Torapix 2.5/Torapix 5

Apixaban (Torapix 2.5) 2.5 mg Film-Coated Tablet is a yellow coloured, round shaped, biconvex, beveled edge film coated tablet debossed with "H6" on one side and plain on the other side.
Apixaban (Torapix 5) 5 mg Film-Coated Tablet is a pink coloured, oval shaped, biconvex, beveled edge film-coated tablets having "H5" debossed on one side and plain on other side.
Each film-coated tablet contains: Apixaban 2.5 mg/5 mg.

Direct Factor Xa Inhibitor.
Pharmacology: The pharmacodynamic effects of apixaban are reflective of the mechanism of action (FXa inhibition). As a result of FXa inhibition, apixaban prolongs clotting tests such as prothrombin time (PT), INR and activated partial thromboplastin time (aPTT). Changes observed in these clotting tests at the expected therapeutic dose are small and subject to a high degree of variability. They are not recommended to assess the pharmacodynamic effects of apixaban. In the thrombin generation assay, apixaban reduced endogenous thrombin potential, a measure of thrombin generation in human plasma.
Apixaban also demonstrates anti-FXa activity as evident by reduction in factor Xa enzyme activity in multiple commercial anti-FXa kits, however results differ across kits. Data from clinical trials are only available for the Rotachrom Heparin chromogenic assay. Anti-FXa activity exhibits a close direct linear relationship with apixaban plasma concentration, reaching maximum values at the time of apixaban peak plasma concentrations. The relationship between apixaban plasma concentration and anti-FXa activity is approximately linear over a wide dose range of apixaban. The dose- and concentration-related changes observed following Apixaban administration are more pronounced, and less variable, with anti-FXa activity compared with clotting tests.
Mechanism of Action: Apixaban is a potent, oral, reversible, direct and highly selective active site inhibitor of factor Xa. It does not require antithrombin III for antithrombotic activity. Apixaban inhibits free and clot-bound factor Xa, and prothrombinase activity. Apixaban has no direct effects on platelet aggregation, but indirectly inhibits platelet aggregation induced by thrombin. By inhibiting factor Xa, apixaban prevents thrombin generation and thrombus development. Preclinical studies of apixaban in animal models have demonstrated antithrombotic efficacy in the prevention of arterial and venous thrombosis at doses that preserved haemostasis.
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 D5W and delivered via a nasogastric tube, exposure was similar to exposure seen in other clinical trials involving healthy subjects receiving a single oral 5 mg apixaban tablet dose.
Distribution: Plasma protein binding in humans is approximately 87%. The volume of distribution (Vss) is approximately 21 litres.
Metabolism 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 faeces. 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 drug-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).
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-FXa activity. No dose adjustment is necessary in patients with mild, moderate or severe renal impairment except as described in Dosage & Administration.
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 haemodialysis, compared to that seen in subjects with normal renal function. Haemodialysis, 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, haemodialysis is unlikely to be an effective means of managing apixaban overdose.
Hepatic Impairment: Apixaban has not been studied in patients with severe hepatic impairment or active hepatobiliary disease. Apixaban is not recommended in patients with severe hepatic impairment.
In a study comparing subjects with mild to moderate hepatic impairment (classified as Child Pugh A and B, respectively) to healthy control subjects, the single-dose pharmacokinetics and pharmacodynamics of Apixaban 5 mg were not altered in subjects with hepatic impairment. Changes in anti-FXa activity and INR were comparable between subjects with mild to moderate hepatic impairment and healthy subjects. No dose adjustment is required in patients with mild or moderate hepatic impairment; however, given the limited number of subjects studied, caution is advised when using Apixaban in this population.
Elderly: Elderly patients (above 65 years) exhibited higher plasma concentrations than younger patients, with mean AUC values being approximately 32% higher. No dose adjustment is required, except as described in Dosage & Administration.
Gender: Exposure to Apixaban was approximately 18% higher in females than in males. No dose adjustment is required.
Ethnic Origin and Race: The results across phase 1 studies showed no discernible difference in Apixaban pharmacokinetics between White/Caucasian, Asian and Black/African American subjects.
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. No dose adjustment is required, except as described in Dosage & Administration.

