmed by two consecutive tests, treatment with this product may be continued: if the previous adverse reaction is grade 3, the original dose or the dose reduced to 20 mg/dose may be used when resuming the drug; if the previous adverse reaction is grade 4, the dose should be reduced to 20 mg/dose when resuming the drug.
In case of grade 3 or 4 thrombocytopenia (platelet count <50.0×109/L), suspend the drug and give interleukin 11 or thrombopoietin (TPO) treatment; if platelet count <25.0×109/L or bleeding tendency, consider giving component blood transfusion treatment. Regular blood tests (every other day or at least twice a week) should be performed, and when platelets recover to ≥75.0×109/L, and confirmed by two consecutive tests, treatment with this product can be continued: if the previous adverse reaction is grade 3, the original dose or the dose reduced to 20 mg/dose can be used when resuming the drug; if the previous adverse reaction is grade 4, the dose should be reduced to 20 mg/dose when resuming the drug.
Grade 3 or 4 anemia (hemoglobin decreased to <8.0 g/dL): suspend the drug and treat with erythropoietin (EPO); when hemoglobin <5.0 g/dL, component transfusion should be given. Blood tests should be performed regularly (every other day or at least twice a week), and when hemoglobin returns to ≥9.0 g/dL and is confirmed by two consecutive tests, treatment with this product can be continued: if the previous adverse reaction is grade 3, the original dose or the dose reduced to 20 mg/dose can be used when resuming the drug; if the previous adverse reaction is grade 4, the dose should be reduced to 20 mg/dose when resuming the drug.
After treatment and dose reduction for the above hematologic adverse reactions, if grade 4 hematologic adverse reactions or grade 3 neutropenia with a temperature above 38.5°C occur again, treatment with this product should be discontinued.
Management of non-hematological adverse reactions and dose adjustment
In case of grade 3 non-hematological adverse reactions, the drug should be suspended and symptomatic treatment should be given. The physician should conduct regular examination and monitoring of relevant items according to the specific adverse reactions. Cidabendiamide dosing may be resumed when the adverse reactions have resolved to ≤ grade 1, but the dose should be reduced to 20 mg/dose. If grade ≥3 adverse reactions occur again after dose reduction, cidabendiamide treatment should be discontinued.
If Grade 4 non-hematologic adverse reactions occur during dosing, treatment should be discontinued.
Special Populations
There is a lack of information on the use in people with hepatic impairment and renal impairment.
Adverse Reactions
Safety data for cetapenem tablets alone in patients with PTCL were derived primarily from a pivotal, single-arm, open, phase II clinical trial (n=83) and an exploratory, single-arm, open, phase II clinical trial (n=19). In the PTCL pivotal phase II clinical trial, patients were administered 30 mg twice weekly for a mean treatment duration of 4.4 months (range: <1 month to 37.4+ months), with 16 patients (19.3%) treated for ≥6 months and 8 patients (9.6%) treated for more than 1 year. In the exploratory phase II clinical trial of PTCL, patients in both groups received 30 mg/dose and 50 mg/dose, respectively, and both groups took the drug twice a week, with a one-week break after two weeks of continuous dosing. The mean duration of treatment for all patients in this trial was 7.6 months (range: <1 month to 52.1+ months), with 3 patients (15.8%) treated for ≥6 months and 2 patients (10.5%) treated for more than 1 year.
Common adverse reactions
Common adverse reactions observed in clinical trials included: hematologic adverse reactions, including decreased platelet count, decreased white blood cell or neutrophil count, and decreased hemoglobin; systemic adverse reactions, including malaise and fever; gastrointestinal adverse reactions, including diarrhea, nausea, and vomiting; metabolic and nutritional system adverse reactions, including decreased appetite, hypokalemia, and hypocalcemia; and other adverse reactions, including dizziness, rash, etc.
Table 1 lists the adverse events with an incidence of ≥1% in the exploratory and pivotal phase II clinical trials of cedarbenclamide tablets PTCL (without consideration of causality with the drug).
