Date of approval.
Year
Month
Date
Apixaban Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name
Generic name: Apixaban Tablets
English Name: Apixaban Tablets
Hanyu Pinyin: Apaishaban Pian
Ingredients
The main ingredient of this product is Apixaban
Chemical name: 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]-pyridine-3-carboxamide
Chemical structure formula.
Molecular formula: C25H25N5O4
Molecular weight: 459.50
Properties
This product is a yellow round film-coated tablet, which appears white or off-white after removing the coating.
Indications
For the prevention of venous thromboembolic events (VTE) in adult patients undergoing elective hip or knee joint replacement.
Specification
2.5mg
Dosage]
The recommended dose of this product is 2.5mg per dose, taken orally twice daily with water, independent of meals. The first dose should be taken between 12 and 24 hours after surgery. When deciding on the exact time point for dosing during this time window, physicians need to consider both the potential benefits of early anticoagulation to prevent VTE and the risk of post-surgical bleeding.
For patients undergoing hip arthroplasty: the recommended course of treatment is 32 to 38 days.
For patients undergoing knee arthroplasty: the recommended course of treatment is 10 to 14 days.
If a missed dose occurs, the patient should take this product immediately and continue to take it twice daily thereafter. Conversion from injectable anticoagulant to this treatment may begin at the next dosing time point (and vice versa) (see [Drug Interactions]).
If the patient is unable to swallow the entire tablet, the product may be crushed and suspended in water or 5% dextrose solution, or apple juice, or mixed with applesauce for prompt oral administration. Alternatively, crushed tablets may be suspended in 60 mL of water or 5% dextrose solution and administered by nasogastric tube (see [Pharmacokinetics]). The crushed product is stable in water, 5% dextrose solution, apple juice and applesauce within 4 hours.
[Adverse Reactions].
The safety of apixaban was evaluated in a phase II clinical trial and three phase III clinical trials in which a total of 5924 patients undergoing major orthopedic surgery of the lower extremity (elective hip replacement or knee replacement) received apixaban 2.5 mg twice daily for a maximum of 38 days.
In total, 11% of patients treated with apixaban 2.5 mg twice daily experienced adverse reactions. As with other anticoagulants, bleeding may occur during apixaban treatment when there are associated risk factors, such as organ damage that predisposes to bleeding. Common adverse reactions include anemia, bleeding, contusion, and nausea. Adverse reactions should be interpreted in the context of the procedure.
In Table 1 below, adverse reactions in the phase II and III clinical trials described above are listed by systemic organ classification (MedDRA) and frequency of occurrence.
Table 1 Adverse reactions during treatment of patients undergoing elective hip or knee arthroplasty
Common (≥1/100to<1/10) Rare (≥1/1,000to<1/100) Rare (≥1/10,000to<1/1,000) Hematologic and lymphatic system abnormalities Anemia (including postoperative anemia and hemorrhagic anemia, and corresponding laboratory parameters) Thrombocytopenia (including reduced platelet count) Immune system abnormalities Allergic reactions Ocular abnormalities Ocular bleeding (including conjunctival bleeding) Vascular abnormalities Bleeding (including hematoma, vaginal and urethral bleeding) Hypotension (including postoperative hypotension) Respiratory, thoracic and mediastinal abnormalities Epistaxis and hemoptysis Gastrointestinal abnormalities Nausea Gastrointestinal bleeding (including vomiting blood and black stool), blood in the stool Rectal bleeding, gingival bleeding Hepatobiliary abnormalities Elevated alanine aminotransferase and abnormal alanine aminotransferase levels, aspartate Elevated aminotransferase, elevated gamma-glutamyl transpeptidase, abnormal liver function tests, elevated blood alkaline phosphatase levels, elevated blood bilirubin levels Skeletal muscle and connective tissue abnormalities Muscle bleeding Renal and urinary system abnormalities Hematuria (including corresponding abnormal laboratory parameters) Trauma, poisoning, and surgical complications Postoperative contusion bleeding (including postoperative hematoma, wound bleeding, vascular puncture site hematoma, and catheter site bleeding) , wound discharge, incision site bleeding (including incision site hematoma), surgical bleeding As with other anticoagulants, apixaban may cause an elevated risk of occult or overt bleeding in some tissues or organs, which may lead to post-hemorrhagic anemia. Signs, symptoms and severity of bleeding will vary depending on the site, degree or extent of bleeding (see [Precautions] and [Clinical Trials]).
[Contraindication].
Hypersensitivity to the active ingredient or to any of the excipients in the tablet.
Clinically significant active bleeding.
Liver disease with coagulation abnormalities and clinically relevant bleeding risk (see [Pharmacokinetics]).