Apixaban is indicated for the 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 ischemic attack (TIA); age ≥75 years; hypertension; diabetes mellitus; symptomatic heart failure (NYHA Class ≥II) including patients unsuitable for warfarin. Compared to warfarin, Apixaban also results in less bleeding, including intracranial hemorrhage. Apixaban is also indicated for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE). It is also used for the prevention of recurrent DVT and PE in adults.
Apixaban is also indicated in the prevention of venous thromboembolic events (VTE) in adult patients who have undergone elective hip or knee replacement surgery.

Apixaban can be taken with or without food.
If a dose is missed, the patient should take Apixaban immediately and continue with twice daily administration as before.
Recommended Dosage: Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (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 deep vein thrombosis (DVT) and pulmonary embolism (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.
Prevention of VTE: 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.
Renal Impairment: Prevention of stroke and systemic embolism in patients with NVAF: No dose adjustment is recommended in patients with creatinine clearance 15 to 29 mL/min, except as described under Recommended Dosage. 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 deep vein thrombosis (DVT) and pulmonary embolism (PE): 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 stroke and systemic embolism in patients with NVAF: See Recommended Dosage.
Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE): No dose adjustment is required.
Gender: No dose adjustment is required.
Paediatric and Adolescent: The safety and efficacy of Apixaban in children and adolescents below age 18 have not been established. No data are available.
Elderly: Prevention of stroke and systemic embolism in patients with NVAF: See Recommended Dosage.
Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE): No dose adjustment is required.
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.
The 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 procedure as soon as adequate hemostasis has been established.
Patients can continue taking Apixaban while being cardioverted.
Method of Administration: Apixaban should be swallowed with water and may be taken with or without food.
For patients who are unable to swallow whole tablets, Apixaban tablets may be crushed and suspended in water, or 5% dextrose in water (D5W), or apple juice or mixed with apple puree and immediately administered orally. Alternatively, Apixaban tablets may be crushed and suspended in 60 mL of water or D5W and immediately delivered through a nasogastric tube.
Crushed Apixaban tablets are stable in water, D5W, apple juice, and apple puree for up to 4 hours.

Overdose and Treatment: Overdose of apixaban may result in a higher risk of bleeding. In the event of haemorrhagic complications, treatment must be discontinued and the source of bleeding investigated. The initiation of appropriate treatment, e.g., surgical haemostasis, the transfusion of fresh frozen plasma or the administration of a reversal agent for factor Xa inhibitors should be considered.
In controlled clinical trials, 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 effects.
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.

Hypersensitivity to the active substance or to any of the excipients. Clinically significant active bleeding.

Haemorrhage risk: As with other anticoagulants, patients taking Apixaban are to be carefully observed for signs of bleeding. It is recommended to be used with caution in conditions with increased risk of haemorrhage such as: congenital or acquired bleeding disorders; active ulcerative gastrointestinal disease; bacterial endocarditis; thrombocytopenia; platelet disorders; history of haemorrhagic stroke; severe uncontrolled hypertension; and recent brain, spinal or ophthalmological surgery. Apixaban is not recommended in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk. Apixaban administration should be discontinued if severe haemorrhage occurs.