Table 1 Occurrence of adverse events (incidence ≥ 1%) in phase II clinical trials of cedarbenclamide tablets PTCL
Adverse events Pivotal trials (N=83) Exploratory trials (N=19) All levels
Cases (%) Grade 3/4*
Cases (%) All levels
Cases (%) Level 3/4*
Cases (%) Laboratory tests Hematology Decreased platelet count42 (50.6)18 (21.7)9 (47.4%)6 (31.6)Decreased white blood cell count33 (39.8)11 (13.3)5 (26.3%)2 (10.5)Decreased neutrophil count18 (21.7)9 (10.8)1 (5.3)1 (5.3)Hemoglobin concentration transferase elevated7 (8.4)2 (2.4)0 (0.0)0 (0.0)alanine aminotransferase elevated6 (7.2)1 (1.2)0 (0.0)0 (0.0)0 (0.0)blood creatine phosphokinase elevated5 (6.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)aspartate aminotransferase elevated4 (4.8)1 (1.2)1 (5.3)0 ( 0.0)Blood creatine phosphokinase MB decreased4 (4.8)0 (0.0)0 (0.0)0 (0.0)Blood potassium decreased2 (2.4)1 (1.2)0 (0.0)0 (0.0)0 (0.0)Blood calcium decreased2 (2.4)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)Blood bilirubin increased1 (1.2)0 (0.0)0 (0.0)0 (0.0)0 (0.0)Blood creatinine increased 1 (1.2)0 (0.0)0 (0.0)0 (0.0)0 (0.0)Elevated blood myoglobin1 (1.2)0 (0.0)0 (0.0)0 (0.0)0 (0.0)Lower blood phosphorus1 (1.2)0 (0.0)0 (0.0)0 (0.0)0 (0.0)Electrocardiogram Prolonged QTc interval11 (13.3)1 (1.2)2 (10.5)0 (0.0)
Urinalysis
Urine protein4 (4.8)0 (0.0)1 (5.3)0 (0.0)Urine glucose1 (1.2)0 (0.0)1 (5.3)0 (0.0)Urine bilinogen1 (1.2)0 (0.0)0 (0.0)0 (0.0)0 (0.0)Immunity Blood immunoglobulin G decreased1 (1.2)0 (0.0)0 (0.0)0 (0.0)0 (0.0)Blood immunoglobulin G elevated1 ( 1.2)0 (0.0)0 (0.0)0 (0.0)0 (0.0)Systemic condition malaise8 (9.6)0 (0.0)3 (15.8)0 (0.0)Fever7 (8.4)0 (0.0)4 (21.1)0 (0.0)Fatigue3 (3.6)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)Peripheral edema2 (2.4)0 (0.0)1 (5.3)1 (5.3)Soft tissue inflammation1 (1.2)0 (0.0)0 (0.0)0 (0.0)0 (0.0)Gastrointestinal system disorders Diarrhea7 (8.4)0 (0.0)1 (5.3)0 (0.0)Nausea7 (8.4)0 (0.0)2 (10.5)0 (0.0)Vomiting4 (4.8)1 (1.2)1 (5.3)0 (0.0)Oral ulcers1 (1.2) nutritional disorders Decreased appetite7 (8.4)2 (2.4)1 (5.3)0 (0.0)Hypokalemia5 (6.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)Hypocalcemia2 (2.4)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)Hypoproteinemia1 (1.2)0 (0.0)0 (0.0)0 (0.0)0 (0.0)Heart disease Pericardial effusion6 ( 7.2)0 (0.0)2 (10.5)0 (0.0)Infections and infectious diseases Pulmonary infections5 (6.0)1 (1.2)0 (0.0)0 (0.0)0 (0.0)Upper respiratory tract infections3 (3.6)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)Sinusitis2 (2.4)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)Chronic sinusitis2 (2.4)0 ( 0.0)0 (0.0)0 (0.0)0 (0.0)Respiratory tract infections1 (1.2)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)Pruritus1 (1.2)0 (0.0)0 (0.0)0 (0.0)0 (0.0)Neurological disorders Dizziness3 (3.6)0 (0.0)0 (0.0)0 (0.0)0 (0.0)Drowsiness1 (1.2)1 (1.2)0 (0.0)0 (0.0)0 (0.0)Headache1 (1.2)1 (1.2)0 (0.0)0 (0.0)0 (0.0)Hypersensitivity1 (1.2)0 (0.0 Upper airway obstruction1 (1.2)0 (0.0)0 (0.0)0 (0.0)0 (0.0)Musculoskeletal and connective tissue disorders Back pain1 (1.2)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)1 (1.2)0 ( 0.0)0 (0.0)0 (0.0)0 (0.0)Limb pain1 (1.2)0 (0.0)0 (0.0)0 (0.0)0 (0.0)Lymphatic system disorders Lymphadenopathy1 (1.2)1 (1.2)0 (0.0)0 (0.0)0 (0.0)Lymph node pain1 (1.2)0 (0.0)0 (0.0)0 (0.0)0 (0.0)Kidney and urinary system disorders Renal insufficiency1 (1.2)0 ( 0.0)0 (0.0)0 (0.0)0 (0.0)Hematuria0 (0.0)0 (0.0)1 (5.3)0 (0.0)Mental illness Cognitive impairment1 (1.2)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)Vascular disease Venous thrombosis1 (1.2)0 (0.0)0 (0.0)0 (0.0)0 (0.0)* as per National Cancer Institute (NCI) CTC-AE V3.0 criteria for grading.