[Precautions].
Risk of Bleeding
As with other anticoagulants, patients taking apixaban should be closely monitored for signs of bleeding. Apixaban should be used with caution in patients with the following bleeding risks: congenital or acquired bleeding disorders; active gastrointestinal ulcer disease; bacterial endocarditis; thrombocytopenia; abnormal platelet function; history of bleeding stroke; uncontrolled severe hypertension; recent brain, spine, or ophthalmic surgery. If severe bleeding occurs, apixaban should be discontinued (see [Drug Overdose]).
Temporary discontinuation of medication
Discontinuation of anticoagulants (including apixaban) in the presence of active bleeding, elective surgery, or invasive procedures may put patients at increased risk for thrombosis. If for any reason it is necessary to temporarily discontinue apixaban anticoagulation, restart apixaban therapy as soon as possible.
Renal impairment
No dose adjustment is required in patients with mild or moderate renal impairment (see [Pharmacokinetics]).
Limited clinical data in patients with severe renal impairment (creatinine clearance of 15-29 ml/min) suggest elevated plasma concentrations of apixaban in this patient population, and caution should be exercised when using apixaban alone or in combination with acetylsalicylic acid in these patients due to the potential for increased risk of bleeding. (See [Pharmacokinetics]).
Apixaban is not recommended in patients with creatinine clearance <15 ml/min or in dialysis patients because clinical data are not available for these patients (see [Pharmacokinetics]).
Elderly patients (>65 years)
Clinical experience with apixaban in combination with acetylsalicylic acid in elderly patients (>65 years of age) is limited. Caution should be exercised in the combination of these two drugs in elderly patients due to the possible increased risk of bleeding.
Liver damage
Apixaban is contraindicated in patients with liver disease associated with coagulation abnormalities and clinically relevant bleeding risk (see [Contraindications]).
Apixaban is not recommended for patients with severe hepatic impairment (see [Pharmacokinetics]).
Dose adjustment is not required in patients with mild hepatic impairment
Due to the potential for endogenous coagulation abnormalities in patients with moderate hepatic impairment and the limited clinical experience with apixaban in such patients, dosing recommendations cannot be provided for patients with moderate hepatic impairment.
Because patients with elevated liver enzymes ALT/AST> 2 x ULN or elevated total bilirubin ≥ 1.5 x ULN were not enrolled in clinical trials, apixaban should be used with caution in these populations (see [Pharmacokinetics]). ALT should be routinely tested preoperatively.
Interaction with Cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) Dual Potent Inhibitors.
Apixaban is not recommended for patients taking systemic therapy with dual potent inhibitors of CYP3A4 and P-gp; such inhibitors include pyrrole antifungals (e.g., ketoconazole, itraconazole, voriconazole, and posaconazole) and HIV protease inhibitors (e.g., ritonavir). These drugs can increase the mean AUC of apixaban by a factor of 2 (see [Drug Interactions]), with an even greater increase in the mean AUC of apixaban if other factors contributing to increased apixaban exposure are also present (e.g., severe renal impairment).
Interaction with CYP3A4 and P-gp dual potent inducers.
When combined with CYP3A4 and P-gp dual potent inducers (e.g., rifampin, phenytoin, phenobarbital, or St. John’s wort), apixaban can reduce the mean exposure of apixaban by approximately 50%. Caution should be exercised when used in combination with CYP3A4 and P-gp dual potent inducers (see [Drug Interactions]).
Interactions with other drugs affecting hemostasis.
Apixaban in combination with antiplatelet agents increases the risk of bleeding. Particular caution should be exercised when patients are taking concomitant non-steroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid. After surgery, the combination of apixaban with other platelet aggregation inhibitors or other antithrombotic drugs is not recommended (see [Drug Interactions]).
Spinal/epidural anesthesia or puncture.
In patients receiving antithrombotic agents to prevent thrombosis, there is a risk of epidural or spinal cord hematoma complications when spinal/epidural anesthesia or puncture is used, which may result in long-term or permanent paralysis. Postoperative use of an indwelling epidural catheter or concomitant use of medications that affect hemostasis may increase the risk of these events. Do not take the first dose of apixaban until at least 5 hours after removal of the epidural or intrathecal indwelling catheter. Trauma or repeated epidural or spinal punctures may also increase the risk of the above. Patients should be monitored frequently for signs and symptoms of neurologic impairment (e.g., leg numbness or weakness, bowel or bladder dysfunction). If neurological impairment is observed, it must be diagnosed and treated immediately. In patients already receiving anticoagulation or in preparation for anticoagulation for thrombosis prevention, the physician should weigh the potential benefits and risks before performing spinal/epidural anesthesia or puncture.
