Apixaban 2.5 mg (Apiklot): Yellow, round shaped, biconvex, film coated tablets debossed with "I1" on one side and plain on other side.
Apixaban 5 mg (Apiklot): Pink, oval shaped, biconvex, film coated tablets debossed with "I2" on one side and plain on the other side.
Each film-coated contains: Apixaban 5 mg, Apixaban 2.5 mg
Antithrombotic Agent (Direct Factor XA Inhibitor).
Pharmacology: Pharmacodynamics: Mechanism of Action: Apixaban is an oral, reversible, and selective active site inhibitor of FXa. It does not require antithrombin III for antithrombotic activity. Apixaban inhibits free and clot-bound FXa, and prothrombinase activity. Apixaban has no direct effect on platelet aggregation, but indirectly inhibits platelet aggregation induced by thrombin. By inhibiting FXa, apixaban decreases thrombin generation and thrombus development.
Pharmacokinetics: Absorption: The absolute bioavailability of apixaban is approximately 50% for doses up to 10 mg. Apixaban is rapidly absorbed with maximum concentrations (Cmax) appearing 3 to 4 hours after tablet intake. Intake with food does not affect apixaban AUC or Cmax at the 10 mg dose. Apixaban can be taken with or without food.
Apixaban demonstrates linear pharmacokinetics with dose proportional increases in exposure for oral doses up to 10 mg. At doses ≥25 mg apixaban displays dissolution limited absorption with decreased bioavailability. Apixaban exposure parameters exhibit low to moderate variability reflected by a within-subject and inter-subject variability of ~20% CV and ~30% CV, respectively.
Following oral administration of 10 mg of apixaban as 2 crushed 5 mg tablets suspended in 30 mL of water, exposure was comparable to exposure after oral administration of 2 whole 5 mg tablets. Following oral administration of 10 mg of apixaban as 2 crushed 5 mg tablets with 30 g of apple puree, the Cmax and AUC were 21% and 16% lower, respectively, when compared to administration of 2 whole 5 mg tablets. The reduction in exposure is not considered clinically relevant.
Following administration of a crushed 5 mg apixaban tablet suspended in 60 mL of G5W and delivered via a nasogastric tube, exposure was similar to exposure seen in other clinical studies involving healthy subjects receiving a single oral 5 mg apixaban tablet dose. Given the predictable, dose-proportional pharmacokinetic profile of apixaban, the bioavailability results from the conducted studies are applicable to lower apixaban doses.
Distribution: Plasma protein binding in humans is approximately 87%. The volume of distribution (Vss) is approximately 21 litres.
Biotransformation and elimination: Apixaban has multiple routes of elimination. Of the administered apixaban dose in humans, approximately 25% was recovered as metabolites, with the majority recovered in feces. Renal excretion of apixaban accounts for approximately 27% of total clearance. Additional contributions from biliary and direct intestinal excretion were observed in clinical and nonclinical studies, respectively. Apixaban has a total clearance of about 3.3 L/h and a half-life of approximately 12 hours.
O-demethylation and hydroxylation at the 3-oxopiperidinyl moiety are the major sites of biotransformation. Apixaban is metabolised mainly via CYP3A4/5 with minor contributions from CYP1A2, 2C8, 2C9, 2C19, and 2J2. Unchanged apixaban is the major active substance-related component in human plasma with no active circulating metabolites present. Apixaban is a substrate of transport proteins, P-gp and breast cancer resistance protein (BCRP).
Elderly: Elderly patients (above 65 years) exhibited higher plasma concentrations than younger patients, with mean AUC values being approximately 32% higher and no difference in Cmax.
Renal impairment: There was no impact of impaired renal function on peak concentration of apixaban. There was an increase in apixaban exposure correlated to decrease in renal function, as assessed via measured creatinine clearance. In individuals with mild (creatinine clearance 51-80 mL/min), moderate (creatinine clearance 30-50 mL/min) and severe (creatinine clearance 15-29 mL/min) renal impairment, apixaban plasma concentrations (AUC) were increased 16, 29, and 44% respectively, compared to individuals with normal creatinine clearance. Renal impairment had no evident effect on the relationship between apixaban plasma concentration and anti-Factor Xa activity.
In subjects with end-stage renal disease (ESRD), the AUC of apixaban was increased by 36% when a single dose of apixaban 5 mg was administered immediately after hemodialysis, compared to that seen in subjects with normal renal function. Hemodialysis, started two hours after administration of a single dose of apixaban 5 mg, decreased apixaban AUC by 14% in these ESRD subjects, corresponding to an apixaban dialysis clearance of 18 mL/min. Therefore, hemodialysis is unlikely to be an effective means of managing apixaban overdose.