Serious Adverse Events
Of the 83 patients in the pivotal phase II clinical trial of cetapenem tablets, 8 serious adverse events (SAEs) occurred in 7 patients (8.4%), of which 1 patient each experienced increased white blood cell count, sudden cardiac death, decreased platelet count, lactic acidosis, intestinal perforation, and gangrene of the right toe, respectively, of which 3 (sudden cardiac death, lactic acidosis, intestinal perforation) resulted in a fatal outcome (see One patient succumbed to left lung pneumonia and right axillary lymph node enlargement. Of the 19 patients in the exploratory phase II clinical trial, one patient (5.3%) experienced both thrombocytopenia and fever.
Adverse events leading to discontinuation of the drug
Of the 83 patients in the pivotal phase II clinical trial of cidabendiamide tablets, 14 (16.9%) patients discontinued cidabendiamide tablets due to adverse events. Reasons for discontinuation included decreased platelet count in 3 cases (3.6%), decreased white blood cell count and abnormal liver function in 2 cases each (2.4%), and decreased appetite, intestinal perforation, cough and sputum, pulmonary infection and renal insufficiency, lactic acidosis, drowsiness, and increased white blood cell count in 1 case each (1.2%). Among the 19 patients in the exploratory phase II clinical trial, 3 patients (15.8%) discontinued cetapenem tablets due to adverse events, including 2 patients who discontinued the drug due to 2 simultaneous adverse events. Reasons for discontinuation included decreased platelet count in 2 cases (10.5%) and decreased white blood cell count, positive urine protein, and right lower extremity edema in 1 case each (5.3%).
Adverse events leading to dose adjustment
Of the 83 patients in the pivotal phase II clinical trial of cetapenemide tablets, 6 (7.2%) patients had dose adjustments due to adverse events: grade 3 platelet count reduction in 3 (3.6%), grade 3 leukocyte count reduction in 2 (2.4%), grade 2 malaise, grade 2 decreased appetite, grade 4 leukocyte count reduction, grade 4 neutrophil count reduction, and grade 4 platelet count decreased in 1 case (1.2%) each. The dose was adjusted to 25 mg in one patient and then increased to 30 mg after three doses, while the dose was adjusted to 20 mg in the other five patients and was maintained until the end of the trial.
Contraindications
This product is contraindicated in patients with hypersensitivity to cetapenem or any of its components, in female patients during pregnancy, and in patients with severe cardiac insufficiency [New York Heart Association (NYHA) class IV cardiac insufficiency].
Precautions]
General Precautions
Hematological adverse reactions
Hematologic adverse reactions such as decreased platelet count, decreased white blood cell count, and decreased hemoglobin concentration may occur with cetapenemide tablet therapy. In the exploratory and pivotal phase II clinical trial (n=102) of cedarbenclamide tablets as monotherapy for PTCL, reduced platelet counts occurred in 51 (50.0%) patients, reduced white blood cell counts in 38 (37.3%) patients, reduced neutrophil counts in 19 (18.6%) patients, and reduced hemoglobin concentrations in 9 (8.8%) patients. Of these, grade ≥3 thrombocytopenia, leukocyte count reduction, neutrophil count reduction, and decreased hemoglobin concentration were 24 (23.5%), 13 (12.7%), 10 (9.8%), and 5 (4.9%), respectively (see [Adverse Reactions] Table 1 for details).
Approximately 75% of the first hematologic adverse reactions occurred within six weeks of dosing. Weekly routine blood tests are recommended during the course of drug administration.
When grade ≥3 hematologic adverse reactions occur, symptomatic management and dosing should be suspended, routine blood tests should be performed at least every other day, and dosing can be resumed after the associated hematologic adverse reactions have resolved to dosing conditions (see [Dosage and Administration] Treatment of Hematologic Adverse Reactions and Dose Adjustment for details).
Abnormal liver function
In the exploratory and pivotal phase II clinical trial of cetapenem tablets as monotherapy for PTCL (n=102), abnormal liver function tests were observed in some patients, including 7 cases (6.9%) with elevated gamma-glutamyl transferase (gamma-GGT), 6 cases (5.9%) with elevated alanine aminotransferase (ALT), 5 cases (4.9%) with elevated aspartate aminotransferase ( AST), and 1 case (1.0%) with elevated bilirubin. These abnormalities were mostly grade 1 to 2, and grade 3 abnormalities were elevated γ-GGT in 2 cases (2.0%) and elevated ALT and AST in 1 case (1.0%) each.
