Apixaban

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

Apixaban has not been studied in paediatric patients with hepatic impairment.

Adult patients

In adult patients with mild or moderate renal impairment, 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), no dose adjustment is necessary.
• for the prevention of stroke and systemic embolism in patients with NVAF and serum creatinine ≥1.5 mg/dL (133 micromole/L) associated with age ≥80 years or body weight ≤60 kg, a dose reduction is necessary. In the absence of other criteria for dose reduction (age, body weight), no dose adjustment is necessary.

In adult 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.

Paediatric population

Based on adult data and limited data in paediatric patients, no dose adjustment is necessary in paediatric patients with mild to moderate renal impairment. Apixaban is not recommended in paediatric patients with severe renal impairment.

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.

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). These medicinal products may increase apixaban exposure by 2-fold, or greater in the presence of additional factors that increase apixaban exposure (e.g., severe renal impairment).

No clinical data are available in paediatric patients receiving concomitant systemic treatment with strong inhibitors of both CYP 3A4 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 apixaban with strong CYP3A4 and P-gp inducers (e.g., rifampicin, phenytoin, carbamazepine, phenobarbital or St. John’s 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 observed with coadministration of apixaban with strong inducers of both CYP3A4 and P-gp compared with using apixaban alone.

In patients receiving concomitant systemic treatment with strong inducers of both CYP3A4 and P-gp the following recommendations apply:

• 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 should be used with caution;
• for the treatment of DVT and treatment of PE, apixaban should not be used since efficacy may be compromised.

No clinical data are available in paediatric patients receiving concomitant systemic treatment with strong inducers of both CYP 3A4 and P-gp.

Administration of activated charcoal reduces apixaban exposure.

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.

Apixaban has not been studied in clinical studies in patients undergoing hip fracture surgery to evaluate efficacy and safety in these patients. Therefore, it is not recommended in these patients.

Patients with active cancer can be at high risk of both venous thromboembolism and bleeding events. When apixaban is considered for DVT or PE treatment in cancer patients, a careful assessment of the benefits against the risks should be made.

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. As a precautionary measure, it is preferable to avoid the use of apixaban 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. A risk to the suckling child cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from apixaban therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

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

In adults, 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 (see the table below for adverse reaction profile and frequencies by indication).

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.

Tabulated list of adverse reactions

The table below 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) in adults for VTEp, NVAF, and VTEt and in paediatric patients from 28 days to <18 years of age for VTEt and prevention of recurrent VTE.

The frequencies of adverse reactions reported in the following talbe for paediatric patients are derived from study CV185325, in which they received apixaban for treatment of VTE and prevention of recurrent VTE.

Tabulated adverse reactions:

^* There were no occurrences of generalised pruritus in CV185057 (long term prevention of VTE).
^† The term “Brain haemorrhage” encompasses all intracranial or intraspinal haemorrhages (i.e., haemorrhagic stroke or putamen, cerebellar, intraventricular, or subdural haemorrhages).
^‡ Includes anaphylactic reaction, drug hypersensitivity, and hypersensitivity.
^§ Includes heavy menstrual bleeding, intermenstrual bleeding, and vaginal haemorrhage.

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.

Paediatric population

The safety of apixaban has been investigated in 1 Phase I and 3 Phase II/III clinical studies including 970 patients. Of these patients, 568 patients received one or more doses of apixaban for average total exposure of 1, 24, 331 and 80 days, respectively. The patients received weight adjusted doses of an age-appropriate formulation of apixaban.

Overall, the safety profile of apixaban in paediatric patients 28 days to <18 years of age was similar to that in adults and was generally consistent across different paediatric age groups.

The most commonly reported adverse reactions in paediatric patients were epistaxis, and abnormal vaginal haemorrhage (see the table above for adverse reaction profile and frequencies by indication).

In paediatric patients, epistaxis (very common), abnormal vaginal haemorrhage (very common), hypersensitivity and anaphylaxis (common), pruritus (common), hypotension (common), haematochezia (common), aspartate aminotransferase increased (common), alopecia (common), and post procedural haemorrhage (common) were reported more frequently as compared to adults treated with apixaban, but in the same frequency category as the paediatric patients in the standard of care (SOC) arm; the only exception was abnormal vaginal haemorrhage, which was reported as common in the SOC arm. In all but one case, hepatic transaminase elevations were reported in paediatric patients receiving concomitant chemotherapy for an underlying malignancy.