Hepatic impairment: In a study comparing 8 subjects with mild hepatic impairment, Child-Pugh A score 5 (n=6) and score 6 (n = 2), and 8 subjects with moderate hepatic impairment, Child-Pugh B score 7 (n = 6) and score 8 (n = 2), to 16 healthy control subjects, the single-dose pharmacokinetics and pharmacodynamics of apixaban 5 mg were not altered in subjects with hepatic impairment. Changes in anti-Factor Xa activity and INR were comparable between subjects with mild to moderate hepatic impairment and healthy subjects.
Gender: Exposure to apixaban was approximately 18% higher in females than in males.
Ethnic origin and race: The results across phase I studies showed no discernible difference in apixaban pharmacokinetics between White/Caucasian, Asian and Black/African American subjects. Findings from a population pharmacokinetic analysis in patients who received apixaban were generally consistent with the phase I results.
Body weight: Compared to apixaban exposure in subjects with body weight of 65 to 85 kg, body weight >120 kg was associated with approximately 30% lower exposure and body weight <50 kg was associated with approximately 30% higher exposure.
Prevention of venous thromboembolic events (VTE) in adult patients who have undergone elective hip or knee replacement surgery.
Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation (NVAF), with one or more risk factors, such as prior stroke or transient ischaemic attack (TIA); age ≥75 years; hypertension; diabetes mellitus; symptomatic heart failure (NYHA Class ≥II).
Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults.
Prevention of VTE (VTEp): Elective hip or knee replacement surgery: The recommended dose of Apixaban is 2.5 mg taken orally twice daily. The initial dose should be taken 12 to 24 hours after surgery.
Physicians may consider the potential benefits of earlier anticoagulation for VTE prophylaxis as well as the risks of post-surgical bleeding in deciding on the time of administration within this time window.
In patients undergoing hip replacement surgery: The recommended duration of treatment is 32 to 38 days.
In patients undergoing knee replacement surgery: The recommended duration of treatment is 10 to 14 days.
Prevention of stroke and systemic embolism in patients with AF: NVAF: The recommended dose of Apixaban is 5 mg taken orally twice daily.
Age, body weight, serum creatinine: In patients with at least 2 of the following characteristics, age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL (133 micromole/L), the recommended dose of Apixaban is 2.5 mg twice daily.
Treatment of DVT and PE: The recommended dose of Apixaban is 10 mg taken orally twice daily for 7 days, followed by 5 mg taken orally twice daily.
Prevention of recurrent DVT and PE: The recommended dose of Apixaban is 2.5 mg taken orally twice daily after at least 6 months of treatment for DVT or PE.
Renal Impairment: Prevention of VTE in surgical patients: Elective hip or knee replacement surgery: No dose adjustment is necessary in patients with mild, moderate or severe (creatinine clearance 15-29 mL/min) renal impairment. Because there is limited clinical experience in patients with creatinine clearance <15 mL/min and no data in patients undergoing dialysis, Apixaban is not recommended in these patients.
Prevention of stroke and systemic embolism in patients with AF: NVAF: No dose adjustment is recommended in patients with creatinine clearance 15 to 29 mL/min, except as described in Recommended Dosage: Prevention of stroke and systemic embolism in patients with AF: NVAF as previously mentioned. Because there is no clinical experience in patients with creatinine clearance <15 mL/min, a dosing recommendation cannot be provided.
There are no data in patients undergoing dialysis, therefore, Apixaban is not recommended in these patients.
Treatment of VTE: No dose adjustment is necessary in patients with mild, moderate, or severe (creatinine clearance 15-29 mL/min) renal impairment. Because there is limited clinical experience in patients with creatinine clearance <15 mL/min and no data in patients undergoing dialysis, Apixaban is not recommended in these patients.
Hepatic Impairment: Apixaban may be used with caution in patients with mild or moderate hepatic impairment (Child Pugh A or B). No dose adjustment is required in patients with mild or moderate hepatic impairment. Apixaban is not recommended in patients with severe hepatic impairment).
Body Weight: Prevention of VTE in surgical patients: Elective hip or knee replacement surgery: No dose adjustment required.
Prevention of stroke and systemic embolism in patients with AF: NVAF: See Recommended Dosage: Prevention of stroke and systemic embolism in patients with AF: NVAF as previously mentioned.
Treatment of VTE: No dose adjustment required.
Gender: No dose adjustment required.
Pediatric and Adolescent: The efficacy and safety of Apixaban in children below age 18 have not been established. No data are available.
Elderly: Prevention of VTE in surgical patients: Elective hip or knee replacement surgery: No dose adjustment required.
Prevention of stroke and systemic embolism in patients with AF: NVAF: See Recommended Dosage: Prevention of stroke and systemic embolism in patients with AF: NVAF as previously mentioned.
Treatment of VTE: No dose adjustment required (see Pharmacology: Pharmacokinetics under Actions).