Before taking this product, if γ-GGT, ALT or AST > 2.5 times the upper limit of normal, it is recommended to withhold the drug and wait until the relevant indexes are reduced to normal values before the first dose of the drug. Liver function-related indicators should be tested at least once every three weeks during the course of drug administration. If abnormalities of grade ≥3 liver function indicators occur, drug administration should be suspended, symptomatic treatment should be carried out, and the frequency of liver function indicators should be increased until the adverse reactions are alleviated to ≤1 or pre-drug level, and the dosage should be reduced when drug administration is resumed (for details, see [Dosage and Administration] Treatment of Non-Hematological Adverse Reactions and Dosage Adjustment).
No studies have been conducted in the hepatic impairment population. It should be taken with caution in patients with moderate/severe hepatic impairment.
Abnormal renal function
In the exploratory and pivotal phase II clinical trial (n=102) of cetapenem tablets monotherapy for PTCL, abnormalities in grade 1 or 2 renal function tests were observed in some patients, including 5 cases (4.9%) with proteinuria, 2 cases (2.0%) with positive urine glucose, and 1 case (1.0%) with elevated blood creatinine, all of which improved within 1 to 2 weeks.
It is recommended that renal function indicators should be tested at least once every three weeks during the course of drug administration. If a renal function test indicator shows ≥ grade 3 abnormality, drug administration should be suspended, symptomatic treatment should be carried out, and the frequency of relevant renal function indicators should be increased until the adverse reaction is alleviated to ≤ grade 1 or pre-drug level, and the dosage should be reduced when drug administration is resumed (for details, see [Dosage and Administration] Treatment of Non-Hematological Adverse Reactions and Dosage Adjustment).
No studies have been conducted in the renal impairment population. It should be taken with caution in patients with moderate/severe renal impairment.
Special Precautions
Sudden cardiac death
In the pivotal phase II clinical trial of PTCL, a patient with NK/T nasal type who relapsed after multiple courses of radiotherapy and chemotherapy treatment developed high fever and swelling of both arms that gradually worsened before taking the drug, and continued to have high fever and increased painful swelling of both arms even after three doses of this product, with sudden onset and worsening of shortness of breath and respiratory and cardiac arrest after 5 hours, and the analysis concluded that sudden cardiac death was likely. Due to the lack of relevant examination data, the relationship between the death and the administration of this product could not be determined yet. During the administration of this product, monitoring of cardiac safety-related indicators, including but not limited to ECG and cardiac ultrasound, should be performed regularly.
Prolonged QTc interval
In the exploratory and pivotal phase II clinical trial (n=102) of cetapenem tablets monotherapy for PTCL, QTc interval prolongation was observed in 13 patients (12.7%), of which 12 (11.8%) were grade 1-2 and 1 (1.0%) was grade 3. Most of these QTc prolongations were episodic and not accompanied by clinical symptoms, and most patients with QTc abnormalities returned to the normal range of values at the end of cidabendiamide treatment. Drugs with a similar mechanism of action to this product have been reported to cause severe QTc interval prolongation, and it is recommended that any abnormalities in blood potassium, calcium or magnesium tests prior to the first dose of this product should not be administered until the relevant markers have returned to normal. Electrocardiogram and electrolyte examination are recommended every 3 weeks during the administration of this product. If QTc > 500 ms occurs, the drug should be suspended, increase the frequency of ECG examination, and after the abnormality is relieved or excluded, the dosage should be reduced when the drug is resumed (see [Dosage and Administration] Treatment of non-hematological adverse reactions and dosage adjustment for details). This product should be used with caution in patients with a history of QTc interval prolongation, patients with congenital QT prolongation syndrome, patients taking antiarrhythmic drugs or other drugs that may prolong QTc, or after consultation with a cardiologist.
Pericardial effusion
In the PTCL pivotal phase II clinical trial and the exploratory phase II clinical trial in a total of 102 patients, a total of 8 patients (7.8%) were observed to develop small or very small amounts of pericardial effusion without clinical symptoms. Severe pericardial effusion has been reported with drugs of similar mechanism of action and it is recommended to monitor pericardial effusion by cardiac ultrasound every 6 weeks during the administration of this drug. In case of more serious abnormalities, the drug should be suspended and the frequency of cardiac echocardiography should be increased until the abnormality resolves or is ruled out, and after consultation with a cardiologist. Resumption of dosing should be treated with dose reduction (see [Dosage and Administration] Treatment of Non-Hematologic Adverse Reactions and Dose Adjustment for details).
Infections
In the exploratory and pivotal phase II clinical trial of cetapenem tablets as monotherapy in PTCL (n=102), 14 patients (13.7%) experienced infection-related adverse events, including one patient with a grade 3 lung infection. During the administration of this product, attention should be paid to the presence of fever or symptoms of infection in various systems such as respiratory, urinary tract and skin, and appropriate examination and symptomatic treatment should be performed as soon as possible if symptoms are present.
