Summary of Prescribing Information (SPI)

Eliquis® SPI_ LPDELI052021: Based on LPDELI052021 (Version no. 13), dated 17th June 2021 : Generic name of product:Apixaban Brand name of product: Eliquis®Indication: 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), including those 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). Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adult patients.Pharmaceutical Form: Each film-coated tablet contains: Apixaban 5 mg color used: Titanium dioxide USP & Iron oxide red USP-NF and Apixaban 2.5mg, color used: Titanium dioxide USP & Iron oxide yellow USP-NF. List of Excipients: Tablet Core: anhydrous lactose, microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulfate, magnesium stearate. Film Coat - lactose monohydrate, Hypromellose, titanium dioxide, triacetin, and yellow iron oxide (2.5 mg tablets) or red iron oxide (5 mg tablets).Dosage: 2.5 mg & 5 mg Film coated Tablets. Prevention of VTE (VTEp): elective hip or knee replacement surgery: The recommended dose is 2.5 mg taken orally twice daily. The initial dose should be taken 12 to 24 hours after surgery. 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 non-valvular atrial fibrillation (NVAF): The recommended dose of apixaban is 5 mg taken orally twice daily. Dose reduction- The recommended dose of apixaban is 2.5 mg taken orally twice daily in patients with NVAF and at least two of the following characteristics: age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL (133 micromole/L). Therapy should be continued long term. Treatment of DVT, treatment of PE and prevention of recurrent DVT and PE (VTEt): The recommended dose of apixaban for the treatment of acute DVT and treatment of PE is 10 mg taken orally twice daily for the first 7 days(Maximum daily dosage: 20mg), followed by 5 mg taken orally twice daily(Maximum daily dosage: 10mg). As per available medical guidelines, short duration of treatment (at least 3 months) should be based on transient risk factors (e.g. recent surgery, trauma, immobilization). The recommended dose of apixaban for the prevention of recurrent DVT and PE is 2.5 mg taken orally twice daily. When prevention of recurrent DVT and PE is indicated, the 2.5 mg twice daily dose should be initiated following completion of 6 months of treatment with apixaban 5 mg twice daily or with another anticoagulant. Maximum daily dosage: 5mg. The duration of overall therapy should be individualized after careful assessment of the treatment benefit against the risk for bleeding. Missed dose-If a dose is missed, the patient should take apixaban immediately and then continue with twice daily intake as before. Switching-Switching treatment from parenteral anticoagulants to apixaban (and vice versa) can be done at the next scheduled dose. Switching from vitamin K antagonist (VKA) therapy to apixaban. When converting patients from vitamin K antagonist (VKA) therapy to apixaban, warfarin or other VKA therapy should be discontinued and apixaban started when the international normalized ratio (INR) is <2. Switching from apixaban to VKA therapy - Administration of apixaban should be continued for at least 2 days after beginning VKA therapy. After 2 days of coadministration of apixaban with VKA therapy, an INR should be obtained prior to the next scheduled dose of apixaban. Coadministration of apixaban and VKA therapy should be continued until the INR is ≥2.Method of Administration: Oral use. Apixaban should be swallowed with water, 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.Contraindications: Hypersensitivity to the active substance or to any of the excipients, Active clinically significant bleeding. Hepatic disease associated with coagulopathy and clinically relevant bleeding risk, Lesion or condition if considered a significant risk factor for major bleeding. This may include current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial hemorrhage, known or suspected esophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities. Concomitant treatment with any other anticoagulant agent e.g., unfractionated heparin (UFH), low molecular weight heparins (enoxaparin, Dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral anticoagulants (warfarin, rivaroxaban, dabigatran, etc.) except under specific circumstances of switching anticoagulant therapy, when UFH is given at doses necessary to maintain an open central venous or arterial catheter or when UFH is given during catheter ablation for atrial fibrillationWarnings and Precautions: Patients undergoing catheter ablation (NVAF)- Patients can continue apixaban use while undergoing catheter ablation. Patients undergoing cardioversion - Apixaban can be initiated or continued in NVAF patients who may require cardioversion. For patients not previously treated with anticoagulants, exclusion of left atrial thrombus using an image guided approach (e.g. transesophageal echocardiography (TEE) or computed tomographic scan (CT)) prior to cardioversion should be considered, in accordance with established medical guidelines. For patients initiating treatment with apixaban, 5 mg should be given twice daily for at least 2.5 days (5 single doses) before cardioversion. The dosing regimen should be reduced to 2.5 mg apixaban given twice daily for at least 2.5 days (5 single doses) if the patient meets the criteria for dose reduction. 