Drug interactions-

Apixaban +

Medical products affecting hemostatis-
care should be taken if comcomittantly taken NSAIDs  including acetyl salicylic acid
Not recommended to be taken with other antithrobotic agents

With inhibitors of Cytochrome P450 3A ( CYPP3A) and P-glycoprotein ( P-gp)-
can be administred with caution in patients receiving concomittant treatment with strong
systemic treatment of both CYP3A4 and P-gp ) such as azole -antimycotics eg ketoconazole,
itraconazole, voriconazole, and posaconazole) HIV protease inhibitors eg.( Ritonavir )

With inducers of both CYP3A4 and P-gp-
concomittant use of with strong cYP3A4  and p-pg inducers eg ( Rifampin, phenytoin, 
carbamazepine, phenobarbital or St Johns Wort may lead to app 50% reduction
in drug exposure. Use caution when co-administering with strong inducers of both
CYP3A4 and P-gp

 Ketoconazole-
Co-admin of apixaban with ketoconazole ( a strong inhibitor of CYP3A4 and Ppg ) led to
2 fold increase in AUC and 1.6 fold increase in Camx. No dosage adjustment for apixaban
was necessary with concomittant ketoconazole therapy .

However apixaban should be used with caution in patients receiving cocomittant systemic
treatment with azole-antimycotics such as ketoconazole or other strong inhibitors of both
CYP3A4 and Pgp

 Digoxin-
coadmin of apaxiban and digoxin did not affect digoxin AUC or Cmax

Naproxen -
Coadmin of apixaban and naproxen a commonly used NSAID did not have any affect
on naproxen AUC or Cmax

 Atenolol-
Coadmin of apixaban and atenolol a common beta-blocker did not alter pharmacokinetics
of atenolol.

Interaction with other medical products affecting hemostatis-
Threre is no experience with the use of recombinant factor Vlla in individuals receiving apixaban
Re-dosing of recombinant factor Vlla could be considered and titrated depending on
improvement of bleeding

Adverse reactions-

COMMON- ( > 1/100 to < 1/10 ) 

Blood and lymphatic system  disorders-  anemia ( including postoperative and hemorrhagic
                                                         anemia and respective laboratory parameters)

Vascular disorders-       haemorrhage including hematoma, and vaginal urethral hemorrhage

Gastro-intestinal disorders-              nausea

Injury , poisoning and procedural complications-         contusion

UNCOMMOM- ( > 1/1000 to < 1/100 )

Blood and lymphatic system disorders-      thrombocytoma ( including platelet count decreases)

Vascular disorders-              hypotension ( including procedural hypotension )

Respiratory ,thoraic and mediastinal disorders-      epitaxis

Gastro-intestinal disorders-       gastrointestinal hemorrhage ( including hematesisis and malena)
                                                     hematochezia

Hepatolbiliary disorders-       Tranaminases increased ( including alanine aminotransferase
                                                  increased and alanine aminotransferase abnormal )
                                                  aspartate aminotransferase increased
                                                  gammaglutamyltransferase increased,
                                                  liver function abnormal,
                                                  blood alkaline phosphatase increased
                                                  blood bilirubin increased

Renal and urinary disorders-       hematuria ( including post procedural hematoma,
                                                        wound haemorrhage  vessel puncture hematoma
                                                        and catheter site haemorrhage)
                                                        wound secretion, incision site haemorrhage ( including
                                                        incision site hematoma )
                                                        operative hemorrhage 
 
RARE ( > 1/10000 to < 1/1000)

Eye disorders-                           hypersensitivity
                                                    other hemorrhage ( including conjuntival hemorrhage )

Gastro-intestinal disorders-      rectal hemorrhage, gingival bleeding

Musculo-skeletal and connective tissue disorders-       muscle haemorrhage

Hypersensitivity to the active substance or any other excipients

Special Precautions-
Bleeding- as with other other anticoagulants patients apixaban are to be carfefully observed
for signs of bleeding