There is no clinical experience with concomitant administration of apixaban with intrathecal or epidural indwelling catheters. If needed, apixaban should be given 20 to 30 hours (i.e., 2 half-lives) between the last dose and catheter removal, based on PK data, and should be discontinued at least once before catheter removal. Apixaban should not be administered until at least 5 hours after catheter removal. Similar to all new anticoagulants, there is limited experience with dosing in patients undergoing spinal/epidural anesthesia; therefore, extreme caution should be exercised when administering apixaban to patients undergoing spinal/epidural anesthesia.
Hip fracture surgery.
There are no clinical trials evaluating the efficacy and safety of apixaban in patients undergoing hip fracture surgery; therefore, apixaban is not recommended for these patients.
Laboratory Parameters.
Based on the mechanism of action of apixaban, the effect of this product on coagulation parameters (e.g., PT, INR, APTT) is consistent with expectations. The magnitude of change in these coagulation parameters is small and highly variable when the expected therapeutic dose is used (see [Pharmacology and Toxicology]).
Excipient Information.
This product contains lactose. Patients with rare hereditary galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this product.
Effects on driving and mechanical handling ability.
Apixaban has no effect or this effect is negligible on the ability to drive and operate machinery.
Do not use if the inner package is opened or damaged.
For Pregnant and Lactating Women
Pregnancy
No direct or indirect reproductive toxicity of apixaban has been found in animal studies. There is no information on the use of apixaban in women during pregnancy.
Lactating women
It is not known whether apixaban or its metabolites enter human milk.
Available data from animal studies indicate that apixaban can enter breast milk. In rat milk, a high milk-to-maternal plasma drug concentration ratio (Cmax of approximately 8 and AUC of approximately 30) was found, possibly due to active drug transport into the milk. The risk to neonates and infants cannot be ruled out.
A decision must be made whether to discontinue breastfeeding or to discontinue/avoid apixaban therapy.
[Pediatric Dosage].
There are no data on the safety and efficacy of apixaban in patients under 18 years of age.
Geriatric Use]
No dose adjustment is required.
Drug Interactions
CYP3A4 and P-gp inhibitors.
When apixaban was combined with ketoconazole (400 mg once daily), a dual potent inhibitor of CYP3A4 and P-gp, the mean AUC of apixaban increased 2-fold and the mean Cmax increased 1.6-fold. Apixaban is not recommended for patients taking systemic therapy with CYP3A4 and P-gp dual potent inhibitors, which include pyrrole antifungals (e.g., ketoconazole, itraconazole, voriconazole, and posaconazole) and HIV protease inhibitors (e.g., ritonavir) (see [Precautions]).
Active substances that are not dual potent inhibitors of CYP3A4 and P-gp (e.g., diltiazem, naproxen, clarithromycin, amiodarone, verapamil, quinidine) are expected to increase apixaban plasma concentrations to a lesser extent. When apixaban is combined with non-potent CYP3A4 and/or P-gp inhibitors, no dose adjustment is required. For example, diltiazem (360 mg once daily), a moderate CYP3A4 and weak P-gp inhibitor, increased the mean AUC of apixaban by 1.4-fold and the mean Cmax by 1.3-fold. Naproxen (500 mg, single dose), a P-gp inhibitor that does not inhibit CYP3A4, increased the mean AUC of apixaban by 1.5-fold and the mean Cmax by 1.6-fold. Clarithromycin (500 mg twice daily), a P-gp inhibitor and a strong inhibitor of CYP3A4, which increased mean apixaban AUC by 1.6-fold and increased Cmax by 1.3-fold, respectively.
CYP3A4 and P-gp inducers.
The combination of apixaban with rifampicin, a dual potent inducer of CYP3A4 and P-gp, reduced the mean AUC of apixaban by 54% and the mean Cmax by 42%. The combination of apixaban with other CYP3A4 and P-gp dual potent inducers (e.g. phenytoin, phenobarbital or St. John’s wort) may also result in a decrease in the blood concentration of apixaban. No dose adjustment is required when combined with the above drugs; however, caution should be exercised when combined with some CYP3A4 and P-gp dual potent inducers (see [Precautions]).
Anticoagulants
After combining apixaban (5 mg, single dose) with enoxaparin (40 mg, single dose), an additive effect was found in terms of anti-factor Xa effect.
If patients are combined with any other anticoagulant, this should be a concern due to the increased risk of bleeding (see [Precautions]).
Platelet aggregation inhibitors and nonsteroidal anti-inflammatory drugs.
No pharmacokinetic or pharmacodynamic interactions were observed when apixaban was combined with acetylsalicylic acid (325 mg once daily).
