Apixaban 2,5mg or 5mg Pfizer Tablets

Prevention of VTE: elective hip or knee replacement surgery

APIXABAN BMS is indicated for the prevention of venous thromboembolic events (VTE) in adult patients who have undergone elective hip or knee replacement surgery.

Prevention of stroke and systemic embolism: nonvalvular atrial fibrillation (NVAF)

APIXABAN BMS is also indicated to reduce the risk of stroke, systemic embolism, and death in patients with nonvalvular atrial fibrillation with one or more risk factors.

Treatment of VTE

APIXABAN BMS is indicated for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and prevention of recurrent DVT and PE.

APIXABAN BMS can be taken with or without food. If a dose is missed, the patient should take APIXABAN BMS immediately and then continue with twice daily administration as before.

Recommended dosage

Prevention of VTE: elective hip or knee replacement surgery

The recommended dose of APIXABAN BMS 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: NVAF

The recommended dose of APIXABAN BMS is 5 mg taken orally twice daily.

Age, body weight, serum creatinine

In patients with at least 2 of the following characteristics, age u2265 80 years, body weight u2264 60 kg, or serum creatinine u2265 1,5 mg/dL (133 micromole/L), the recommended dose of APIXABAN BMS is 2,5 mg twice daily.

Treatment of DVT and PE

The recommended dose of APIXABAN BMS 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 BMS is 2,5 mg taken orally twice daily after at least 6 months of treatment for DVT or PE.

Body weight

Prevention of VTE: elective hip or knee replacement surgery

No dose adjustment required (see section 5.2).

Prevention of stroke and systemic embolism: NVAF

See section 4.2, Prevention of stroke and systemic embolism: NVAF, Recommended dosage, Age, body weight, serum creatinine.

Treatment of VTE

No dose adjustment required (see section 5.2).

Converting from or to parenteral anticoagulants

In general, switching treatment from parenteral anticoagulants to APIXABAN BMS (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 BMS, discontinue warfarin or other VKA therapy and start APIXABAN BMS when the international normalised ratio (INR) is below 2,0. When converting from APIXABAN BMS to warfarin or other VKA therapy, continue APIXABAN BMS for 48 hours after the first dose of warfarin or other VKA therapy.

Patients undergoing cardioversion

APIXABAN BMS 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 Pfizer twice daily (2,5 mg twice daily in patients who qualify for a dose reduction) should be given before cardioversion to ensure adequate anticoagulation. If cardioversion is required before 5 doses of APIXABAN BMS 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. Confirmation should be sought prior to cardioversion that the patient has taken APIXABAN BMS as prescribed. Decisions on initiation and duration of treatment should take established guideline recommendations for anticoagulant treatment in patients undergoing cardioversion into account.

Special populations

Renal impairment

Prevention of VTE: elective hip or knee replacement surgery

In surgical patients no dose adjustment is necessary in patients with mild, moderate or severe (creatinine clearance 15 - 29 mL/min) renal impairment (see section 5.2). Because there is limited clinical experience in patients with creatinine clearance < 15 mL/min and there are no data in patients undergoing dialysis, APIXABAN BMS is not recommended in these patients (see section 4.4, Renal impairment, Prevention of VTE: elective hip or knee replacement surgery and section 5.2).

Prevention of stroke and systemic embolism: NVAF

In patients with AF no dose adjustment is recommended in patients with creatinine clearance 15 - 29 mL/min, except as described under section 4.2, Prevention of stroke and systemic embolism: NVAF. 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 BMS is not recommended in these patients (see section 5.2).

Treatment of VTE

No dose adjustment is necessary in patients with mild, moderate or severe (creatinine clearance 15 u2013 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 BMS is not recommended in these patients (see section 5.2).

Hepatic impairment

APIXABAN BMS 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 (see section 4.4, Hepatic impairment and section 5.2, Hepatic impairment). APIXABAN BMS is not recommended in patients with severe hepatic impairment (see section 4.4, Hepatic impairment and section 5.2, Hepatic impairment).

Elderly

Prevention of VTE: elective hip or knee replacement surgery

No dose adjustment required (see section 5.2).

Prevention of stroke and systemic embolism: NVAF

See section 4.2, Prevention of stroke and systemic embolism: NVAF, Recommended dosage, Age, body weight, serum creatinine.

Treatment of VTE

No dose adjustment required (see section 5.2).