Blood clots
In the exploratory and pivotal phase II clinical trial (n=102) of cetapenem tablets as monotherapy in PTCL, one patient experienced a grade 1 venous thrombosis adverse event. The relationship between venous thrombosis and administration of this product is unclear. Drugs with a similar mechanism of action to this product have been reported to cause thromboembolic events, and it is recommended to be aware of the possibility of thrombosis during the administration of this product. If signs or symptoms related to thrombosis occur, prompt diagnosis and treatment should be given, and the physician may make a decision to continue or discontinue this product based on a combination of circumstances. Avoid use of this product in patients with active bleeding, coughing up blood, hemoptysis, or new onset thrombotic disease. Avoid concomitant use of drugs that have an effect on coagulation during treatment with this product.
Male Reproductive Effects
Animal studies have shown that cidabendiamide may cause a decrease in sperm density in male rats, suggesting that this product may have some effect on male fertility. Male patients should avoid reproductive planning during and for 3 months after treatment with this drug.
For Pregnant and Lactating Women]
Pregnancy
No studies have been conducted on the use of cetapenem tablets in pregnant women. The results of reproductive toxicity tests in rats showed that cidabendiamide was maternally toxic to pregnant female rats at a dose equivalent to approximately two times the human dose, and resulted in delayed fetal development, increased internal organ and skeletal variability, increased number of stillbirths, increased rate of post-delivery loss, and malformed fetal appearance, suggesting that cidabendiamide has toxic effects on the development of animal embryos.
Cidabendiamide tablets are contraindicated during pregnancy. Patients should be informed of the potential risk to the fetus if they take the product during pregnancy or if they become pregnant during the administration of the drug. Women of childbearing potential should be advised to avoid pregnancy during treatment with cidabendiamide tablets.
Lactating women
It is uncertain whether this product is secreted through human breast milk. It is recommended that nursing mothers discontinue breastfeeding while receiving this product.
[Pediatric Use].
The efficacy and safety of cetapenem tablets have not been studied in patients under 18 years of age and are therefore not recommended.
Geriatric Use]
A pharmacokinetic study of 33 patients with T-cell lymphoma showed a trend toward shorter time to peak, longer elimination half-life, and increased peak absorption concentration and exposure in elderly patients (≥65 years of age), but no statistical differences were observed. Population pharmacokinetic analysis suggested that age had no significant effect on the pharmacokinetic behavior of cidabendiamide. Physicians may guide patients to administer the drug or make dose adjustments based on the comprehensive profile of elderly patients.
[Drug Interactions].
No formal human drug interaction studies have been conducted with cidabendiamide.
In vitro studies have shown no significant direct inhibition of the major subtypes of human hepatic microsomal CYP450 enzymes by cidabendiamide. The IC50 values for direct inhibition of CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP2E1 were all greater than 30 µM, while the IC50 values for direct inhibition of CYP2C8, CYP2D6, CYP3A4 (testosterone as substrate), and CYP3A4 (midazolam as substrate) were 4.33, 14.9, and 6.8 µM, respectively. 6.27 and 2.8 µM, respectively, which are higher than the steady-state peak concentration (0.14 µM) at the clinically recommended dose of this product.
In vitro CYP450 enzyme induction assays using human hepatocytes showed no induction of CYP3A4 and CYP1A2 at 0.1 µM. At 0.5 and 3 µM concentrations, the induction effect on CYP1A2 was about 30.2-41.7% and 67.74-84.9% of the positive control, respectively, and had no effect on CYP3A4.
In a phase Ib clinical study of this product in combination with paclitaxel and carboplatin in non-small cell lung cancer as an indication, no significant effect of cidabendiamide on the in vivo pharmacokinetic parameters of paclitaxel (a substrate of CYP3A4) was observed, and no significant effect of paclitaxel or carboplatin on the in vivo kinetic parameters of cidabendiamide was observed.
[Drug overdose].
The symptoms that may result from an overdose of cidabenamide are not known, and there is no specific treatment for an overdose of cidabenamide. In case of overdose, symptomatic and supportive treatment, including gastric lavage, should be administered by a medical professional.
Clinical trials]
A total of two clinical trials of cidabendiamide tablets as monotherapy for relapsed or refractory PTCL were conducted, including an exploratory, single-arm, open, multicenter, phase II trial and a pivotal, single-arm, open, multicenter, phase II trial.
