Pixeclot 2,5 Mg/5 Mg Tablets

Prevention of VTE: elective hip or knee replacement surgery

PIXECLOT 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)

PIXECLOT 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.

Posology

Recommended dosage

Prevention of VTE: elective hip or knee replacement surgery

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

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). There is limited clinical experience in patients with creatinine clearance < 15 mL/min and there are no data in patients undergoing dialysis, therefore PIXECLOT 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. There is no clinical experience in patients with creatinine clearance < 15 mL/min, therefore a dosing recommendation cannot be provided.

There are no data in patients undergoing dialysis, therefore, PIXECLOT is not recommended in these patients.

Hepatic impairment

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

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 Posology, Prevention of stroke and systemic embolism: NVAF.

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 Posology, Prevention of stroke and systemic embolism: NVAF.

Paediatric population

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

Converting from or to parenteral anticoagulants

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

Patients undergoing cardioversion

PIXECLOT can be initiated or continued in NVAF patients who may require cardioversion.

Surgery and invasive procedures

PIXECLOT 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.

Method of administration

PIXECLOT can be taken with or without food. If a dose is missed, the patient should take PIXECLOT immediately and then continue with twice daily administration as before. For patients who are unable to swallow whole tablets, PIXECLOT 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, PIXECLOT may be crushed and suspended in 60 ml of water or D5W and promptly delivered through a nasogastric tube (see section 5.2). Crushed PIXECLOT 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 listed in section 6.1.
• Clinically significant active bleeding.
• PIXECLOT is not recommended in patients with severe renal disease (CrCI < 15 mL/min).
• PIXECLOT is not recommended in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk.
• PIXECLOT should not be administered with antiplatelet medicines other than aspirin (see section 4.4).
• 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 haemorrhage, known or suspected oesophageal 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 (see section 4.2), 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 fibrillation (see sections 4.4 and 4.5).

Haemorrhage risk

Patients taking PIXECLOT 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. PIXECLOT administration should be discontinued if severe haemorrhage occurs (see sections 4.8 and 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 VIla may be considered. Currently there is no experience with the use of recombinant factor VIla in individuals receiving PIXECLOT. Standard anticoagulation tests cannot be used to monitor PIXECLOT (see section 4.5).

Although treatment with PIXECLOT 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. There is no reversal medication for PIXECLOT.

Interaction with other medicines affecting haemostasis

Due to an increased bleeding risk, concomitant treatment with any other anticoagulants is contraindicated (see section 4.3). The concomitant use of PIXECLOT with antiplatelet medicines increases the risk of bleeding (see section 4.5). Care is to be taken if patients are treated concomitantly with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs), or non-steroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid (ASA).

Following surgery, other platelet aggregation inhibitors are not recommended concomitantly with PIXECLOT (see section 4.5).

In a clinical study of patients with atrial fibrillation, concomitant use of ASA is reported to have increased the major bleeding risk on apixaban as in PIXECLOT 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. In this clinical study, there was limited (2,1 %) use of concomitant dual antiplatelet therapy.

Patients with prosthetic heart valves

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

Patients with antiphospholipid syndrome

Direct acting Oral Anticoagulants (DOACs) including apixaban as in PIXECLOT are not recommended for patients with a history of thrombosis who are diagnosed with antiphospholipid syndrome. In patients that are triple positive (for lupus anticoagulant, anticardiolipin antibodies, and anti-beta 2-glycoprotein I antibodies), treatment with DOACs could be associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy.

Surgery and invasive procedures

PIXECLOT 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. PIXECLOT 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. PIXECLOT should be restarted after the invasive procedure or surgical intervention as soon as possible provided the clinical situation allows and adequate haemostasis has been established (for cardioversion see section 4.2).

For patients undergoing catheter ablation for atrial fibrillation, PIXECLOT treatment does not need to be interrupted (see sections 4.2, 4.3 and 4.5).

