ASH Clinical News September 2016 | Page 71

Adverse reactions occurring in ≥1 % of patients undergoing hip or knee replacement surgery in the 1 Phase II study and the 3 Phase III studies are listed in Table 4 .

Table 4 :

Adverse Reactions Occurring in ≥1 % of Patients in Either Group Undergoing Hip or Knee Replacement Surgery

ELIQUIS ( apixaban ), n (%) 2.5 mg po bid

N = 5924

Enoxaparin , n (%) 40 mg sc qd or 30 mg sc q12h N = 5904

Nausea 153 ( 2.6 ) 159 ( 2.7 )

Anemia ( including postoperative and hemorrhagic anemia , and respective laboratory parameters )

153 ( 2.6 ) 178 ( 3.0 )

Contusion 83 ( 1.4 ) 115 ( 1.9 )

Hemorrhage ( including hematoma , and vaginal and urethral hemorrhage )

Postprocedural hemorrhage ( including postprocedural hematoma , wound hemorrhage , vessel puncture site hematoma and catheter site hemorrhage )

Transaminases increased ( including alanine aminotransferase increased and alanine aminotransferase abnormal )

67 ( 1.1 ) 81 ( 1.4 )

54 ( 0.9 ) 60 ( 1.0 )

50 ( 0.8 ) 71 ( 1.2 )

Aspartate aminotransferase increased 47 ( 0.8 ) 69 ( 1.2 ) Gamma-glutamyltransferase increased 38 ( 0.6 ) 65 ( 1.1 )

Less common adverse reactions in apixaban-treated patients undergoing hip or knee replacement surgery occurring at a frequency of ≥0.1 % to < 1 %:

Blood and lymphatic system disorders : thrombocytopenia ( including platelet count decreases ) Vascular disorders : hypotension ( including procedural hypotension ) Respiratory , thoracic , and mediastinal disorders : epistaxis

Gastrointestinal disorders : gastrointestinal hemorrhage ( including hematemesis and melena ), hematochezia

Hepatobiliary disorders : liver function test abnormal , blood alkaline phosphatase increased , blood bilirubin increased

Renal and urinary disorders : hematuria ( including respective laboratory parameters )

Injury , poisoning , and procedural complications : wound secretion , incision-site hemorrhage ( including incision-site hematoma ), operative hemorrhage

Less common adverse reactions in apixaban-treated patients undergoing hip or knee replacement surgery occurring at a frequency of < 0.1 %:

Gingival bleeding , hemoptysis , hypersensitivity , muscle hemorrhage , ocular hemorrhage ( including conjunctival hemorrhage ), rectal hemorrhage

Treatment of DVT and PE and Reduction in the Risk of Recurrence of DVT or PE

The safety of ELIQUIS has been evaluated in the AMPLIFY and AMPLIFY-EXT studies , including 2676 patients exposed to ELIQUIS 10 mg twice daily , 3359 patients exposed to ELIQUIS 5 mg twice daily , and 840 patients exposed to ELIQUIS 2.5 mg twice daily .

Common adverse reactions ( ≥1 %) were gingival bleeding , epistaxis , contusion , hematuria , rectal hemorrhage , hematoma , menorrhagia , and hemoptysis .

AMPLIFY Study

The mean duration of exposure to ELIQUIS was 154 days and to enoxaparin / warfarin was 152 days in the AMPLIFY study . Adverse reactions related to bleeding occurred in 417 ( 15.6 %) ELIQUIS-treated patients compared to 661 ( 24.6 %) enoxaparin / warfarin-treated patients . The discontinuation rate due to bleeding events was 0.7 % in the ELIQUIS-treated patients compared to 1.7 % in enoxaparin / warfarin-treated patients in the AMPLIFY study .

In the AMPLIFY study , ELIQUIS was statistically superior to enoxaparin / warfarin in the primary safety endpoint of major bleeding ( relative risk 0.31 , 95 % CI [ 0.17 , 0.55 ], P-value < 0.0001 ).

Bleeding results from the AMPLIFY study are summarized in Table 5 .

Table 5 :

Bleeding Results in the AMPLIFY Study

ELIQUIS N = 2676 n (%)

Enoxaparin / Warfarin N = 2689 n (%)

Relative Risk ( 95 % CI )

Adverse reactions occurring in ≥1 % of patients in the AMPLIFY study are listed in Table 6 .