Converting from or to Parenteral Anticoagulants: In general, switching treatment from parenteral anticoagulants to Apixaban (and vice versa) can be done at the next scheduled dose.
Converting from or to Warfarin or Other Vitamin K Antagonists (VKA): When converting patients from warfarin or other VKA therapy to Apixaban, discontinue warfarin or other VKA therapy and start Apixaban when the international normalized ratio (INR) is below 2.0.
When converting from Apixaban to warfarin or other VKA therapy, continue Apixaban for 48 hours after the first dose of warfarin or other VKA therapy.
Surgery and Invasive Procedures: Apixaban should be discontinued at least 48 hours prior to elective surgery or invasive procedures with a moderate or high risk of unacceptable or clinically significant bleeding. Apixaban should be discontinued at least 24 hours prior to elective surgery or invasive procedures with a low risk of bleeding or where the bleeding would be non-critical in location and easily controlled. If surgery or invasive procedures cannot be delayed, exercise appropriate caution taking into consideration an increased risk of bleeding. This risk of bleeding should be weighed against the urgency of intervention. In nonvalvular atrial fibrillation patients, bridging anticoagulation during the 24 to 48 hours after stopping Apixaban and prior to the intervention is not generally required. Apixaban should be restarted after the surgical or other procedures as soon as adequate hemostasis has been established.
Apixaban can be initiated or continued in NVAF patients who may require cardioversion. For patients not previously treated with anticoagulants, at least 5 doses of Apixaban 5 mg twice daily [2.5 mg twice daily in patients who qualify for a dose reduction (see as previously mentioned)] should be given before cardioversion to ensure adequate anticoagulation. If cardioversion is required before 5 doses of Apixaban can be administered, a 10 mg loading dose should be given, followed by 5 mg twice daily. The dosing regimen should be reduced to a 5 mg loading dose followed by 2.5 mg twice daily if the patient meets the criteria for dose reduction (see as previously mentioned). The administration of the loading dose should be given at least 2 hours before cardioversion.
Confirmation should be sought prior to cardioversion that the patient has taken Apixaban as prescribed. Decisions on initiation and duration of treatment should take established guideline recommendations for anticoagulant treatment in patients undergoing cardioversion into account.
Method of administration: Oral use.
Apixaban should be swallowed with water, with or without food.
Overdose of apixaban may result in a higher risk of bleeding. In the event of hemorrhagic complications, treatment must be discontinued and the source of bleeding investigated. The initiation of appropriate treatment, e.g., surgical hemostasis, the transfusion of fresh frozen plasma or the administration of a reversal agent for factor Xa inhibitors should be considered.
In controlled clinical studies, orally-administered apixaban in healthy subjects at doses up to 50 mg daily for 3 to 7 days (25 mg twice daily (bid) for 7 days or 50 mg once daily (od) for 3 days) had no clinically relevant adverse reactions.
In healthy subjects, administration of activated charcoal 2 and 6 hours after ingestion of a 20 mg dose of apixaban reduced mean apixaban AUC by 50% and 27%, respectively, and had no impact on Cmax. Mean half-life of apixaban decreased from 13.4 hours when apixaban was administered alone to 5.3 hours and 4.9 hours, respectively, when activated charcoal was administered 2 and 6 hours after apixaban. Thus, administration of activated charcoal may be useful in the management of apixaban overdose or accidental ingestion. For situations when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding, a reversal agent for factor Xa inhibitors is available. Administration of prothrombin complex concentrates (PCCs) or recombinant factor VIIa may also be considered. Reversal of apixaban pharmacodynamic effects, as demonstrated by changes in the thrombin generation assay, was evident at the end of infusion and reached baseline values within 4 hours after the start of a 4-factor PCC 30 minute infusion in healthy subjects. However, there is no clinical experience with the use of 4-factor PCC products to reverse bleeding in individuals who have received apixaban. Currently there is no experience with the use of recombinant factor VIIa in individuals receiving apixaban. Re-dosing of recombinant factor VIIa could be considered and titrated depending on improvement of bleeding.
Depending on local availability, a consultation of a coagulation expert should be considered in case of major bleedings.
Hemodialysis decreased apixaban AUC by 14% in subjects with end-stage renal disease (ESRD), when a single dose of apixaban 5 mg was administered orally. Therefore, hemodialysis is unlikely to be an effective means of managing apixaban overdose.
Apixaban is contraindicated in patients with the following conditions: Active pathological bleeding; Severe hypersensitivity reaction to Apixaban (i.e., anaphylactic reactions).
Increased Risk of Stroke with Discontinuation of Apixaban: Discontinuing Apixaban in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from Apixaban to warfarin in clinical trials in patients with nonvalvular atrial fibrillation. If Apixaban must be discontinued for a reason other than pathological bleeding consider coverage with another anticoagulant.