Temporary discontinuation

Discontinuing anticoagulants, including apixaban as in PIXECLOT, for active bleeding, elective surgery, or invasive procedures places patients at an increased risk of thrombosis. Lapses in therapy should be avoided and if anticoagulation with PIXECLOT must be temporarily discontinued for any reason, therapy should be restarted as soon as possible.

Patients with renal impairment

For the prevention of stroke and systemic embolism in patients with NVAF, patients with severe renal impairment (creatinine clearance 15 - 29 mL/min), and patients with serum creatinine u2265 1,5 mg/dL (133 micromole/ L) associated with age u2265 80 years or body weight u2264 60 kg should receive the lower dose of apixaban 2,5 mg twice daily (see section 4.2). In patients with creatinine clearance < 15 mL/min, or in patients undergoing dialysis, there is no clinical experience therefore apixaban is not recommended (see sections 4.2 and 5.2).

Elderly patients

Increasing age may increase haemorrhagic risk (see section 5.2). Also, the coadministration of apixaban as in PIXECLOT with ASA in elderly patients should be used cautiously because of a potentially higher bleeding risk.

Body weight

Low body weight (< 60 kg) may increase haemorrhagic risk (see section 5.2).

Patients with hepatic impairment

Apixaban as in PIXECLOT is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk (see section 4.3). It is not recommended in patients with severe hepatic impairment (see section 5.2). It should be used with caution in patients with mild or moderate hepatic impairment (Child Pugh A or B) (see sections 4.2 and 5.2). Patients with elevated liver enzymes ALT/AST > 2 x ULN or total bilirubin u2265 1,5 x ULN were reportedly excluded in clinical studies. Therefore, PIXECLOT should be used cautiously in this population (see section 5.2). Prior to initiating PIXECLOT, liver function testing should be performed.

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

The use of PIXECLOT 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). These medicines may increase apixaban exposure by 2-fold (see section 4.5) or greater in the presence of additional factors that increase apixaban exposure (e.g., severe renal impairment).

Interaction with inducers of both CYP3A4 and P-gp

The concomitant use of apixaban as in PIXECLOT with strong CYP3A4 and P-gp inducers (e.g., rifampicin, phenytoin, carbamazepine, phenobarbital or St. Johnu2019s Wort) may lead to a ~50 % reduction in apixaban exposure. In a clinical study in atrial fibrillation patients, diminished efficacy and a higher risk of bleeding were reportedly observed with coadministration of apixaban with strong inducers of both CYP3A4 and P-gp compared with using apixaban alone.

Inhibitors of CYP3A4 and P-gp

Coadministration of apixaban as in PIXECLOT 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 C max. The use of PIXECLOT 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) (see section 4.4). 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 PIXECLOT is required when coadministered with medicine 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 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 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 AUC and C max respectively.

Inducers of CYP3A4 and P-gp

Coadministration 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 PIXECLOT 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 PIXECLOT is required during concomitant therapy with such medicines, however in patients receiving concomitant systemic treatment with strong inducers of both CYP3A4 and P-gp should be used with caution for the prevention of stroke and systemic embolism in patients with NVAF and for the prevention of recurrent DVT and PE. PIXECLOT 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 (see section 4.4).

Anticoagulants, platelet aggregation inhibitors, SSRIs/SNRIs and NSAIDs

Due to an increased bleeding risk, concomitant treatment with any other anticoagulants is contraindicated 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 fibrillation (see section 4.3). 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 when apixaban was coadministered with ASA 325 mg once a day. Apixaban coadministered with clopidogrel (75 mg once a day) or with the combination of clopidogrel 75 mg and ASA 162 mg once daily, or with prasugrel (60 mg followed by 10 mg once daily) in Phase I studies did reportedly not show a relevant increase in template bleeding time, or further inhibition of platelet aggregation, compared to administration of the antiplatelet medicines 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 C max, 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, there may be individuals with a more pronounced pharmacodynamic response when antiplatelet medicines are coadministered with apixaban. PIXECLOT should be used with caution when coadministered with SSRIs/SNRIs, NSAIDs, ASA and/or P2Y12 inhibitors because these medicines typically increase the bleeding risk (see section 4.4). There is limited experience of co-administration with other platelet aggregation inhibitors (such as GPIIb/IIIa receptor antagonists, dipyridamole, dextran or sulfinpyrazone) or thrombolytic medicines. As such medicines increase the bleeding risk, co-administration of these with PIXECLOT is not recommended (see section 4.4).

