Banpixan 2,5 mg and 5 mg Tablets

Prevention of VTE: elective hip or knee replacement surgery

BANPIXAN 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)

BANPIXAN 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.

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

Posology

Prevention of VTE: elective hip or knee replacement surgery

The recommended dose of BANPIXAN 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 BANPIXAN 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 BANPIXAN is 2,5 mg twice daily.

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, Age, body weight, serum clearance recommended dosage.

Converting from or to parenteral anticoagulants

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

Patients undergoing cardioversion

BANPIXAN can be initiated or continued in NVAF patients who may require cardioversion. For patients not previously treated with anticoagulants, at least 5 doses of BANPIXAN 5 mg 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 BANPIXAN 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 BANPIXAN 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 (creatine clearance 15 u2013 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, BANPIXAN is not recommended in these patients (see section 4.4 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 to 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.

Hepatic impairment

BANPIXAN 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 and section 5.2). BANPIXAN is not recommended in patients with severe hepatic impairment (see section 4.4 and section 5.2).

Elderly population

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, Posology and method of administration, Prevention of stroke and systemic embolism: NVAF.

Surgery and invasive procedures

BANPIXAN 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.

Paediatric and adolescent

The efficacy and safety of BANPIXAN is children below age 18 have not been established. No data are available.

Method of administration

For oral use.

• Hypersensitivity to apixaban or to any of the excipients (listed in section 6.1).
• Clinically significant active bleeding.
• BANPIXAN is not recommended in patients with severe renal disease (CrCl < 15 mL/min).
• BANPIXAN is not recommended in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk.
• BANPIXAN 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 BANPIXAN are to be carefully observed for signs of bleeding. BANPIXAN 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. BANPIXAN 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 recombinant factor VIIa may be considered. However, there is no clinical experience with the use of 4-factor PCC medicines to reverse bleeding in individuals who have received apixaban. Reversal of apixaban 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 currently no experience with the use of recombinant factor VIIa in individuals receiving apixaban. Standard anticoagulation tests cannot be used to monitor BANPIXAN (see section 4.5).

There is no reversal medication for BANPIXAN. Temporary discontinuation of BANPIXAN

Discontinue BANPIXAN in the presence of active bleeding, elective surgery, or invasive procedures that place patients at an increased risk of haemorrhage. Restart BANPIXAN therapy 12 u2013 24 hours after the danger of haemorrhage has ceased.

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

BANPIXAN 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 BANPIXAN exposure by 2-fold (see section 4.5).

Interaction with strong inducers of both CYP3A4 and P-gp

The concomitant use of BANPIXAN with strong CYP3A4 and P-gp inducers (e.g. rifampicin, phenytoin, carbamazepine, phenobarbitone or St. Johnu2019s Wort) may lead to a ~ 50 % reduction in apixaban exposure. Use caution when co-administering BANPIXAN with strong inducers of both CYP3A4 and P-gp (see section 4.5). For the treatment of DVT of PE, BANPIXAN is not recommended in patients receiving concomitant systemic treatment with strong inducers of both CYP3A4 and P-gp (see section 4.5). For prevention of recurrent DVT and PE, use caution when co-administering BANPIXAN with strong inducers of both CYP3A4 and P-gp (see section 4.5).

Interaction with other medicines affecting haemostasis

The concomitant use of BANPIXAN 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 BANPIXAN following surgery (see section 4.5). In patients with atrial fibrillation and a condition that warrants chronic use of aspirin, BANPIXAN 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 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 BANPIXAN have not been studied in patients with prosthetic heart valves, with or without atrial fibrillation. Therefore, the use of BANPIXAN 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 BANPIXAN in patients with APS, is inconclusive/incomplete. There is some evidence that treatment with BANPIXAN 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

BANPIXAN 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 BANPIXAN

Discontinue BANPIXAN in the presence of active bleeding, elective surgery, or invasive procedures that place patients at an increased risk of haemorrhage. Restart BANPIXAN therapy 12 u2013 24 hours after the danger of haemorrhage has ceased.

Spinal/epidural anaesthesia or puncture

Prevention of VTE: elective hip or knee replacement surgery

When neuraxial anaesthesia (spinal/epidural anaesthesia) or spinal/epidural puncture is employed, patients treated with antithrombotic medicines, such as BANPIXAN, 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 is planned, BANPIXAN should be stopped 48 hours beforehand. Indwelling epidural or intrathecal catheters must be removed at least 6 hours prior to the first dose of BANPIXAN. 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 of anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis.