Table 6 : Adverse Reactions Occurring in ≥1 % of Patients Treated for DVT and PE in the AMPLIFY Study

ELIQUIS N = 2676 n (%)

Enoxaparin / Warfarin N = 2689 n (%)

AMPLIFY-EXT Study

The mean duration of exposure to ELIQUIS was approximately 330 days and to placebo was 312 days in the AMPLIFY-EXT study . Adverse reactions related to bleeding occurred in 219 ( 13.3 %) ELIQUIS-treated patients compared to 72 ( 8.7 %) placebo-treated patients . The discontinuation rate due to bleeding events was approximately 1 % in the ELIQUIS-treated patients compared to 0.4 % in those patients in the placebo group in the AMPLIFY-EXT study .

Bleeding results from the AMPLIFY-EXT study are summarized in Table 7 .

Table 7 :

Bleeding Results in the AMPLIFY-EXT Study

ELIQUIS ( apixaban ) 2.5 mg bid N = 840 n (%)

ELIQUIS 5 mg bid N = 811 n (%)

Placebo

N = 826 n (%)

Major 2 ( 0.2 ) 1 ( 0.1 ) 4 ( 0.5 ) CRNM * 25 ( 3.0 ) 34 ( 4.2 ) 19 ( 2.3 ) Major + CRNM 27 ( 3.2 ) 35 ( 4.3 ) 22 ( 2.7 ) Minor 75 ( 8.9 ) 98 ( 12.1 ) 58 ( 7.0 ) All 94 ( 11.2 ) 121 ( 14.9 ) 74 ( 9.0 )

* CRNM = clinically relevant nonmajor bleeding . Events associated with each endpoint were counted once per subject , but subjects may have contributed events to multiple endpoints .

Adverse reactions occurring in ≥1 % of patients in the AMPLIFY-EXT study are listed in Table 8 . Table 8 :

Adverse Reactions Occurring in ≥1 % of Patients Undergoing Extended Treatment for DVT and PE in the AMPLIFY-EXT Study

ELIQUIS 2.5 mg bid N = 840 n (%)

ELIQUIS 5 mg bid N = 811 n (%)

Placebo

N = 826 n (%)

Epistaxis 13 ( 1.5 ) 29 ( 3.6 ) 9 ( 1.1 ) Hematuria 12 ( 1.4 ) 17 ( 2.1 ) 9 ( 1.1 ) Hematoma 13 ( 1.5 ) 16 ( 2.0 ) 10 ( 1.2 ) Contusion 18 ( 2.1 ) 18 ( 2.2 ) 18 ( 2.2 ) Gingival bleeding 12 ( 1.4 ) 9 ( 1.1 ) 3 ( 0.4 )

Other Adverse Reactions

Less common adverse reactions in ELIQUIS-treated patients in the AMPLIFY or AMPLIFY-EXT studies occurring at a frequency of ≥0.1 % to < 1 %:

Blood and lymphatic system disorders : hemorrhagic anemia

Gastrointestinal disorders : hematochezia , hemorrhoidal hemorrhage , gastrointestinal hemorrhage , hematemesis , melena , anal hemorrhage

Injury , poisoning , and procedural complications : wound hemorrhage , postprocedural hemorrhage , traumatic hematoma , periorbital hematoma

Musculoskeletal and connective tissue disorders : muscle hemorrhage

Reproductive system and breast disorders : vaginal hemorrhage , metrorrhagia , menometrorrhagia , genital hemorrhage

Vascular disorders : hemorrhage Skin and subcutaneous tissue disorders : ecchymosis , skin hemorrhage , petechiae Eye disorders : conjunctival hemorrhage , retinal hemorrhage , eye hemorrhage

Investigations : blood urine present , occult blood positive , occult blood , red blood cells urine positive

General disorders and administration-site conditions : injection-site hematoma , vessel puncture-site hematoma

DRUG INTERACTIONS

Apixaban is a substrate of both CYP3A4 and P-gp . Inhibitors of CYP3A4 and P-gp increase exposure to apixaban and increase the risk of bleeding . Inducers of CYP3A4 and P-gp decrease exposure to apixaban and increase the risk of stroke and other thromboembolic events .

Strong Dual Inhibitors of CYP3A4 and P-gp

For patients receiving ELIQUIS 5 mg or 10 mg twice daily , the dose of ELIQUIS should be decreased by 50 % when it is coadministered with drugs that are strong dual inhibitors of CYP3A4 and P-gp ( e . g ., ketoconazole , itraconazole , ritonavir , or clarithromycin ) [ see Dosage and Administration ( 2.5 ) and Clinical Pharmacology ( 12.3 ) in full Prescribing Information ].