Bleeding: Apixaban increases the risk of bleeding and can cause serious, potentially fatal, bleeding. Concomitant use of drugs affecting hemostasis increases the risk of bleeding. These include aspirin and other antiplatelet agents, other anticoagulants, heparin, thrombolytic agents selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitor, and nonsteroidal anti-inflammatory drugs (NSAIDs).
Patients should be made aware of signs and symptoms of blood loss and instructed to report them immediately or go to an emergency room. Apixaban should be discontinued in patients with active pathological hemorrhage.
There is no established way to reverse the anticoagulant effect of apixaban, which can be expected to persist for about 24 hours after the last dose, i.e., for about two half-lives. A specific antidote for Apixaban is not available. Because of high plasma protein binding, apixaban is not expected to be dialyzable. Protamine sulfate and vitamin K would not be expected to affect the anticoagulant activity of apixaban. There is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) in individuals receiving apixaban.
There is neither scientific rationale for reversal nor experience with systemic hemostatics (desmopressin and aprotinin) in individuals receiving apixaban. Use of procoagulant reversal agents such as prothrombin complex concentrate, activated prothrombin complex concentrate, or recombinant factor VIIa may be considered but has been evaluated in clinical studies. Activated oral charcoal reduces absorption of apixaban, thereby lowering apixaban plasma concentration.
Patients with Prosthetic Heart Valves: The safety and efficacy of Apixaban has not been studied in patients with prosthetic heart valves. Therefore, use of Apixaban is not recommended in these patients.
Effects on ability to drive and use machines: Apixaban has no or negligible influence on the ability to drive and use machines.
Pregnancy: There are no data from the use of apixaban in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. As a precautionary measure, it is preferable to avoid the use of apixaban during pregnancy.
Lactation: It is unknown whether apixaban or its metabolites are excreted in human milk. Available data in animals have shown excretion of apixaban in milk. A risk to the suckling child cannot be excluded.
A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from apixaban therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Summary of the safety profile: The safety of apixaban has been investigated in 4 Phase III clinical studies including more than 15,000 patients: more than 11,000 patients in NVAF studies and more than 4,000 patients in the VTE treatment (VTEt) studies, for an average total exposure of 1.7 years and 221 days respectively.
Common adverse reactions were hemorrhage, contusion, epistaxis, and hematoma.
In the NVAF studies, the overall incidence of adverse reactions related to bleeding with apixaban was 24.3% in the apixaban vs warfarin study and 9.6% in the apixaban vs acetylsalicylic acid study. In the apixaban vs warfarin study the incidence of ISTH major gastrointestinal bleeds (including upper GI, lower GI, and rectal bleeding) with apixaban was 0.76%/year. The incidence of ISTH major intraocular bleeding with apixaban was 0.18%/year.
In the VTEt studies, the overall incidence of adverse reactions related to bleeding with apixaban was 15.6% in the apixaban vs enoxaparin/warfarin study and 13.3% in the apixaban vs placebo study.
Tabulated list of adverse reactions: Table shows the adverse reactions ranked under headings of system organ class and frequency using the following convention: very common (≥1/10) common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data) for NVAF and VTEt respectively. (See table.)
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The use of apixaban may be associated with an increased risk of occult or overt bleeding from any tissue or organ, which may result in post-haemorrhagic anemia. The signs, symptoms, and severity will vary according to the location and degree or extent of the bleeding.
Apixaban is a substrate of both CYP3A4 and P-gp. Inhibitors of CYP3A4 and P-gp increase exposure to apixaban and increase the risk of bleeding. Inducers of CYP3A4 and P-gp decrease exposure to apixaban and increase the risk of stroke.
Strong Dual Inhibitors of CYP3A4 and P-gp: The dose of Apixaban should be decreased to 2.5 mg twice daily when it is coadministered with drugs that are strong dual inhibitors of CYP3A4 and P-gp, (e.g., ketoconazole, itraconazole, ritonavir, or clarithromycin).
In patients already taking Apixaban at a dose of 2.5 mg daily, avoid coadministration with strong dual inhibitors of both CYP3A4 and P-gp.
Strong Dual Inducers of CYP3A4 and P-gp: Avoid concomitant use of Apixaban with strong dual inducers of CYP3A4 and P-gp (e.g., rifampin, carbamazepine, phenytoin, St. John's wort) because such drugs will decrease exposure to apixaban.
Anticoagulants and Antiplatelet Agents: Coadministration of antiplatelet agents, fibrinolytics, heparin, aspirin, and chronic NSAID use increases the risk of bleeding.
Instruction and Special Precautions for Handling and Disposal: Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Store at temperatures not exceeding 30°C.
B01AF02 - apixaban ; Belongs to the class of direct factor Xa inhibitors. Used in the treatment of thrombosis.
Apiklot FC tab 2.5 mg
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