In phase I trials, no corresponding increases in bleeding time, platelet aggregation, or coagulation parameters (PT, INR, APTT) were observed when apixaban was combined with clopidogrel (75 mg once daily) or with clopidogrel (75 mg once daily) and acetylsalicylic acid (162 mg once daily) compared with antiplatelet agents only.
Naproxen (500 mg), a P-gp inhibitor, increased the mean AUC of apixaban by 1.5-fold and the Cmax by 1.6-fold, resulting in a corresponding prolongation of apixaban-induced coagulation parameters. No change in the effect of naproxen on arachidonic acid-induced platelet aggregation was observed with apixaban in combination with naproxen, and no clinically meaningful prolongation of bleeding time was observed.
Despite these data, individual patients may experience a more pronounced pharmacological response when taking antiplatelet agents and apixaban in combination. Caution should be exercised when coadministering apixaban with NSAIDs, including acetylsalicylic acid, as these agents can generally increase the risk of bleeding. In a clinical study of patients with acute coronary syndromes, triple therapy with apixaban, acetylsalicylic acid, and clopidogrel significantly increased the risk of bleeding. Apixaban is not recommended in combination with drugs that can cause severe bleeding, such as: common heparin and heparin derivatives (including low molecular weight heparin (LMWH)), oligosaccharides that inhibit coagulation factor Xa (e.g., sodium sulforaphane), direct inhibitors of thrombin II (e.g., desiludine), thrombolytic agents, GPIIb/IIIa receptor antagonists, thienopyridines (e.g., clopidogrel), dipyridamole, dexrazoxane Sulfinpyrazone, vitamin K antagonists, and other oral anticoagulants.
Other combined medications.
No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when apixaban was combined with atenolol or famotidine. The combination of 10 mg apixaban and 100 mg atenolol did not have a clinically significant effect on the pharmacokinetics of apixaban, and the mean AUC and Cmax of apixaban were reduced by 15% and 18%, respectively, when compared to apixaban alone. The combination of 10 mg apixaban and 40 mg famotidine had no effect on the AUC or Cmax of apixaban
No effect was observed.
Effect of apixaban on other drugs.
In vitro experiments found that apixaban did not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2D6 or CYP3A4 activity (IC50 > 45 μM) and weakly inhibited CYP2C19 activity (IC50 > 20 μM) at concentrations well above peak plasma concentrations in patients. Apixaban concentrations up to 20 μM did not induce CYP1A2, CYP2B6, or CYP3A4/5. Therefore, apixaban is not expected to alter the metabolic clearance of combined doses metabolized by these enzymes. Apixaban is not a significant P-gp inhibitor.
As described below, apixaban was not found to have a clinically meaningful effect on the pharmacokinetics of digoxin, naproxen, or atenolol in trials conducted in healthy volunteers.
Digoxin: Concomitant administration of apixaban (20 mg once daily) and the P-gp substrate digoxin (0.25 mg once daily) had no effect on the AUC or Cmax of digoxin. Therefore, apixaban does not inhibit P-gp-mediated substrate transport.
Naproxen: Concurrent single doses of apixaban (10 mg) and naproxen (500 mg), a commonly used nonsteroidal anti-inflammatory drug, had no effect on the AUC or Cmax of naproxen.
Atenolol: Concomitant single doses of apixaban (10 mg) and a commonly used beta-blocker, atenolol (100 mg), did not alter the pharmacokinetics of atenolol.
[Drug overdose].
There is no antidote for apixaban. Apixaban overdose may result in an increased risk of bleeding. When bleeding complications occur, the drug should be discontinued immediately and the cause of bleeding should be identified. Appropriate therapeutic measures, such as surgical hemostasis and fresh frozen plasma transfusion, should be considered.
In a controlled clinical trial, healthy volunteers received up to 50 mg of apixaban orally for 3 to 7 days (25 mg twice daily for 7 days or 50 mg once daily for 3 days) [equivalent to 10 times the maximum recommended daily dose in humans] without clinically meaningful adverse effects.
A preclinical trial with dogs found that oral administration of activated charcoal within 3 hours of apixaban administration reduced apixaban exposure; therefore, the use of activated charcoal may be considered in the management of apixaban overdose.
If life-threatening bleeding cannot be controlled with the above therapeutic measures, prothrombin-concentrating complexes (PCCs) or recombinant factor VIIa may be considered. In healthy subjects, the 4-factor prothrombin-concentrating complexes (PCCs) have been shown to reverse the pharmacological effects of apixaban tablets by thrombin generation assays. However, there is no clinical experience in individual patients taking apixaban tablets to demonstrate whether the use of 4-factor prothrombin complex concentrate products can reverse bleeding. Although there is no experience with the use of recombinant factor VIIa in patients taking apixaban, repeated administration of recombinant coagulation factor VIIa with dose adjustment based on improvement in bleeding may be considered.