Paediatric population

The efficacy and safety of APIXABAN BMS in children below age 18 have not been established. No data are available.

Method of administration

For oral use. For patients who are unable to swallow whole tablets, APIXABAN BMS tablets may be crushed and suspended in water, 5 % dextrose in water (D5W), or apple juice, or mixed with applesauce and promptly administered orally (see section 5.2). Alternatively, APIXABAN BMS tablets may be crushed and suspended in 60 mL of water or D5W and promptly delivered through a nasogastric tube (see section 5.2). Crushed APIXABAN BMS tablets are stable in water, D5W, apple juice, and applesauce for up to 4 hours.

• Hypersensitivity to the active substance (apixaban) or to any of the excipients of APIXABAN BMS (listed in section 6.1)
• Clinically significant active bleeding
• APIXABAN BMS is not recommended in patients with severe renal disease (CrCl < 15 mL/min)
• APIXABAN BMS is not recommended in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk
• APIXABAN BMS should not be administered with antiplatelet medicines other than aspirin (see section 4.4)
• Patients with antiphospholipid syndrome (APS) with persistent positivity for all three antiphospholipid antibodies (patients with triple positive APS)

Haemorrhage risk

Patients taking APIXABAN BMS are to be carefully observed for signs of bleeding. APIXABAN BMS 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 BMS administration should be discontinued if severe haemorrhage occurs (see section 4.9).

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 above measures, administration of prothrombin complex concentrates (PCCs) or recombinant factor VIIa may be considered. Reversal of APIXABAN BMS pharmacodynamic effects, as demonstrated by changes in the thrombin generation assay, has been demonstrated after administration of 4-factor PCCs in healthy subjects. However, there is no clinical experience with the use of 4-factor PCC medicines to reverse bleeding in individuals who have received APIXABAN BMS. Currently there is no experience with the use of recombinant factor VIIa in individuals receiving APIXABAN BMS.

Standard anticoagulation tests cannot be used to monitor APIXABAN BMS (see section 4.5).

Interaction with other medicines affecting haemostasis

The concomitant use of APIXABAN BMS with antiplatelet medicines increases the risk of bleeding. Care is to be taken if patients are treated concomitantly with non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin. Other platelet aggregation inhibitors or other antithrombotic medicines are not recommended concomitantly with APIXABAN BMS following surgery (see section 4.5).

In patients with atrial fibrillation and a condition that warrants chronic use of aspirin, APIXABAN BMS may be used with due regard to increased risk of major bleeding. In a clinical trial of patients with atrial fibrillation, concomitant use of aspirin increased the major bleeding risk on APIXABAN BMS from 1,8 % per year to 3,4 % per year and increased the bleeding risk on warfarin from 2,7 % per year to 4,6 % per year.

Patients with prosthetic heart valves

Safety and efficacy of APIXABAN BMS have not been studied in patients with prosthetic heart valves, with or without atrial fibrillation. Therefore, the use of APIXABAN BMS is not recommended in this setting.

Patients with antiphospholipid syndrome

Treatment of patients with established APS is not recommended as evidence regarding safety and efficacy, including the benefit/harm balance of APIXABAN BMS in patients with APS, is inconclusive/incomplete. There is some evidence that treatment with APIXABAN BMS may be associated with an increased risk of recurrent arterial thrombotic events in patients with APS compared to treatment of these patients with warfarin, a vitamin K antagonist.

Surgery and invasive procedures

APIXABAN BMS should be discontinued 2 to 3 days prior to elective surgery or invasive procedures such as neuraxial regional anaesthesia. 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.

Temporary discontinuation of APIXABAN BMS

Discontinue APIXABAN BMS, in the presence of active bleeding, elective surgery, or invasive procedures that place patients at an increased risk of haemorrhage. Restart APIXABAN BMS therapy 12 - 24 hours after the danger of haemorrhage has ceased.