Recommended to be used with caution in conditions with increased risk of haemorrhage,
such as cogenital or acquired bleeding disorders, active ulcerative gastro-intestinal disease ,
 bacterial endocarditis, thrombocytopenia, platelet disorders, history of hemorrhagic stroke,
severe uncontrolled hypertension, and recent brain, spinal or opthalmological surgery

Abixaban should be discontinued if severe hemorrhage occurs

Haemorrhage complications- treatment must be discontinued and source of bleeding investigated
The intiation of appropiate treatment eg surgical hemostatasis or tranfusion of fresh frozen plasma
should be considered if life-threatening bleeding cannot be controlled by the above measures.
Administration of recombinant  factor Vlla may be considered.

Renal impairment-  no dosage adjustment was necessary in patients with mild, moderate or
severe ( creatinine clearance 15-29ml.min )

Because of limited experience in patients with creatinine clearance < 15ml/min ) and there
data in patients undergoing dialysis apixaban is not recommended in these patients

Hepatic impairment- apixiban may be used with caution with mild or moderate hepatic
impairment

No dosage adjustment is required with mild to moderate hepatic impairment

Apixaban is not  recomended in patients with severe hepatic impairment

Apixaban is contraindicated in patients with hepatic disease associated with coagulopathy
and clinically relevant bleeding risks.

Hazardous tasks- Apixiban has no or neglible influence on the ability to drive or use machines

Pregnancy- apixaban is not recommended during pregnancy

Breast feeding- a decison must be taken to either discontinue breast-feeding or the drug,
since the risk to newborns cannot be excluded 

Children- The efficacy and safety of use in children below 18 years of age have not yet
been established

Elderly- Elderly patients above 65 yeras of age exhibited higher plasms concentration
than younger patients. No dosage adjustment needed.

Gender - Exposure to apixaban was approximately 18% higher in females than in males.
No dosage adjustments were necessary

Ethinic origin and race- Results showed no discerinable difference in apixaban
 pharmacokinetics between whites/caucasians, Asians, and black/African Americans subjects.
Findings from a population pharmacokinetics in patients following effective hip or knee
replacements with consistent with phase I results
No dosage adjustment

Dosage-
Recommended dose is 2.5mg taken orally twice daily. The initial dose should be taken
12 to 24 hours after surgery

In patients undrgoing 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

If a dose is missed the patient should take the dose imediately and then conitinue with twice
daily intake as before

The tablet can be taken with or without food.

Pharmacology-

Apixaban is a selective inhibitor of the coagulation factor Xa (FXa) . It does not require
antithrombin III for antithrombotic activity.

Apixaban inhibits free and clot-bound factor Xa and prothrombinase activity.
Apixaban has no direct effects on platelet aggregation ,but directly inhibits platelate aggregation
induced by thrombin. By inhibiting factor Xa ,apixaban prevents generation and thrombus
 development

Pharmacokinetics-
The absolute bioavailability of abixaban is approximately 50% for doses up to 10mg.
apaxiban is rapidly absorbed with maximum conncentration Cmax appearing 3 to 4 hours
after tablet intake

Intake with food does not affect abaxiban AUC or Cmax at the 10mg dose. Apaxiban can be
taken with or without food

Metabolism-
Apixaban has multiple routes of elimination . Of the administred apixaban 25% was recovered
as metabolites, with the majority receovered in feces. Renal excretion of apixaban accounts
for 27%  of total clearance.

The tablet can be taken with or without food

Pregnancy-
Apixaban is not recommended during pregnancy

Breastfeeding-
A decison must be taken to either discontinue breast-feeding or the drug,
since the risk to newborns canno be excluded 

Children-
The efficacy and safety of use in children below 18 yeras of age have not yet
been established

Elderly-
 Elderly patients above 65 yeras of age exhibited higher plasma concentration
than younger patients. No dosage adjustment needed.