[Clinical Trials].
The Apixaban Clinical Research Program was designed to demonstrate the efficacy and safety of Apixaban for the prevention of venous thromboembolism in adult patients undergoing elective hip or knee arthroplasty. A total of 8,464 patients were randomly assigned to two pivotal, double-blind, international multicenter trials comparing apixaban 2.5 mg twice daily (4,236 patients) with enoxaparin 40 mg once daily (4,228 patients). There were 1,262 patients aged 75 years and older (618 patients in the apixaban group), 1,004 patients with low body weight (≤60 kg) (499 patients in the apixaban group), 1,495 patients with a BMI ≥33 kg/m2 (743 patients in the apixaban group) and 415 patients with moderate renal impairment (203 patients in the apixaban group).
A total of 5,407 patients undergoing elective hip arthroplasty were enrolled in the ADVANCE-3 trial and 3,057 patients undergoing elective knee arthroplasty were enrolled in the ADVANCE-2 trial. Subjects received either apixaban 2.5 mg orally twice daily or enoxaparin 40 mg subcutaneously once daily. The first dose of apixaban was administered 12 to 24 hours after surgery, and enoxaparin was administered 9 to 15 hours before surgery. The duration of administration for both apixaban and enoxaparin was 32 to 38 days in the ADVANCE-3 trial and 10 to 14 days in the ADVANCE-2 trial.
Based on the medical history of patients in the ADVANCE-3 and ADVANCE-2 study populations (8,464 patients), 46% had hypertension, 10% had hyperlipidemia, 9% had diabetes, and 8% had coronary artery disease.
Compared with enoxaparin, in patients undergoing elective hip arthroplasty or knee arthroplasty, apixaban significantly reduced the incidence of the primary endpoint-all VTE/all-cause mortality composite endpoint-and the significant VTE endpoint events-proximal deep vein thrombosis (DVT), nonfatal pulmonary embolism (PE), and VTE-related The incidence of the composite endpoint of death was statistically superior (see Table 2).
Table 2: Efficacy metric results from the pivotal phase III trial
Trial ADVANCE-3 (hip) ADVANCE-2 (knee) Trial Dose
Dose
Duration of treatment Apixaban
2.5 mg po bid
35 ± 3 days enoxaparin
40 mg sc od
35 ± 3 days p-value Apixaban
2.5mg po bid
12 ± 2 days enoxaparin
40 mg sc od
12 ± 2 days p-value Total VTE/all-cause mortality events/number of patients
Incident rate 27/1949
1.39%74/1917
3.86%<0.0001147/976
15.06%243/997
24.37%<0.0001 Relative risk
95% CI0.36
(0.22, 0.54) 0.62
(0.51, 0.74) Significant VTE endpoint event event/number of patients
Incident rate 10/2199
0.45%25/2195
1.14%0.010713/1195
1.09%26/1199
2.17%0.0373 Relative risk
95% CI0.40
(0.15, 0.80) 0.50
(0.26, 0.97)
Patients taking apixaban 2.5 mg twice daily had comparable rates of the safety endpoint-composite endpoints of major bleeding events, major bleeding and clinically significant non-major (CRNM) bleeding, and all bleeding events compared with enoxaparin 40 mg once daily (see Table 3). Surgical site bleeding was included in all bleeding criteria.
Table 3: Bleeding outcomes in the pivotal phase III trial*
ADVANCE-3 (hip) ADVANCE-2 (knee) Apixaban
2.5 mg po bid
35 ± 3 days enoxaparin
40 mg sc od
35 ± 3 days Apixaban
2.5 mg po bid
12 ± 2 days enoxaparin
40 mg sc od
12 ± 2 days total treated n = 2673n = 2659n = 1501n = 1508 during treatment1 major bleeding 22 (0.8%)18 (0.7%)9 (0.6%)14 (0.9%) fatal 0000 major bleeding + CRNM 129 (4.8%)134 (5.0%)53 (3.5%)72 (4.8%) all bleeding 313 ( 11.7%)334 (12.6%)104 (6.9%)126 (8.4%)2 major bleeding during postoperative treatment9 (0.3%)11 (0.4%)4 (0.3%)9 (0.6%) fatal 0000 major bleeding + CRNM96 (3.6%)115 (4.3%)41 (2.7%)56 (3.7%)all bleeding 261 ( 9.8%)293 (11.0%)89 (5.9%)103 (6.8%)* Surgical site bleeding was included in all bleeding criteria.