Spinal/epidural anaesthesia or puncture

When neuraxial anaesthesia (spinal/epidural anaesthesia) or spinal/epidural puncture is employed, patients treated with antithrombotic medicines, such as APIXABAN BMS, for prevention of thromboembolic complications are at risk of developing an epidural or spinal haematoma which can result in long-term or permanent paralysis. The risk of these events may be increased by the post-operative use of indwelling epidural catheters or the concomitant use of medicines affecting haemostasis. When an indwelling epidural or intrathecal catheter procedure is planned, APIXABAN BMS should be stopped 48 hours beforehand. Indwelling epidural or intrathecal catheters must be removed at least 6 hours prior to the first dose of APIXABAN BMS. The risk may also be increased by traumatic or repeated epidural or spinal puncture. Patients are to be frequently monitored for signs and symptoms of neurological impairment (e.g., numbness or weakness of the legs, bowel or bladder dysfunction). If neurological compromise is noted, urgent diagnosis and treatment is necessary. Prior to neuraxial intervention, the medical practitioner should consider the potential benefit versus the risk in anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis.

Acute PE in haemodynamically unstable patients or patients who require thrombolysis or pulmonary embolectomy

Treatment of VTE

Initiation of APIXABAN BMS is not recommended as an alternative to unfractionated heparin for the initial treatment of patients with PE who present with haemodynamic instability or who may receive thrombolysis or pulmonary embolectomy.

Interaction with strong inhibitors of both Cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp)

APIXABAN BMS 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 (e.g., ketoconazole, itraconazole, voriconazole and posaconazole), HIV protease inhibitors (e.g., ritonavir). These medicines may increase APIXABAN BMS exposure by 2-fold (see section 4.5).

Effect of other medicines on APIXABAN BMS

Inhibitors of CYP3A4 and P-gp

Co-administration of APIXABAN BMS 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 BMS AUC and a 1,6-fold increase in mean APIXABAN BMS C max (see section 4.4, Interaction with inhibitors of both Cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp)). The dose of APIXABAN BMS must not exceed 2,5 mg twice daily when used with these medicines.

Active substances which are not considered strong inhibitors of both CYP3A4 and P-gp (e.g., diltiazem, naproxen, clarithromycin, amiodarone, verapamil, quinidine) are expected to increase APIXABAN BMS plasma concentration to a lesser extent. No dose adjustment for APIXABAN BMS is required when co-administered with medicines that are not strong inhibitors of both CYP3A4 and P-gp. 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 BMS AUC and a 1,3-fold increase in C max. 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 BMS AUC and C max, 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 BMS AUC and C max respectively.

Inducers of CYP3A4 and P-gp

Co-administration of APIXABAN BMS with rifampicin, a strong inducer of both CYP3A4 and P-gp, led to an approximate 54 % and 42 % decrease in mean APIXABAN BMS AUC and C max, respectively. The concomitant use of APIXABAN BMS with other strong CYP3A4 and P-gp inducers (e.g., phenytoin, carbamazepine, phenobarbital (phenobarbitone) or St. Johnu2019s Wort) may also lead to reduced APIXABAN BMS plasma concentrations. No dose adjustment for APIXABAN BMS is required during concomitant therapy with such medicines, however strong inducers of both CYP3A4 and P-gp should be co-administered with caution (see section 4.4, Interaction with strong inducers of both CYP3A4 and P-gp). For the treatment of DVT and PE, concomitant therapy with strong inducers of both CYP3A4 and P-gp is not recommended (see section 4.4). For the prevention of recurrent DVT and PE, strong inducers of both CYP3A4 and P-gp should be co-administered with caution (see section 4.4).

Anticoagulants, platelet aggregation inhibitors, and NSAIDs

After combined administration of enoxaparin (40 mg single dose) with APIXABAN BMS (5 mg single dose), an additive effect on anti-FXa activity was observed. Pharmacokinetic or pharmacodynamic interactions were not evident in healthy subjects when APIXABAN BMS was co-administered with aspirin 325 mg once a day. APIXABAN BMS co-administered with clopidogrel (75 mg once daily) or with the combination of clopidogrel 75 mg and aspirin 162 mg once daily or with prasugrel (60 mg followed by 10 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 medicines without APIXABAN BMS. Increases in clotting tests (PT, INR, and aPTT) were consistent with the effects of APIXABAN BMS alone. However, the co-administration of APIXABAN BMS with clopidogrel, ticagrelor or other antiplatelet medicines, except aspirin, are not recommended due to the resulting associated increased risk of major bleeds (see section 4.3).