In the event of haemorrhagic complications, treatment must be discontinued and the source of bleeding investigated. The initiation of appropriate treatment, e.g. Surgical haemostasis or the transfusion of fresh frozen plasma, should be considered. If life-threatening bleeding cannot be controlled by the previously mentioned measure, administration of prothrombin complex concentrates (PCCs) or recombinant factor VIIa may be considered.
Temporary discontinuation of Apixaban: Discontinuing anticoagulants, including Apixaban, for active bleeding, elective surgery, or invasive procedures places patients at an increased risk of thrombosis. Avoid lapses in therapy, and if anticoagulation with Apixaban must be temporarily discontinued for any reason, restart therapy as soon as possible.
Although treatment with apixaban does not require routine monitoring of exposure, a calibrated quantitative anti-Factor Xa assay may be useful in exceptional situations where knowledge of apixaban exposure may help to inform clinical decisions, e.g., overdose and emergency surgery. Due to an increased bleeding risk, concomitant treatment with any other anticoagulants is contraindicated.
Renal Impairment: *Prevention of stroke and systemic embolism in patients with NVAF: There are no data in patients undergoing dialysis, therefore, Apixaban is not recommended in these patients.
*Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE): 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 is not recommended in patients with severe hepatic impairment. Apixaban may be used with caution in patients with mild or moderate hepatic impairment (Child Pugh A or B).
Interactions with inhibitors of both Cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp): Apixaban can be administered with caution in patients receiving concomitant systemic treatment with strong inhibitors of both Cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp), such as azole-antimycotics (eg. ketoconazole, itraconazole, voriconazole and posaconazole), HIV protease inhibitors (eg, ritonavir). These medicinal products may increase apixaban exposure by 2-fold.
Interactions with inducers of both CYP3A4 and P-gp: The concomitant use of Apixaban with strong CYP3A4 and P-gp inducers (eg, rifampin, phenytoin, carbamazepine, phenobarbital or St. John's Wort) may lead to a -50% reduction in Apixaban exposure. Use caution when co-administering Apixaban with strong inducers of both CYP3A4 and P-gp.
For the treatment of DVT or PE, Apixaban is not recommended in patients receiving concomitant systemic treatment with strong inducers of both CYP3A4 and P-gp. For prevention of recurrent DVT and PE, use caution when co-administering Apixaban with strong inducers of both CYP3A4 and P-gp.
Interaction with other medicinal products affecting the hemostasis: The concomitant use of Apixaban with antiplatelet agents increases the risk of bleeding. Care is to be taken if patients are treated concomitantly with non-steroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid (ASA). Other platelet aggregation inhibitors or other antithrombotic agents are not recommended concomitantly with Apixaban following surgery.
In patients with atrial fibrillation and a condition that warrants mono or dual antiplatelet therapy, a careful assessment of the potential benefits against the potential risks should be made before combining this therapy with Apixaban.
Patients with prosthetic heart valves: Safety and efficacy of Apixaban have not been studied in patients with prosthetic heart valves, with or without atrial fibrillation. Therefore, the use of Apixaban is not recommended in this setting.
Effects on ability to drive and use machines: Apixaban has no or negligible influence on the ability to drive and use machineries.
Use in Children: The efficacy and safety of Apixaban in children below age 18 have not yet been established. No data are available.
Use in the Elderly: Increasing age may increase haemorrhagic risk.