1Includes events that occurred after the first administration of enoxaparin (before surgery)
2Includes events occurring after the first administration of apixaban (after surgery)
In the ADVANCE-2 trial, a total of 180 patients from 6 study centers in China were randomized to double-blind study drug therapy (90 in each treatment group). In the ADVANCE-3 trial, a total of 245 patients at 7 study centers in China were randomized to double-blind study drug treatment (121 in the apixaban group; 124 in the enoxaparin group).
The overall effectiveness characteristics of apixaban in Chinese subjects were consistent with the overall study results. In the Chinese subgroup, fewer endpoint events were observed in the apixaban 2.5 mg BID treatment group than in the enoxaparin 40 mg QD treatment group (see Table 4).
Table 4: Efficacy of the pivotal phase III trial (Chinese subgroup results)
Trial ADVANCE-3 (hip) ADVANCE-2 (knee) Trial dose
Dose
Duration of treatment Apixaban
2.5 mg po bid
35 ± 3 days enoxaparin
40 mg sc od
35 ± 3 days Apixaban
2.5mg po bid
12 ± 2 days enoxaparin
40 mg sc od
12 ± 2 days Total VTE/all-cause mortality events/number of patients
Incident rate 0/86
0% 4/77
5.19% 7/67
10.45%17/73
23.29% Relative risk
95% CI0
(0.00, 0.86) 0.45
(0.20, 0.99) Significant VTE endpoint event event/number of patients
Incidence of events0/94
0% 0/88
0% 1/78
1.28% 4/82
4.88% Relative risk
95% CI not estimable 0.26
(0.02, 1.71)
The overall safety profile of apixaban in Chinese subjects was consistent with the safety profile in global studies. Apixaban was safe and well tolerated in Chinese subjects, with few bleeding events reported throughout the trial (see Table 5). In addition, the overall adverse event rate among Chinese subjects was much lower, and no Chinese subjects died.
Table 5: Bleeding safety results in the Chinese subgroup of the pivotal phase III trial*
ADVANCE-3 (hip) ADVANCE-2 (knee) Apixaban
2.5 mg po bid
35 ± 3 days enoxaparin
40 mg sc od
35 ± 3 days Apixaban
2.5 mg po bid
12 ± 2 days enoxaparin
40 mg sc od
12 ± 2 days total treated n = 117n = 120n = 86n = 88 during treatment1 major bleeding 0 (0.0%)2 (1.67%)0 (0.0%)0 (0.0%) fatal 0000 major bleeding + CRNM1 (0.85%) 4 (3.33%)0 (0.0%)1 (1.14%) all bleeding4 (3.42%)5 (4.17%) 1 (1.16%)1 (1.14%)2 major bleeding during postoperative treatment0 (0.3%)1 (0.83%)0 (0.0%)0 (0.0%) fatal 0000 major bleeding + CRNM0 (0.0%)3 (2.5%)0 (0.0%)1 (1.14%)all bleeding3 (2.56%)4 (3.33%)1 (1.16%)1 ( 1.14%)* All bleeding criteria included surgical site bleeding.
1Includes events that occurred after the first administration of enoxaparin (before surgery)
2Includes events occurring after the first administration of apixaban (after surgery)
In phase II and III studies performed in patients undergoing elective hip and knee replacement surgery, the overall incidence of adverse events such as bleeding, anemia, and transaminase abnormalities (e.g., alanine aminotransferase levels) was numerically less in patients in the apixaban group than in the enoxaparin group.
In the knee replacement surgery study, four cases of PE occurred in the apixaban group and none in the enoxaparin group during the intention-to-treat period for unknown reasons. In the Chinese subgroup study, no PE occurred in both groups.
Pharmacology and toxicology]
Pharmacological effects
Apixaban is a potent, orally effective reversible, direct, highly selective inhibitor of the active site of factor Xa, whose antithrombotic activity is not dependent on antithrombin III. Apixaban inhibits free and thrombus-bound factor Xa and inhibits thrombinogenase activity. Apixaban has no direct effect on platelet aggregation, but indirectly inhibits thrombin-induced platelet aggregation. Through the inhibition of factor Xa, apixaban inhibits thrombin production and inhibits thrombus formation. The results of preclinical tests in animal models show that apixaban has antithrombotic effects at dose levels that do not affect hemostatic function and prevents arterial and venous thrombosis.
Pharmacodynamics
The pharmacodynamic effect of apixaban is a reflection of its mechanism of action (inhibition of factor Xa). Since apixaban inhibits factor Xa, it prolongs the parameters of coagulation tests such as prothrombin time (PT), INR, and activated partial thromboplastin time (aPTT). The magnitude of change in these coagulation parameters is small and highly variable at the expected therapeutic dose and is not recommended for evaluating the efficacy of apixaban.