Naproxen (500 mg), an inhibitor of P-gp, led to a 1,5-fold and 1,6-fold increase in mean APIXABAN BMS AUC and C max, in healthy subjects, respectively. Corresponding increases in clotting tests were observed for APIXABAN BMS. No clinically relevant prolongation of bleeding time was observed after concomitant administration of APIXABAN BMS and naproxen. APIXABAN BMS should be used with caution when co-administered with NSAIDs (including aspirin) because these medicines typically increase the bleeding risk. Medicines associated with serious bleeding are not recommended concomitantly with APIXABAN BMS, such as: unfractionated heparins and heparin derivatives (including low molecular weight heparins (LMWH)), FXa inhibiting oligosaccharides (e.g. fondaparinux), direct thrombin II inhibitors (e.g., desirudin), thrombolytic medicines, 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 (see section 4.4, Interaction with other medicines affecting haemostasis).

Other concomitant therapies

No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when APIXABAN BMS was co-administered with atenolol or famotidine. Co-administration of APIXABAN BMS 10 mg with atenolol 100 mg did not have a clinically relevant effect on the pharmacokinetics of APIXABAN BMS. Following administration of the two medicines together, mean APIXABAN BMS AUC and C max were 15 % and 18 % lower than when administered alone. The administration of APIXABAN BMS 10 mg with famotidine 40 mg had no effect on APIXABAN BMS AUC or C max.

Safety has not been established.

Pregnancy

APIXABAN BMS is not recommended during pregnancy. Treatment may increase the risk of haemorrhage during pregnancy and delivery.

Breastfeeding

It is unknown whether APIXABAN BMS or its metabolites are excreted in human milk. In rat milk, a high milk to maternal plasma ratio (C max about 8, AUC about 30) was found, possibly due to active transport into the milk. A risk to newborns and infants cannot be excluded. Women taking APIXABAN BMS should not breastfeed their infants.

APIXABAN BMS has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

The safety of APIXABAN BMS has been investigated in 7 Phase III clinical studies including more than 21,000 patients: more than 5,000 patients in VTEp studies, 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 20 days, 1,7 years and 221 days respectively. Common adverse reactions were haemorrhage, contusion, epistaxis, and haematoma (see Table 1 for adverse reaction profile and frequencies by indication).

In the VTEp studies, in total, 11 % of the patients treated with APIXABAN 2,5 mg Pfizer twice daily experienced adverse reactions. The overall incidence of adverse reactions related to bleeding with APIXABAN BMS was 10 % in the APIXABAN BMS vs enoxaparin studies. In the NVAF studies, the overall incidence of adverse reactions related to bleeding with APIXABAN BMS was 24,3 % in the APIXABAN BMS vs warfarin study and 9,6 % in the APIXABAN BMS vs acetylsalicylic acid study. In the APIXABAN BMS vs warfarin study the incidence of ISTH major gastrointestinal bleeds (including upper GI, lower GI, and rectal bleeding) with APIXABAN BMS was 0,76 %/year. The incidence of ISTH major intraocular bleeding with APIXABAN BMS was 0,18 %/year. In the VTEt studies, the overall incidence of adverse reactions related to bleeding with APIXABAN BMS was 15,6 % in the APIXABAN BMS vs enoxaparin/warfarin study and 13,3 % in the APIXABAN BMS vs placebo study.

Tabulated list of adverse reactions

Table 1 shows the adverse reactions ranked under headings of system organ class and frequency using the following convention: very common (u2265 1/10); common (u2265 1/100 to < 1/10); uncommon (u2265 1/1 000 to < 1/100); rare (u2265 1/10 000 to < 1/1 000); very rare (< 1/10 000); not known (cannot be estimated from the available data) for VTEp, NVAF, and VTEt respectively.

There is no antidote to APIXABAN BMS. Overdose of APIXABAN BMS may result in a higher risk of bleeding. Administration of activated charcoal 2 and 6 hours after ingestion of a 20-mg dose of APIXABAN BMS reduced mean APIXABAN BMS AUC by 50 % and 27 %, respectively, and had no impact on C max. Mean half-life of APIXABAN BMS decreased from 13,4 hours when APIXABAN BMS was administered alone to 5,3 hours and 4,9 hours, respectively, when activated charcoal was administered 2 and 6 hours after APIXABAN BMS. Thus, administration of activated charcoal may be useful in the management of APIXABAN BMS overdose or accidental ingestion. Haemodialysis is unlikely to be an effective means of managing APIXABAN BMS overdose. Treatment should be symptomatic and supportive.