Pregnancy: There are limited data from the use of Apixaban in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. Apixaban is not recommended during pregnancy.
Breastfeeding: 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 newborns and infants cannot be excluded.
A decision must be made to either discontinue breast-feeding or to discontinue/abstain from Apixaban therapy.
Fertility: Studies in animals dosed directly with Apixaban have shown no effect on fertility.

*Treatment-emergent adverse reactions in NVAF patients: Immune System Disorders: Uncommon: Hypersensitivity (including drug hypersensitivity such as rash and anaphylactic reaction such as allergic edema).
Nervous System Disorders: Uncommon: Brain hemorrhage, other intracranial or intraspinal hemorrhage (including subdural hematoma, subarachnoid hemorrhage, and spinal hematoma).
Eye Disorders: Common: Eye hemorrhage (including conjunctival hemorrhage).
Vascular Disorders: Common: Other hemorrhage, hematoma.
Uncommon: Intra-abdominal hemorrhage.
Respiratory, Thoracic and Mediastinal Disorders: Common: Epistaxis.
Uncommon: Hemoptysis.
Rare: Respiratory tract hemorrhage (including pulmonary alveolar hemorrhage, laryngeal hemorrhage, and pharyngeal hemorrhage).
Gastrointestinal Disorders: Common: Gastrointestinal hemorrhage (including hematemesis and melena), rectal hemorrhage, gingival bleeding.
Uncommon: Hemorrhoidal hemorrhage, hematochezia, mouth hemorrhage.
Rare: Retroperitoneal hemorrhage.
Renal and Urinary Disorders: Common: Hematuria.
Reproductive System and Breast Disorders: Uncommon: Abnormal vaginal hemorrhage, urogenital hemorrhage.
General Disorders and Administration Site Condition: Uncommon: Application site bleeding.
Investigations: Uncommon: Occult blood positive.
Injury, Poisoning and Procedural Complications: Common: Confusion.
Uncommon: Traumatic hemorrhage, post procedural hemorrhage, incision site hemorrhage.
*Treatment-emergent adverse reactions in VTE patients: Blood and Lymphatic System Disorders: Rare: Hemorrhagic anemia, hemorrhagic diathesis, spontaneous hematoma.
Nervous System Disorders: Rare: Cerebral hemorrhage, hemorrhagic stroke.
Eye Disorders: Uncommon: Conjunctival hemorrhage.
Rare: Eye hemorrhage, retinal hemorrhage, scleral hemorrhage, vitreous hemorrhage.
Ear and Labyrinth Disorders: Rare: Ear hemorrhage.
Cardiac Disorders: Rare: Pericardial hemorrhage.
Vascular Disorders: Common: Hematoma.
Rare: Hemorrhage, intra-abdominal hematoma, hemorrhagic shock.
Respiratory, Thoracic, and Mediastinal Disorders: Common: Epistaxis.
Uncommon: Hemoptysis.
Rare: Pulmonary alveolar hemorrhage.
Gastrointestinal Disorders: Common: Gingival bleeding.
Uncommon: Rectal hemorrhage, hematochezia, hemorrhoidal hemorrhage, gastrointestinal hemorrhage, hematemesis.
Rare: Melena, anal hemorrhage, gastric ulcer hemorrhage, mouth hemorrhage, abdominal wall hematoma, Mallory-Weiss syndrome, gastric hemorrhage, peptic ulcer hemorrhage, small intestine hemorrhage.
Skin and Subcutaneous Tissue Disorders: Uncommon: Ecchymosis, skin hemorrhage.
Rare: Petechiae, purpura, increased tendency to bleed, blood blister, skin ulcer hemorrhage.
Musculoskeletal and Connective Tissue Disorders: Rare: Muscle hemorrhage.
Renal and Urinary Disorders: Common: Hematuria.
Rare: Urinary tract hemorrhage.
Reproductive System and Breast Disorders: Common: Menorrhagia.
Uncommon: Vaginal hemorrhage, metrorrhagia.
Rare: Menometrorrhagia, uterine hemorrhage, genital hemorrhage, breast hematoma, hematospermia, postmenopausal hemorrhage.
General Disorders and Administration Site Conditions: Uncommon: Injection site hematoma, vessel puncture site hematoma.
Rare: Injection site hemorrhage, infusion site hematoma.
Investigations: Uncommon: Blood urine present, occult blood positive.
Rare: Occult blood, red blood cells urine positive.
Injury, Poisoning, and Procedural Complications: Common: Confusion.
Uncommon: Wound hemorrhage, post procedural hemorrhage, traumatic hematoma.
Rare: Periorbital hematoma, vascular pseudoaneurysm, subcutaneous hematoma, procedural hematoma, post procedural hematoma, post procedural hematuria, extradural hematoma, renal hematoma, subdural hemorrhage.