In the exploratory phase II trial, 19 patients with PTCL were enrolled in two groups, with one group (N=9) receiving 30 mg per dose and the other group (N=10) receiving 50 mg per dose. patients in both groups received a twice-weekly dosing regimen with a one-week discontinuation after two weeks of dosing until progression or intolerable adverse events. The primary efficacy measure of the trial was the objective remission rate (ORR). Remissions included complete remission (CR), complete remission not established (CRu), and partial remission (PR). Efficacy was evaluated using the International Workshop Response Criteria for Non-Hodgkin’s lymphoma (IWC), as recommended by the NCCN 2008 edition and developed by the International Working Group, every 6 weeks, based on the results of the investigator evaluation.
In the pivotal phase II trial, 83 patients with PTCL were enrolled, all of whom received 30 mg of cidabendiamide tablets as monotherapy twice weekly until disease progression or the onset of intolerable adverse effects. Of the patients enrolled, 79 had pathological diagnoses that met the inclusion criteria for efficacy evaluation. The primary efficacy index of the trial was ORR. remission included CR, CRu and PR. efficacy evaluation was performed every 6 weeks, mainly based on IWC criteria for lymph nodes and organ lesions. The evaluation of skin lesions was also added, and the six largest skin lesions were selected and evaluated by the sum of the products of the largest draped diameters (SPD), and finally combined with lymph node and organ lesions and skin lesions for a comprehensive evaluation. The main efficacy index, ORR, was evaluated by the investigator and independent expert committee, respectively, and the results were subject to independent audit.
Baseline characteristics and key efficacy results of the exploratory phase II trial and pivotal phase II trial of PTCL are presented in Tables 2 and 3, respectively.
Table 2 Baseline characteristics of patients in the PTCL Phase II clinical trial
Project Exploratory phase II trial Pivotal phase II trial
(N=79) 30 mg (N=9) 50 mg (N=10) Gender, n (%)
Male 6 (66.7)8 (80.0)53 (67.1)
Female3 (33.3)2 (20.0)26 (32.9) Age (years)
Median (range) 53 (38-77)52 (29-71)53 (20-77) ECOG score, n (%) 08 (88.9)3 (30.0)28 (35.4) 11 (11.1)7 (70.0)50 (63.3) 20 (0.0)0 (0.0)1 (1.3) Time since first disease diagnosis (years)
Median (range) 1.5 (0.2-8.1) 1.1 (0.2-2.5) 1.1 (0.1-9.1) PTCL subtype, n (%) PTCL-non-specific 9 (100.0) 10 (100.0) 23 (29.1) NK/T-cell lymphoma, nasal 0 (0.0) 0 (0.0) 16 (20.3) Mesenchymal large cell lymphoma 0 (0.0)0 (0.0)16 (20.3)
Angioimmunoblastoma T-cell lymphoma
0 (0.0)0 (0.0)9 (11.4)
Other 0 (0.0)0 (0.0)15 (19.0) Number of prior chemotherapy regimens (number)
Median (range)3 (2-5)2 (1-6)3 (1-9)
Table 3 Efficacy results of phase II clinical trials of PTCL
Project Exploratory phase II trial Pivotal phase II trial 30 mg
(N=9) 50mg
(N=10) Investigators
(N=79) Independent review
(N=79)Remission rate, n (%)CR1 (11.1)1 (10.0)8 (10.1)7 (8.9)CRu0 (0.0)1 (10.0)3 (3.8)4 (5.1)PR0 (0.0)1 (10.0)12 (15.2)11 (13.9)ORR (CR+CRu+PR)1 (11.1)3 (30.0) 23 (29.1)22 (27.8)95% confidence interval 0.3-48.26.7-65.219.4-40.418.3-39.0 Duration of remission (months) median
Range 58.7
(58.7+)#14.5
(8.5-57.4+)#9.9
(1.1+-40.8+)#*95% confidence interval/4.9-24.13.7 – 16.1 Note: #: “+” indicates that the data are censored, i.e., the endpoint event had not been reached at the time of the count (statistics as of June 2014)
June 2014).
*: Indicator has not been independently reviewed.
This product was approved for registration and marketing under the conditional approval process, which means that the manufacturer will subsequently need to provide further clinical study data, including evidence of long-term survival benefit and results of randomized controlled studies compared with standard chemotherapy. The State Food and Drug Administration will evaluate the updated study information annually and incorporate the necessary updates into the specification.
Pharmacology and Toxicology
Pharmacology and Toxicology
Pharmacological effects
It is a selective inhibitor of benzamide histone deacetylase (HDAC) subtypes, mainly targeting subtypes 1, 2 and 3 of class I HDAC and subtype 10 of class IIb, and has a regulatory effect on abnormal epigenetic functions of tumors. Cidabenamide triggers chromatin remodeling by inhibiting the relevant HDAC isoforms to increase the acetylation level of chromatin histones, which results in altered expression of genes targeting multiple signaling pathways (i.e., epigenetic alterations), thereby inhibiting the tumor cell cycle and inducing apoptosis, and has overall modulatory activity on cellular immunity, inducing and enhancing the expression of natural killer (NK) cells and antigen specific cytotoxic T cells (CTL) mediated tumor killing. Cidabendiamide also has the function of inducing tumor stem cell differentiation and reversing epithelial mesenchymal phenotypic transformation (EMT) of tumor cells through epigenetic regulation mechanism, which in turn plays a potential role in restoring the sensitivity of drug-resistant tumor cells to drugs and inhibiting tumor metastasis and recurrence.