Other concomitant therapies

No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when apixaban as in PIXECLOT was coadministered with atenolol or famotidine. Coadministration 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 when administered alone. The administration of apixaban 10 mg with famotidine 40 mg had no effect on apixaban AUC or C max.

Pregnancy

There are no data from the use of apixaban in pregnant women. Animal studies reportedly do not indicate direct or indirect harmful effects with respect to reproductive toxicity. Treatment may increase the risk of haemorrhage during pregnancy and delivery. As a precautionary measure, it is preferable to avoid the use of PIXECLOT during pregnancy.

Breastfeeding

It is unknown whether apixaban or its metabolites are excreted in human milk. Available data in animals have reportedly shown excretion of apixaban in milk. A risk to the suckling child cannot be excluded.

Fertility

Studies in animals dosed with apixaban have reportedly shown no effect on fertility.

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

a) Summary of the safety profile

The safety of apixaban has reportedly been investigated in 4 Phase III clinical studies including more than 15000 patients: more than 11000 patients in NVAF studies and more than 4,000 patients in the VTE treatment (VTEt) studies, for an average total exposure of 1,7 years and 221 days respectively. Common adverse reactions were haemorrhage, contusion, epistaxis, and haematoma (see Table 2 for adverse reaction profile and frequencies by indication). In the NVAF studies, the overall incidence of adverse reactions is reportedly related to bleeding with apixaban was 24,3 % in the apixaban vs warfarin study and 9,6 % in the apixaban vs acetylsalicylic acid study. In the apixaban vs warfarin study the incidence of ISTH major gastrointestinal bleeds (including upper GI, lower GI, and rectal bleeding) with apixaban was 0,76 %/year. The incidence of ISTH major intraocular bleeding with apixaban was 0,18 %/year. In the VTEt studies, the overall incidence of adverse reactions related to bleeding with apixaban was reportedly 15,6 % in the apixaban vs enoxaparin/warfarin study and 13,3 % in the apixaban vs placebo study.

b) Tabulated list of adverse reactions

The table below shows all adverse drug reactions (ADRs) observed during clinical trials and postmarket spontaneous reports with apixaban as in PIXECLOT.

Prevention of VTE: elective hip or knee replacement surgery

System Organ Class Frequency Frequent Less Frequent Unknown Blood and lymphatic system disorders Anaemia Thrombocytopenia -- Immune system disorders -- Hypersensitivity, Allergic oedema and anaphylaxis, Pruritus Angioedema Nervous system disorders -- Brain haemorrhageu2020 -- Eye disorders -- Eye haemorrhage (including conjunctival haemorrhage) -- Vascular disorders Haemorrhage, Haematoma Hypotension (including procedural hypotension) Intra-abdominal haemorrhage Respiratory, thoracic and mediastinal disorders Epistaxis Haemoptysis, Respiratory tract haemorrhage -- Gastrointestinal disorders Nausea, Gastrointestinal haemorrhage, Mouth haemorrhage, Rectal haemorrhage, Gingival bleeding Haemorrhoidal haemorrhage, Haematochezia Retroperitoneal haemorrhage Hepatobiliary disorders Gamma-glutamyltransferase increased, Alanine aminotransferase increased Liver function test abnormal, aspartate aminotransferase increased, Blood alkaline phosphatase increased, Blood bilirubin increased. -- Skin and subcutaneous tissue disorders Skin rash Alopecia -- Musculoskeletal and connective tissue disorders -- Muscle haemorrhage -- Renal and urinary disorders Haematuria -- -- Reproductive system and breast disorders Abnormal vaginal haemorrhage, Urogenital haemorrhage -- -- General disorders and administration site conditions -- Application site bleeding -- Investigations -- Occult blood positive -- Injury, poisoning and procedural complications Contusion 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, Traumatic haemorrhage --