Inhibitors of CYP3A4 and P-gp: Coadministration of apixaban with ketoconazole (400 mg once a day), a strong inhibitor of both CYP3A4 and P-gp, led to a 2-fold increase in mean apixaban AUC and a 1.6-fold increase in mean apixaban Cmax.
The use of Apixaban is not recommended in patients receiving concomitant systemic treatment with strong inhibitors of both CYP3A4 and P-gp, such as azole-antimycotics (e.g., ketoconazole, itraconazole, voriconazole and posaconazole) and HIV protease inhibitors (e.g., ritonavir). Active substances which are not considered strong inhibitors of both CYP3A4 and P-gp, (eg., amiodarone, clarithromycin, diltiazem, fluconazole, naproxen, quinidine, verapamil) are expected to increase apixaban plasma concentration to a lesser extent. No dose adjustment for apixaban is required when co-administered with agents that are not strong inhibitors of both CYP3A4 and P-gp. For example, diltiazem (360 mg once a day), considered a moderate CYP3A4 and a weak P-gp inhibitor, led to a 1.4-fold increase in mean apixaban AUC and a 1.3-fold increase in Cmax. Naproxen (500 mg, single dose) an inhibitor of P-gp but not an inhibitor of CYP3A4, led to a 1.5-fold and 1.6-fold increase in mean apixaban AUC and Cmax, respectively. Clarithromycin (500 mg, twice a day), an inhibitor of P-gp and a strong inhibitor of CYP3A4, led to a 1.6-fold and 1.3-fold increase in mean apixaban AUC and Cmax respectively. No dose adjustment for Apixaban is required when co-administered with less potent inhibitors of CYP3A4 and/or P-gp.
Inducers of CYP3A4 and P-gp: Co-administration of apixaban with rifampicin, a strong inducer of both CYP3A4 and P-gp, led to an approximate 54% and 42% decrease in mean apixaban AUC and Cmax, respectively. The concomitant use of apixaban with other strong CYP3A4 and P-gp inducers (e.g., phenytoin, carbamazepine, phenobarbital or St. John's Wort) may also lead to reduced apixaban plasma concentrations. No dose adjustment for apixaban is required during concomitant therapy with such medicinal products, however strong inducers of both CYP3A4 and P-gp should be co-administered with caution.
For the treatment of DVT and PE, concomitant therapy with strong inducers of both CYP3A4 and P-gp is not recommended. For the prevention of recurrent DVT and PE, strong inducers of both CYP3A4 and P-gp should be co-administered with caution.
Interaction with other medicinal products affecting hemostasis: The concomitant use of Apixaban with antiplatelet agents increases the risk of bleeding. Care is to be taken if patients are treated concomitantly with non-steroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid (ASA). Other platelet aggregation inhibitors or other antithrombotic agents are not recommended concomitantly with Apixaban following surgery.
In patients with atrial fibrillation and a condition that warrants mono or dual antiplatelet therapy, a careful assessment of the potential benefits against the risks should be made before combining this therapy with Apixaban.
Anticoagulants, platelet aggregation inhibitors and NSAIDs: After combined administration of enoxaparin (40 mg single dose) with Apixaban (5 mg single dose), an additive effect on anti-Factor Xa activity was observed.
Pharmacokinetic or pharmacodynamic interactions were not evident in healthy subjects when apixaban was co-administered with ASA 325 mg once a day. Apixaban co-administered with clopidogrel (75 mg once a day), or with the combination of clopidogrel 75 mg and ASA 162 mg once daily in phase 1 studies did not show a relevant increase in bleeding time or further inhibition of platelet aggregation compared to administration of the antiplatelet agents without Apixaban. Increases in clotting tests (PT, INR and aPTT) were consistent with the effects of Apixaban alone.
Naproxen (500 mg), an inhibitor of P-gp, led to a 1.5-fold and 1.6-fold increase in mean Apixaban AUC and Cmax, in healthy subjects, respectively. Corresponding increases in clotting tests were observed for Apixaban. No changes were observed in the effect of naproxen on arachidonic acid-induced platelet aggregation and no clinically relevant prolongation of bleeding time was observed after concomitant administration of Apixaban and naproxen.
Despite these findings, Apixaban should be used with caution when co-administered with NSAIDs (including ASA) because these medicinal products typically increase the bleeding risk.
Agents associated with serious bleeding are not recommended concomitantly with Apixaban, such as: unfractionated heparins and heparin derivatives (including low molecular weight heparins (LMWH), FXa inhibiting oligosaccharides (eg, fondaparinux), direct thrombin II inhibitors (eg, desirudin), thrombolytic agents, GPIIb/IIIa receptor antagonists, dipyridamole, dextran, sulfinpyrazone, vitamin K antagonists, and other oral anticoagulants. It should be noted that unfractionated heparin can be administered at doses necessary to maintain a patent central venous or arterial catheter.
In patients with atrial fibrillation and a condition that warrants mono or dual antiplatelet therapy, a careful assessment of the potential benefits against the potential risks should be made before combining this therapy with Apixaban.
Effect of Apixaban on other drugs: Digoxin: Coadministration of apixaban (20 mg once a day) and digoxin (0.25 mg once a day), a P-gp substrate, did not affect digoxin AUC or Cmax. Therefore, apixaban does not inhibit P-gp mediated substrate transport.
Naproxen: Coadministration of single doses of apixaban (10 mg) and naproxen (500 mg), a commonly used NSAID, did not have any effect on the naproxen AUC or Cmax.
Atenolol: Co-administration of a single dose of Apixaban (10 mg) and atenolol (100 mg), a common beta-blocker, did not alter the pharmacokinetics of atenolol.
Other concomitant therapies: No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when Apixaban was co-administered with atenolol or famotidine. Co-administration of a single dose of apixaban (10 mg) with atenolol (100 mg), a common beta-blocker, did not alter the pharmacokinetics of atenolol.
Laboratory Parameters: Clotting tests (e.g. PT, INR and aPTT) are affected as expected by the mechanism of action of apixaban. Changes observed in these clotting tests at the expected therapeutic dose are small and subject to a high degree of variability.
Pediatric Population: Interaction studies have only been performed in adults.

Store at temperatures not exceeding 30°C.

Anticoagulants, Antiplatelets & Fibrinolytics (Thrombolytics)

B01AF02 - apixaban ; Belongs to the class of direct factor Xa inhibitors. Used in the treatment of thrombosis.

Rx