Toxicological studies
General toxicity: The results of a single administration toxicity test study of cidabendiamide showed that the maximum tolerated dose (MTD) for transoral administration in mice was greater than 5 g/kg, and the maximum non-lethal dose for single oral administration in dogs was 0.25 g/kg.
Oral administration of cidabendiamide (1.5, 4.5, 13.5 mg/kg) for 6 months (4 dosing cycles with a 4-week recovery period) in SD rats and 6 months (4 dosing cycles with a 4-week recovery period) in Beagle dogs showed gastrointestinal reactions, reduced white blood cell lineage counts, ocular cataract-like pathological changes, prolonged ECG ST segment, increased blood glucose levels and reduced glycogen storage in hepatocytes were observed as toxic effects in at least one animal species. In animals administered at moderate and high doses (i.e., higher than actual human exposure), toxic reactions such as decreased erythrocyte lineage, increased aspartate aminotransferase (AST), spleen and thymus atrophy, focal myocardial necrosis and inflammatory cell infiltration, gastrointestinal bruising and hemorrhage, impaired development and maturation of testicular spermatogonia and ovarian oocytes, chronic prostatitis, chronic inflammatory cell infiltration of the bladder plasma layer, and Interstitial nephritis and other toxic reactions. One month after discontinuation of the drug, all of these abnormalities were restored except for interstitial nephritis in rats. The NOAEL in beagle dogs was 0.5 mg/kg, which is equivalent to 20 mg per dose in a 70 kg human. A NOAEL was not obtained in the rat test.
Genotoxicity: Cidabendiamide did not show genotoxic effects in the microbial revertant mutation assay, the mammalian cultured cell chromosome aberration assay, or the rodent micronucleus assay.
Reproductive toxicity: A general reproductive toxicity study showed that oral administration of cidabendiamide to rats resulted in a decrease in sperm density in males, with no significant abnormalities in other reproduction-related indicators; cidabendiamide did not show significant abnormalities in reproduction-related indicators such as body weight, food intake, pregnancy rate, placental uterine weight, corpus luteum count, number of implanted glands, number of live fetuses, number of dead fetuses, number of absorbed fetuses, preimplantation mortality and postimplantation mortality in female rats The results of the reproductive toxicity study in rats after 6 days of conception showed that maternal toxicity was observed in the 4.5 and 13.5 mg/kg groups, as evidenced by reduced body weight and food intake in pregnant rats, and embryonic fetal toxicity was observed in the 13.5 mg/kg group, as evidenced by retarded growth, increased visceral and skeletal variability, and increased number of stillbirths, post-delivery loss and malformed fetal appearance in individual animals. The dose is about 1/2 of the human dose (30 mg) per dose, suggesting that there is a risk of toxicity to the potentially fertile population with long-term use in oncology patients.
Carcinogenicity: No carcinogenicity test has been conducted.
Pharmacokinetics]
Absorption
The pharmacokinetic profile of cetapenem was studied and analyzed in 33 patients with T-cell lymphoma. After a single postprandial oral dose of 30 mg cidabendiamide tablets, the mean time to peak (Tmax) in vivo was about 4 hours, the mean peak plasma drug concentration (Cmax) was about 60 ng/mL, the mean area under the drug-time curve (AUC0-t) was about 660 ng×h/mL, and the mean terminal elimination half-life (t1/2_z) was about 17 hours. Table 4 shows the mean pharmacokinetic parameters in 33 patients after a single oral dose of cedarbenclamide tablets 30 mg after a meal.
Table 4 Pharmacokinetic parameters of single postprandial dose of cidabendiamide tablets
Tmax
hCmax ng/mLAUC0-t h×ng/mLAUC0-∞ h×ng/mLMRT0-t
ht1/2_z
hVd/F
LCL/F
L/h mean 3.959.6658.5765.814.916.71210.053.0 standard deviation 3.547.0383.9435.15.48.4832.139.9
The pharmacokinetic behavior of multiple consecutive oral doses of 30 mg cidabendiamide tablets was evaluated in 19 patients with T-cell lymphoma. The mean AUC0-t value after the 8th dose was 1.8-fold higher compared to a single dose, and the difference was statistically significant (p<0.01). The relationship between the increased exposure of this product in vivo after multiple consecutive doses and the efficacy and/or safety of the drug is unclear.
