Apixaban

Apixaban should be used with caution when coadministered with SSRIs/SNRIs or NSAIDs (including acetylsalicylic acid) because these medicinal products typically increase the bleeding risk. A significant increase in bleeding risk was reported with the triple combination of apixaban, ASA and clopidogrel in a clinical study in patients with acute coronary syndrome.

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 apixaban with other strong CYP3A4 and P-gp inducers (e.g. phenytoin, carbamazepine, phenobarbital or St. John’s Wort) may also lead to reduced apixaban plasma concentrations. No dose adjustment for apixaban is required during concomitant therapy with such medicinal products, however 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.

Coadministration of apixaban with ketoconazole (400 mg once a day), a strong inhibitor of both CYP3A4 and P-gp, led to a 2-fold increase in mean apixaban AUC and a 1.6-fold increase in mean apixaban C_max.

The use of apixaban is not recommended in patients receiving concomitant systemic treatment with strong inhibitors of both CYP3A4 and P-gp, such as azole-antimycotics (e.g. ketoconazole, itraconazole, voriconazole and posaconazole) and HIV protease inhibitors (e.g. ritonavir).

Active substances which are not considered strong inhibitors of both CYP3A4 and P-gp, (eg. diltiazem, naproxen, clarithromycin, amiodarone, verapamil, quinidine) are expected to increase apixaban plasma concentration to a lesser extent. No dose adjustment for apixaban is required when coadministered with agents that are not strong inhibitors of both CYP3A4 and P-gp. For example, diltiazem (360 mg once a day), considered a moderate CYP3A4 and a weak P-gp inhibitor, led to a 1.4-fold increase in mean apixaban AUC and a 1.3-fold increase in C_max. Apixaban (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.

Coadministration of apixaban with ketoconazole (400 mg once a day), a strong inhibitor of both CYP3A4 and P-gp, led to a 2-fold increase in mean apixaban AUC and a 1.6-fold increase in mean apixaban C_max.

The use of apixaban is not recommended in patients receiving concomitant systemic treatment with strong inhibitors of both CYP3A4 and P-gp, such as azole-antimycotics (e.g. ketoconazole, itraconazole, voriconazole and posaconazole) and HIV protease inhibitors (e.g. ritonavir).

Active substances which are not considered strong inhibitors of both CYP3A4 and P-gp, (eg. diltiazem, naproxen, clarithromycin, amiodarone, verapamil, quinidine) are expected to increase apixaban plasma concentration to a lesser extent. No dose adjustment for apixaban is required when coadministered with agents that are not strong inhibitors of both CYP3A4 and P-gp. For example, diltiazem (360 mg once a day), considered a moderate CYP3A4 and a weak P-gp inhibitor, led to a 1.4-fold increase in mean apixaban AUC and a 1.3-fold increase in 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.

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 apixaban with other strong CYP3A4 and P-gp inducers (e.g., phenytoin, carbamazepine, phenobarbital or St. John’s Wort) may also lead to reduced apixaban plasma concentrations. No dose adjustment for apixaban is required during concomitant therapy with such medicinal products, however 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.

In patients with severe renal impairment (creatinine clearance 15-29 mL/min) the following recommendations apply:

• For the prevention of VTE in elective hip or knee replacement surgery (VTEp), for the treatment of DVT, treatment of PE and prevention of recurrent DVT and PE (VTEt) apixaban is to be used with caution;
• For the prevention of stroke and systemic embolism in patients with NVAF, patients should receive the lower dose of apixaban 2.5 mg twice daily.

In patients with creatinine clearance <15 mL/min, or in patients undergoing dialysis, there is no clinical experience therefore apixaban is not recommended.

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 (AST) >2 x ULN or total bilirubin ≥1.5 x ULN were excluded in clinical trials. Therefore apixaban should be used with caution in this population. Prior to initiating apixaban, liver function testing should be performed.

Administration of activated charcoal reduces apixaban exposure.

Apixaban 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 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 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 as prescribed. Decisions on initiation and duration of treatment should take established guideline recommendations for anticoagulant treatment in patients undergoing cardioversion into account.

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.

It is unknown whether apixaban or its metabolites are excreted in human milk. Available data in animals have shown excretion of apixaban in 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.

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 fertility.

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

Summary of the safety profile

The safety of apixaban 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.

In the VTEp studies, in total, 11% of the patients treated with apixaban 2.5 mg twice daily experienced adverse reactions. The overall incidence of adverse reactions related to bleeding with apixaban was 10% in the apixaban vs enoxaparin studies.

In the NVAF studies, the overall incidence of adverse reactions 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 15.6% in the apixaban vs enoxaparin/warfarin study and 13.3% in the apixaban vs placebo study.

List of adverse reactions

The following list shows the adverse reactions ranked under headings of system organ class and frequency using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥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 were no occurrences of generalized pruritus in CV185057 (long term prevention of VTE)
^† The term “Brain haemorrhage” encompasses all intracranial or intraspinal haemorrhages (ie., haemorrhagic stroke or putamen, cerebellar, intraventricular, or subdural haemorrhages).

The use of apixaban 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.