In in vitro studies using several commercially available anti-factor Xa kits, apixaban was seen to reduce the enzymatic activity of factor Xa, also suggesting its anti-factor Xa activity; however, the results varied between kits. Only the Rotachrom heparin colorimetric assay, for which clinical trial data are available, found a close and direct linear correlation between the anti-Factor Xa activity of apixaban and its plasma concentration, with the anti-Factor Xa activity reaching a maximum when the plasma concentration reached a peak. Over a wide dose range, the concentration of apixaban showed a linear relationship with its anti-Factor Xa activity, and the accuracy of the Rotachrom test met the requirements of clinical laboratories. The changes in anti-Factor Xa activity due to changes in dose and concentration of apixaban were more significant and less variable than the changes in coagulation parameters.
The steady-state peak and trough values of anti-Factor Xa activity were predicted to be 1.3 IU/ml (5th/95th percentile 0.67-2.4 IU/ml) and 0.84 IU/ml (5th/95th percentile 0.37-1.8 IU/ml) after apixaban 2.5 mg twice daily, i.e., the peak/trough ratio of anti-Factor Xa activity during the dosing interval was less than 1.6 times. ratio was less than 1.6-fold.
Although routine monitoring of exposure is not required when taking apixaban, Rotachrom® anti-Factor Xa analysis may be useful in special situations where knowledge of apixaban exposure is needed to aid clinical decision making, such as drug overdose and emergency surgery.
Toxicology Studies
Genotoxicity.
Apixaban Ames test, Chinese hamster ovary cell chromosome aberration test, and rat bone marrow micronucleus test results were all negative.
Reproductive toxicity.
The results of fertility and early embryonic development toxicity tests in rats showed that no significant effects on maternal fertility and no significant effects on offspring growth and development were observed for apixaban administered at doses up to 600 mg/kg. A 1.2-1.6-fold prolongation of PT and aPTT values of coagulation parameters in parental rats was seen in all dosing groups (50, 200 and 600 mg/kg/day).
No significant drug-related abnormalities in offspring growth and development were observed in pregnant rats and pregnant rabbits given apixaban up to 3000 mg/kg/day and 1500 mg/kg/day, respectively, orally.
The results of perinatal reproductive toxicity test in rats showed that the NOAEL for effects on maternal reproductive function was 1000 mg/kg/day and the NOAEL for effects on offspring growth and development was 25 mg/kg/day. Reduced offspring mating and fertility indices were seen in the ≥200 mg/kg/day group with a maternal rat AUC ≥ 14 times the recommended human dose (RHD) AUC, with uncertain clinical relevance.
Carcinogenicity.
In mice and rats given apixaban orally for 104 weeks in carcinogenicity tests, no increase in tumor incidence associated with administration was seen in male and female mice given doses up to 1500 mg/kg/day and 3000 mg/kg/day, respectively. In rats given apixaban orally at doses up to 600 mg/kg/day, no drug-related increase in tumor incidence was observed.
[Pharmacokinetics].
Absorption
The absolute bioavailability of apixaban is about 50% in the dose range of 10mg. Apixaban is rapidly absorbed, reaching maximum concentration (Cmax) 3-4 hours after administration. Eating has no effect on the AUC or Cmax of apixaban 10 mg. Apixaban can be taken with or without a meal.
Apixaban has a linear pharmacokinetic profile in the 10 mg dose range, which is dose dependent. At doses of apixaban ≥ 25 mg, it showed dissolution-limited absorption and decreased bioavailability. The exposure parameters of apixaban exhibited low to moderate variability with intra-individual coefficients of variation (CVs) of approximately 20% and inter-individuals of approximately 30%.
Apixaban 10 mg was administered orally by crushing two 5 mg tablets of apixaban and then mixing them in 30 mL of water. exposure to apixaban taken after crushing was comparable to that of 2 whole 5 mg tablets administered orally. Apixaban 10 mg was administered orally by crushing 2 5 mg tablets and mixing them with 30 g of applesauce.
Cmax and AUC were reduced by 21% and 16%, respectively, compared to the administration of 2 complete tablets.
The reduction in exposure was not considered clinically relevant.
One tablet of 5 mg apixaban crushed and mixed in 60 mL of 5% dextrose solution was administered via a nasogastric tube, and the exposure to apixaban in this manner was similar to that in clinical trials in other healthy subjects receiving a single oral dose of 5 mg apixaban tablets.
The results of the bioavailability study are applicable to low doses of apixaban based on predictable, proportional dose pharmacokinetic information for apixaban.