Prevention of stroke and systemic embolism: NVAF

System Organ Class Frequency Frequent Less Frequent Unknown Blood and lymphatic system disorders Anaemia Thrombocytopenia -- Immune system disorders -- Hypersensitivity, Allergic oedema and anaphylaxis, Pruritus Angioedema Nervous system disorders -- Brain haemorrhageu2020 -- Eye disorders Eye haemorrhage (including conjunctival haemorrhage) -- -- Vascular disorders Haemorrhage, Haematoma, Hypotension (including procedural hypotension) Intra-abdominal haemorrhage -- Respiratory, thoracic and mediastinal disorders Epistaxis Haemoptysis, Respiratory tract haemorrhage -- Gastrointestinal disorders Nausea, Gastrointestinal haemorrhage, Rectal haemorrhage, Gingival bleeding Mouth haemorrhage, Haemorrhoidal haemorrhage, Haematochezia, Retroperitoneal haemorrhage -- Hepatobiliary disorders Gamma-glutamyltransferase increased Liver function test abnormal, aspartate aminotransferase increased, Blood alkaline phosphatase increased, Blood bilirubin increased, Alanine aminotransferase increased -- Skin and subcutaneous tissue disorders -- Skin rash, Alopecia -- Musculoskeletal and connective tissue disorders -- Muscle haemorrhage -- Renal and urinary disorders Haematuria -- -- Reproductive system and breast disorders -- Abnormal vaginal haemorrhage, Urogenital haemorrhage -- General disorders and administration site conditions -- Application site bleeding -- Investigations -- Occult blood positive -- Injury, poisoning and procedural complications Contusion Post procedural haemorrhage (including post procedural haematoma, Wound haemorrhage, Vessel puncture site haematom and catheter site haemorrhage), Wound secretion, Incision site haemorrhage (including incision site haematoma), Operative haemorrhage, Traumatic haemorrhage --

u2020 The term u201cBrain haemorrhageu201d encompasses all intracranial or intraspinal haemorrhages (i.e., haemorrhagic stroke or putamen, cerebellar, intraventricular, or subdural haemorrhages).

The use of apixaban as in PIXECLOT may be associated with an increased risk of occult or overt bleeding from any tissue or organ, which may result in posthaemorrhagic anaemia. The signs, symptoms, and severity will vary according to the location and degree or extent of the bleeding (see section 4.4).

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. Healthcare professionals are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reaction Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

Overdose of PIXECLOT 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 studies, orally-administered apixaban in healthy subjects at doses up to 50 mg daily for 3 to 7 days (25 mg twice daily (bid) for 7 days or 50 mg once daily (od) for 3 days) reportedly had no clinically relevant adverse reactions. In healthy subjects, administration of activated charcoal 2 and 6 hours after ingestion of a 20 mg dose of apixaban reportedly 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 apixaban as in PIXECLOT 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 (see section 4.4). Administration of prothrombin complex concentrates (PCCs) or recombinant factor VIIa may also be considered. Reversal of apixaban pharmacodynamic effects, as demonstrated by changes in the thrombin generation assay, was evident at the end of infusion and reached baseline values within 4 hours after the start of a 4-factor PCC 30-minute infusion in healthy subjects. However, there is no clinical experience with the use of 4-factor PCC products to reverse bleeding in individuals who have received apixaban. Currently there is no experience with the use of recombinant factor VIIa in individuals receiving apixaban. Re-dosing of recombinant factor VIIa could be considered and titrated depending on improvement of bleeding. Depending on local availability, a consultation of a coagulation expert should be considered in case of major bleedings. Haemodialysis decreased apixaban AUC by 14 % in subjects with end-stage renal disease (ESRD), when a single dose of apixaban 5 mg was administered orally. Therefore, haemodialysis is unlikely to be an effective means of managing apixaban overdose.