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. The administration of the loading dose should be given at least 2 hours before cardioversion. For all patients undergoing 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. Patients with NVAF and acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI)- There is limited experience of treatment with apixaban at the recommended dose for NVAF patients when used in combination with antiplatelet agents in patients with ACS and/or undergoing PCI after hemostasis is achieved. Pediatric population - The safety and efficacy of apixaban in children and adolescents below age 18 have not been established. No data are available. 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 bleeding. This includes interventions for which the probability of clinically significant bleeding cannot be excluded or for which the risk of bleeding would be unacceptable. Apixaban should be discontinued at least 24 hours prior to elective surgery or invasive procedures with a low risk of bleeding. This includes interventions for which any bleeding that occurs is expected to be minimal, non-critical in its location or easily controlled. If surgery or invasive procedures cannot be delayed, appropriate caution should be exercised, taking into consideration an increased risk of bleeding. This risk of bleeding should be weighed against the urgency of intervention. Apixaban should be restarted after the invasive procedure or surgical intervention as soon as possible provided the clinical situation allows and adequate hemostasis has been established. For patients undergoing catheter ablation for atrial fibrillation, apixaban treatment does not need to be interrupted. Increased Risk of Thrombotic Events after Premature Discontinuation - Premature discontinuation of any oral anticoagulant, including apixaban, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. If apixaban is discontinued for a reason other than pathological bleeding or completion of a course of therapy, 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 inhibitors, and nonsteroidal anti-inflammatory drugs (NSAIDs). Advise patients of signs and symptoms of blood loss and to report them immediately or go to an emergency room. Discontinue apixaban in patients with active pathological hemorrhage. Reversal of Anticoagulant Effect. The pharmacodynamic effect of apixaban can be expected to persist for at least 24 hours after the last dose, i.e., for about two drug half-lives. Prothrombin complex concentrate (PCC), activated prothrombin complex concentrate or recombinant factor VIIa may be considered, but have not been evaluated in clinical studies. Activated oral charcoal reduces absorption of apixaban, thereby lowering apixaban plasma concentration. Spinal/Epidural Anesthesia or Puncture- Indwelling epidural or intrathecal catheters should not be removed earlier than 24 hours after the last administration of apixaban. The next dose of apixaban should not be administered earlier than 5 hours after the removal of the catheter. The risk may also be increased by traumatic or repeated epidural or spinal puncture. If traumatic puncture occurs, delay the administration of apixaban for 48 hours. Monitor patients frequently for signs and symptoms of neurological impairment (e.g., numbness or weakness of the legs, or bowel or bladder dysfunction). If neurological compromise is noted, urgent diagnosis and treatment is necessary. Prior to neuraxial intervention the physician should consider the potential benefit versus the risk in anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis. Patients with Prosthetic Heart Valves- The safety and efficacy of apixaban have not been studied in patients with prosthetic heart valves. Therefore, use of apixaban is not recommended in these patients. Acute PE in Hemodynamically Unstable Patients or Patients who Require Thrombolysis or Pulmonary Embolectomy- Initiation of apixaban is not recommended as an alternative to unfractionated heparin for the initial treatment of patients with PE who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy. Increased Risk of Thrombosis in Patients with Triple Positive Antiphospholipid Syndrome- Direct-acting oral anticoagulants (DOACs), including apixaban, are not recommended for use in patients with triple-positive antiphospholipid syndrome (APS). Hip fracture surgery- Apixaban has not been studied in clinical trials in patients undergoing hip fracture surgery to evaluate efficacy and safety in these patients. Therefore, it is not recommended in these patients. Laboratory parameters - Clotting tests [e.g., prothrombin time (PT), INR, and activated partial thromboplastin time (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. Information about excipients- Apixaban contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.Use in Special population : Renal impairment : Reduction of Risk of Stroke and Systemic Embolism in Patients with Nonvalvular Atrial Fibrillation The recommended dose is 2.5 mg twice daily in patients with at least two of the following characteristics • age greater than or equal to 80 years • body weight less than or equal to 60 kg • serum creatinine greater than or equal to 1.5 mg/dL Patients with End-Stage Renal Disease on Dialysis - Clinical efficacy and safety studies with apixaban did not enroll patients with end-stage renal disease (ESRD) on dialysis. In patients with ESRD maintained on intermittent hemodialysis, administration of apixaban at the usually recommended dose will result in concentrations of apixaban and pharmacodynamic activity similar to those observed in the ARISTOTLE study. It is not known whether these concentrations will lead to similar stroke reduction and bleeding risk in patients with ESRD on dialysis as was seen in ARISTOTLE. Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery, and Treatment of DVT and PE and Reduction in the Risk of Recurrence of DVT and PE - No dose adjustment is recommended for patients with renal impairment, including those with ESRD on dialysis. Clinical efficacy and safety studies with apixaban did not enroll patients with ESRD on dialysis or patients with a CrCl <15 mL/min; therefore, dosing recommendations are based on pharmacokinetic and pharmacodynamic (antiFXa activity) data in subjects with ESRD maintained on dialysis. Hepatic impairment Apixaban is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk. It is not recommended in patients with severe hepatic impairment. It should 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. Patients with elevated liver enzymes alanine aminotransferase (ALT)/aspartate aminotransferase (A ST) >2 x ULN or total bilirubin ≥ 1.5 x ULN were excluded in clinical trials. Therefore, apixaban should be used with caution in this. Prior to initiating apixaban, liver function testing should be performed. Body weight - VTEp and VTEt - No dose adjustment required. NVAF - No dose adjustment required, unless criteria for dose reduction are met. Low body weight (<60 kg) may increase hemorrhagic risk. Gender- No dose adjustment required. Elderly- VTEp and VTEt – No dose adjustment re quired. NVAF – No dose adjustment required, unless criteria for dose reduction are met. Increasing age may increase hemorrhagic risk. the coadministration of apixaban with ASA in elderly patients should be used cautiously because of a potentially higher bleeding risk. 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. Apixaban is not recommended during pregnancy. Breast-feeding- It is unknown whether apixaban or its metabolites are excreted in human milk. Available data in animals have shown excretion of apixaban in milk. 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 with apixaban have shown no effect on fertilityAdverse reactions (Very common and common): Prevention of VTE in adult patients who have undergone elective hip or knee replacement surgery (VTEp) anemia, hemorrhage, hematoma, nausea and contusion. Prevention of stroke and systemic embolism (NVAF) –anemia, eye hemorrhage including conjunctival hemorrhage, other hemorrhage and hematoma, hypotension (including procedural hypotension), epistaxis, Nausea, Gastrointestinal hemorrhage, rectal hemorrhage, gingival bleeding.  Increased Gamma-glutamyltransferase, hematuria and contusion.increased Treatment of DVT and PE, Prevention of recurrent DVT and PE – Anemia, thrombocytopenia, hemorrhage, hematoma, epistaxis, nausea, gastrointestinal hemorrhage, mouth hemorrhage, rectal hemorrhage, gingival bleeding, Increased Gamma-glutamyltransferase and alanine aminotransferase, skin rash, hematuria, Abnormal vaginal hemorrhage, urogenital hemorrhage and contusion.Drug interactions : Inhibitors of CYP3A4 and P-gp - 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) No dose adjustment for apixaban is required when coadministered with agents that are not strong inhibitors of both CYP3A4 and P-gp like amiodarone, clarithromycin, diltiazem, fluconazole, naproxen, quinidine, verapamil). Inducers of CYP3A4 and P-gp - No dose adjustment for apixaban is required during concomitant therapy with other strong CYP3A4 and P-gp inducers (e.g., rifampicin, phenytoin, carbamazepine, phenobarbital or St. John’s Wort), however in patients receiving concomitant systemic treatment with strong inducers of both CYP3A4 and P-gp apixaban should be used with caution for the prevention of VTE in elective hip or knee replacement surgery, for the prevention of stroke and systemic embolism in patients with NVAF and for the prevention of recurrent DVT and PE. Apixaban is not recommended for the treatment of DVT and PE in patients receiving concomitant systemic treatment with strong inducers of both CYP3A4 and P-gp since efficacy may be compromised. Anticoagulants, platelet aggregation inhibitors, SSRIs/SNRIs and NSAIDs- Apixaban should be used with caution when coadministered with SSRIs/SNRIs, NSAIDs, ASA and/or P2Y12 inhibitors because these medicinal products typically increase the bleeding risk. Pharmacokinetic or pharmacodynamic interactions were not evident when apixaban was coadministered with ASA 325 mg once a day. 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. Platelet aggregation inhibitors (such as GPIIb/IIIa receptor antagonists, dipyridamole, dextran or sulfinpyrazone) or thrombolytic agents. increase the bleeding risk, coadministration of these products with apixaban is not recommendedOverdose: 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 must be investigated. The initiation of appropriate treatment, e.g., surgical hemostasis, the transfusion of fresh frozen plasma should be considered. 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, since the reversal agent is not available, administration of prothrombin complex concentrates (PCCs) or recombinant factor VIIa may be considered. 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.Storage Condition: Store below 30°C. No special handling requirements. Shelf-life 36 Months.LPD version and date: Eliquis SPI_ LPDELI052021: Based on LPDELI052021 (Version no. 13), dated 17th June 2021   

References: 1 Granger CB, Alexander JH, McMurray JJ, et al. Apixaban  versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981-992

®Trademark Proprietor: Bristol-Myers Squibb Holdings Ireland Unlimited Company Licensed user: Pfizer Limited, India

 

#Ruff CT, et al. Lancet. 2014;383(9921):955-62, Hur et al, Acta Orthopaedica 2017; 88 (6): 634–641, Cohen AT et al. Adv Ther 2014;31:473-93

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