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, BANPIXAN 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 BANPIXAN (see section 5.1). Changes observed in these clotting tests at the expected therapeutic dose are small and subject to a high degree of variability (see section 5.1). These parameters should not be used to monitor BANPIXAN therapy.

Special populations

Renal impairment

Prevention of VTE: elective hip or knee replacement surgery

Because there is limited clinical experience in patients with creatinine clearance < 15 mL/min and there are no data in patients undergoing dialysis, BANPIXAN is not recommended in these patients (see section 4.2, section 5.2 and section 4.3).

Prevention of stroke and systemic embolism: NVAF

BANPIXAN has not been studied in patients undergoing dialysis and is not recommended in these patients.

Hepatic impairment

BANPIXAN is not recommended in patients with severe hepatic impairment (see section 5.1 and section 4.3). BANPIXAN may be used with caution in patients with mild or moderate hepatic impairment (Child Pugh A or B) (see section 4.2 and section 5.1).

Paediatric use

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

Lactose intolerance

BANPIXAN contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take BANPIXAN.

Effect of other medicines on BANPIXAN

Inhibitors of CYP3A4 and P-gp

Co-administration of BANPIXAN with ketoconazole (400 mg once a day), a strong inhibitor of both CYP3A4 and P-gp, led to a 2-fold increase in mean BANPIXAN AUC and a 1,6-fold increase in mean apixaban C max (see section 4.4). The dose of BANPIXAN must not exceed 2,5 mg twice daily when used with these medicines. Active substances that are not considered strong inhibitors of both CYP3A4 and P-gp (e.g. diltiazem, naproxen, amiodarone, clarithromycin, verapamil, quinidine) are expected to increase apixaban plasma concentration to a lesser extent. No dose adjustment for BANPIXAN is required when co-administered with less potent inhibitors of CYP3A4 and/or P-gp. Diltiazem (360 mg once a day), for instance, considered a moderate CYP3A4 and a weak P-gp inhibitor, led to a 1,4-fold increase in mean BANPIXAN AUD and 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 BANPIXAN 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 BANPIXAN AUC and C max respectively.

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 C max, respectively. The concomitant use of BANPIXAN with other strong CYP3A4 and P-gp inducers (e.g. phenytoin, carbamazepine, phenobarbitone or St. Johnu2019s Wort) may also lead to reduced BANPIXAN plasma concentrations. No dose adjustment for BANPIXAN is required during concomitant therapy with such agents, however strong inducers of both CYP3A4 and P-gp should be co-administered with caution (see section 4.4). 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 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 (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 was co-administered with aspirin 325 mg once a day. Apixaban co-administered with clopidogrel (75 mg once daily) or with the combination of clopidogrel 75 mg and aspirin 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 BANPIXAN. Increases in clotting tests (PT, INR, and aPTT) were consistent with the effects of apixaban 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), and inhibitor of P-gp, led to a 1,5-fold and 1,6-fold increase in mean apixaban AUC and C max, in healthy subjects, respectively. Corresponding increases in clotting tests were observed for apixaban. No clinically relevant prolongation of bleeding time was observed after concomitant administration of apixaban and naproxen. BANPIXAN should be used with caution when co-administered with NSAIDs (including aspirin) because these medicinal products typically increase the bleeding risk. Medicines associated with serious bleeding are not recommended concomitantly with BANPIXAN, 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 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 (see section 4.4).

Other concomitant therapies

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

Safety has not been established.

Pregnancy

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

Breastfeeding

It is unknown whether BANPIXAN or its metabolites are excreted in human milk. A risk to newborns and infants cannot be excluded. Women taking BANPIXAN should not breastfeed their infants.

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

Summary of the safety profile

Prevention of VTE: elective hip or knee replacement surgery

The safety of apixaban has been evaluated in 5 924 patients exposed to apixaban 2,5 mg twice daily undergoing major orthopaedic surgery of the lower limbs (elective hip replacement or elective knee replacement) treated for up to 38 days. In total, 11 % of the patients treated with apixaban 2,5 mg twice daily experienced adverse reactions. Bleeding may occur during apixaban therapy in the presence of associated risk factors such as organic lesions liable to bleed. Common adverse reactions were anaemia, haemorrhage, contusion and nausea. The use of apixaban may be associated with an increased risk of occult or overt bleeding from any tissue or organ (see section 4.4).