The pharmacokinetic profile of different doses of cidabendiamide tablets administered orally was studied and analyzed in 21 patients with advanced solid tumors and lymphomas. The AUC0-t values were 809±390, 828±509 and 1120±438 ng×h /mL (1:1.0:1.4) after a single postprandial oral dose of 25, 32.5 and 50 mg (dose ratio 1:1.3:2) of cidabendiamide tablets, respectively, suggesting that the in vivo exposure of cidabendiamide tablets showed a non-isometric increasing relationship with increasing dose and may have a dose saturation trend.
Absolute bioavailability studies of cetapenem tablets were not performed.
A pharmacokinetic study of the effect of food was performed in seven patients with T-cell lymphoma. The results showed that oral administration of 30 mg of cidabendiamide tablets 30 minutes after eating a standard meal (one full McDonald’s breakfast meal containing 2 McMuffins, 1 crispy hash browns, 1 pork tenderloin and 1 scrambled egg, totaling approximately 600 kcal) resulted in a 2.3-fold higher mean plasma exposure than in patients taking the same dose on an empty stomach. In clinical trials, it was observed that taking this product after a meal may help to alleviate potential discomfort caused by drug irritation of the gastrointestinal tract in some patients. It is recommended that this product be taken 30 minutes after a meal.
Some variation in the pharmacokinetic parameters of cetapenem tablets was observed in the study in different patients. With increasing patient age, there is a tendency for the drug to have a shorter time to peak in vivo and higher peak absorption concentrations; the mean drug exposure (in AUClast values) in male patients is approximately 80% of that in female patients at the same dose administered. The reasons for these differences and their relationship to efficacy and safety are unclear, and physicians are advised to guide patients in their treatment in conjunction with the evaluation of efficacy and safety, taking into account potential individual differences in the pharmacokinetics of the product.
Distribution
The drug has a large apparent volume of distribution (Vd/F) in humans, suggesting a relatively wide distribution in the body. In vitro studies have shown that cidabendiamine binds to human plasma proteins in the concentration range of 20-150 ng/mL with a rate of 89.1-99.3%.
Metabolism and clearance
Nuclear magnetic resonance (19F NMR) and liquid mass spectrometry (LC-MS/MS) analysis methods were applied to study the in vivo biotransformation and substance balance of cidabendiamine tablets after oral administration in four patients with T-cell lymphoma.
The total urinary and fecal excretion of cidabendiamine accounted for 80.2%±9.5% of the dose at 168 hours (7 days) after administration, with the majority of excretion occurring in the first 72 hours. After absorption, most of the drug was excreted in the urine through the kidneys, accounting for 67.6%±12.7% of the total dose, and excretion in the feces accounted for 12.6%±7.7% of the total dose. The excretion of cetapenem in its original form accounted for 37.6%±9.2% of the total dose and about 39.4% of the urinary excretion; the vast majority of cetapenem was excreted in the feces in its original form, accounting for about 86.9% of the total fecal excretion.
In addition to the prodrug, five major metabolites of cidabendiamine were found in human urine and feces, with two major metabolic pathways, mono-oxidation and amide bond hydrolysis at different locations.
Special Populations
Patients with hepatic impairment
No clinical trial data are available for cetapenem in patients with hepatic impairment. Animal studies and in vitro studies in humans have shown that the liver is one of the major pathways of cedarbenclamide clearance. Analysis of population pharmacokinetic studies showed that mild hepatic impairment does not significantly affect the in vivo pharmacokinetic behavior of cedarbenclamide tablets. There is a lack of assessment of the pharmacokinetic effects of cedarbenclamide in patients with moderate to severe hepatic impairment, and caution is advised in the administration of this product in relevant patients.
Patients with renal impairment
No clinical trial data are available for cetapenem in patients with renal impairment. The results of the population pharmacokinetic study showed that there was no significant difference between cidabendiamide in patients with mildly abnormal renal function indexes compared to patients with normal renal function indexes. There is a lack of evaluation of the pharmacokinetic effects of cidabendiamide in patients with moderate or severe renal impairment, and patients are advised to take this product with caution.
Storage
Keep under 25℃, sealed and protected from light.
Package
Double aluminum blister package, 12 tablets/plate, 2 plates/box.
Expiration date
18 months.
Execution Standard
Approval number】
Manufacturer
Company name: Shenzhen Microchip Biotechnology Co.
Address: No. 21, Jinxiu East Road, Pingshan New District, Shenzhen
Zip code: 518122
Telephone number: 0755-84533320
Fax number: 0755-84533306
Free consultation phone number：4000290392
Website: http://www.epidaza.com