Distribution
In humans, the binding rate to plasma proteins is approximately 87%. The volume of distribution (Vss) is approximately 21 liters.
Metabolism
The major site of biotransformation of apixaban is the o-demethylation or hydroxylation of the 3-piperidinone group. Apixaban is mainly metabolized by CYP3A4/5 and rarely partially by CYP1A2,2C8,2C9,2C19 and 2J2. Prototype apixaban is the major drug-related component in human plasma, and no active circulating metabolites have been identified. Apixaban is a substrate for the transporter protein P-gp and breast cancer resistance protein (BCRP).
Excretion
Apixaban can be eliminated by various routes. After administration of apixaban in humans, approximately 25% appears as metabolites, with the majority being detected in the feces. Renal excretion accounts for approximately 27% of the total clearance. In addition, additional biliary excretion was found in clinical trials and additional direct intestinal excretion was found in non-clinical trials.
The total body clearance of apixaban is approximately 3.3 L/h, with a half-life of approximately 12 hours.
Special Populations.
Renal impairment
Renal impairment had no effect on the maximum plasma concentration of apixaban. Apixaban exposure increases with decreasing renal function (as assessed by creatinine clearance). The area under the plasma concentration curve (AUC) of apixaban was increased by 16%, 29% and 44% in patients with mild renal impairment (creatinine clearance 51-80 ml/min), moderate impairment (creatinine clearance 30-50 ml/min) and severe impairment (creatinine clearance 15-29 ml/min), respectively, compared to those with normal creatinine clearance. Renal impairment had no significant effect on the relationship between plasma concentrations of apixaban and anti-FXa activity.
Liver damage
In a study comparing mild liver damage (Child Pugh class A, with a score of 5 in 6 cases and a score of 6 in 2 cases)
and moderate hepatic impairment patients (Child Pugh class B, of which 6 cases scored 7 and 2 cases scored 8) and healthy subjects (16 cases), there was no change in the pharmacokinetics and pharmacodynamics of apixaban in patients with hepatic impairment after a single administration of apixaban 5 mg. Changes in anti-FXa activity and INR in patients with mild or moderate liver damage were comparable to those in healthy subjects.
Geriatric patients
Plasma concentrations were higher in elderly patients (>65 years) than in younger patients, with a mean AUC approximately 32% higher.
Gender
Apixaban exposure was approximately 18% higher in women than in men. No dose adjustment is required.
Ethnicity and race
Results from phase I clinical trials showed no significant differences in the pharmacokinetics of apixaban among Caucasians/Caucasians, Asians, and Blacks/African Americans. A population pharmacokinetic analysis of patients taking apixaban after undergoing elective hip or knee arthroplasty showed results consistent with the findings of the Phase I trial described above.
Body weight
Compared to patients weighing 65 kg to 85 kg, exposure to apixaban was reduced by approximately 30% in patients weighing 120 kg and increased by approximately 30% in patients weighing 50 kg. No dose adjustment was required.
Pharmacokinetic/pharmacodynamic relationships
The pharmacokinetic/pharmacodynamic (PK/PD) relationship between apixaban blood concentrations and several pharmacodynamic endpoints (anti-Factor Xa activity, INR, PT, aPTT) has been evaluated for doses ranging from 0.5 mg to 50 mg. The relationship between apixaban concentrations and Factor Xa activity is most consistent with a linear model. The PK/PD relationship in patients undergoing elective hip or knee arthroplasty was consistent with the results in healthy subjects.
[Storage].
Keep sealed.
Packaging
Polyvinyl chloride/polyethylene/polyvinylidene chloride solid pharmaceutical laminate rigid tablets and pharmaceutical aluminum foil packaging, boxed.
7 tablets/plate, 1 plate/box; 7 tablets/plate, 2 plates/box; 10 tablets/plate, 1 plate/box; 10 tablets/plate, 2 plates/box; 10 tablets/plate, 6 plates/box.
【Validity】.
24 months.
【Execution standard
【Approval number】
【Drug marketing license holder
* Name: Qilu Pharmaceutical (Hainan) Co.
* Registered Address: No. 273 Nanhai Avenue, Haikou National High-tech Zone – A
Zip code: 570314
Contact：0898-68629588
Fax: 0898-68629588
Website: http://www.qilu-hainan.com
【Manufacturing enterprise】.
*Company Name: Qilu Pharmaceutical (Hainan) Co.
*Production Address: No. 273, Nanhai Avenue, Haikou National High-tech Zone, Haikou City, China – A
Postcode：570314
Contact：0898-68629588
Fax: 0898-68629588
Website: http://www.qilu-hainan.com