Tabulated list of adverse reactions

Table 1 shows the adverse reactions ranked under headings of system organ class and frequency using the following convention: Frequent; Less frequent; Frequency unknown.

Table 1: Tabulated adverse reactions

System organ class Prevention of VTE in adult patients who have undergone elective hip or knee replacement surgery (VTEp) Prevention of stroke and systemic embolism in adult patients with NVAF, with one or more risk factors (NVAF) Treatment of DVT and PE, and prevention of recurrent DVT and PE (VTEt)

Blood and lymphatic system disorders

Anaemia Frequent Frequent Frequent

Thrombocytopenia Less frequent Less frequent Frequent

Immune system disorders

Hypersensitivity, allergic oedema and anaphylaxis Less frequent Less frequent Less frequent

Pruritus Less frequent Less frequent Less frequent

Angioedema Frequency unknown Frequency unknown Frequency unknown

Nervous system disorders

Brain haemorrhage ua749 Frequency unknown Less frequent Less frequent

Eye disorders

Eye haemorrhage (including conjunctival haemorrhage) Less frequent Frequent Less frequent

Vascular disorders

Haemorrhage, haematoma Frequent Frequent Frequent

Hypotension (including procedural hypotension) Less frequent Frequent Less frequent

Intra-abdominal haemorrhage Frequency unknown Less frequent Frequency unknown

Respiratory, thoracic and mediastinal disorders

Epistaxis Less frequent Frequent Frequent

Haemoptysis Less frequent Less frequent Less frequent

Respiratory tract haemorrhage Frequency unknown Less frequent Less frequent

Gastrointestinal disorders

Nausea Frequent Frequent Frequent

Gastrointestinal haemorrhage Less frequent Frequent Frequent

Haemorrhoidal haemorrhage Frequency unknown Less frequent Frequent

Mouth haemorrhage Frequency unknown Less frequent Frequent

Haematochezia Less frequent Less frequent Less frequent

Rectal haemorrhage, gingival bleeding Less frequent Frequent Frequent

Retroperitoneal haemorrhage Frequency unknown Less frequent Frequency unknown

Hepatobiliary disorders

Liver function test abnormal, increased aspartate aminotransferase, increased blood alkaline phosphatase, increased blood bilirubin Less frequent Less frequent Less frequent

Increased gamma-glutamyltransferase Less frequent Frequent Frequent

Increased alanine aminotransferase Less frequent Less frequent Frequent

Skin and subcutaneous tissue disorders

Skin rash Frequency unknown Less frequent Frequent

Alopecia Less frequent Less frequent Less frequent

Musculoskeletal and connective tissue disorders

Muscle haemorrhage Less frequent Less frequent Less frequent

Renal and urinary disorders

Haematuria Less frequent Frequent Frequent

Reproductive system and breast disorders

Abnormal vaginal haemorrhage, urogenital haemorrhage Less frequent Less frequent Frequent

General disorders and administration site conditions

Application site bleeding Frequency unknown Less frequent Less frequent

Investigations

Positive occult blood Frequency unknown Less frequent Less frequent

Injury, poisoning and procedural complications

Contusion Frequent Frequent Frequent

Post procedural haemorrhage (including post procedural haematoma, wound haemorrhage, vessel puncture site haematoma and catheter site haemorrhage), wound secretion, incision site haemorrhage (including incision site haematoma), operative haemorrhage Less frequent Less frequent Less frequent

Traumatic haemorrhage Frequency unknown Less frequent Less frequent

* There were no occurrences of generalized pruritus in CV185057 (long term prevention of VTE).

ua749 The term u201cbrain haemorrhageu201d encompasses all intracranial or intraspinal haemorrhages (i.e. haemorrhagic stroke or putamen, cerebellar, intraventricular, or subdural haemorrhages).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are requested to report any suspected adverse drug reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website.

There is no antidote to apixaban. Overdose of apixaban 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 reduced mean apixaban AUC by 50 % and 27 %, respectively, and had no impact on C max. 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 BANPIXAN overdose or accidental ingestion. Haemodialysis is unlikely to be an effective means of managing BANPIXAN overdose. Treatment should be symptomatic and supportive.