For patients receiving ELIQUIS at a dose of 2.5 mg twice daily , avoid coadministration with strong dual inhibitors of CYP3A4 and P-gp [ see Dosage and Administration ( 2.5 ) and Clinical Pharmacology ( 12.3 ) in full Prescribing Information ].

Strong Dual Inducers of CYP3A4 and P-gp

Avoid concomitant use of ELIQUIS with strong dual inducers of CYP3A4 and P-gp ( e . g ., rifampin , carbamazepine , phenytoin , St . John ’ s wort ) because such drugs will decrease exposure to apixaban [ see Clinical Pharmacology ( 12.3 ) in full Prescribing Information ].

Anticoagulants and Antiplatelet Agents

Coadministration of antiplatelet agents , fibrinolytics , heparin , aspirin , and chronic NSAID use increases the risk of bleeding .

APPRAISE-2 , a placebo-controlled clinical trial of apixaban in high-risk , post-acute coronary syndrome patients treated with aspirin or the combination of aspirin and clopidogrel , was terminated early due to a higher rate of bleeding with apixaban compared to placebo . The rate of ISTH major bleeding was 2.8 % per year with apixaban versus 0.6 % per year with placebo in patients receiving single antiplatelet therapy and was 5.9 % per year with apixaban versus 2.5 % per year with placebo in those receiving dual antiplatelet therapy .

In ARISTOTLE , concomitant use of aspirin increased the bleeding risk on ELIQUIS from 1.8 % per year to 3.4 % per year and concomitant use of aspirin and warfarin increased the bleeding risk from 2.7 % per year to 4.6 % per year . In this clinical trial , there was limited ( 2.3 %) use of dual antiplatelet therapy with ELIQUIS .

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category B

There are no adequate and well-controlled studies of ELIQUIS in pregnant women . Treatment is likely to increase the risk of hemorrhage during pregnancy and delivery . ELIQUIS should be used during pregnancy only if the potential benefit outweighs the potential risk to the mother and fetus .

Treatment of pregnant rats , rabbits , and mice after implantation until the end of gestation resulted in fetal exposure to apixaban , but was not associated with increased risk for fetal malformations or toxicity . No maternal or fetal deaths were attributed to bleeding . Increased incidence of maternal bleeding was observed in mice , rats , and rabbits at maternal exposures that were 19 , 4 , and 1 times , respectively , the human exposure of unbound drug , based on area under plasma-concentration time curve ( AUC ) comparisons at the maximum recommended human dose ( MRHD ) of 10 mg ( 5 mg twice daily ).

Labor and Delivery

Safety and effectiveness of ELIQUIS during labor and delivery have not been studied in clinical trials . Consider the risks of bleeding and of stroke in using ELIQUIS in this setting [ see Warnings and Precautions ].

Treatment of pregnant rats from implantation ( gestation Day 7 ) to weaning ( lactation Day 21 ) with apixaban at a dose of 1000 mg / kg ( about 5 times the human exposure based on unbound apixaban ) did not result in death of offspring or death of mother rats during labor in association with uterine bleeding . However , increased incidence of maternal bleeding , primarily during gestation , occurred at apixaban doses of ≥25 mg / kg , a dose corresponding to ≥1.3 times the human exposure .

Nursing Mothers

It is unknown whether apixaban or its metabolites are excreted in human milk . Rats excrete apixaban in milk ( 12 % of the maternal dose ).

Women should be instructed either to discontinue breastfeeding or to discontinue ELIQUIS ( apixaban ) therapy , taking into account the importance of the drug to the mother .

Pediatric Use Safety and effectiveness in pediatric patients have not been established . Geriatric Use

Of the total subjects in the ARISTOTLE and AVERROES clinical studies , > 69 % were 65 and older , and > 31 % were 75 and older . In the ADVANCE-1 , ADVANCE-2 , and ADVANCE-3 clinical studies , 50 % of subjects were 65 and older , while 16 % were 75 and older . In the AMPLIFY and AMPLIFY-EXT clinical studies , > 32 % of subjects were 65 and older and > 13 % were 75 and older . No clinically significant differences in safety or effectiveness were observed when comparing subjects in different age groups .

Renal Impairment

No dose adjustment is recommended for patients with renal impairment alone , including those with end-stage renal disease ( ESRD ) maintained on hemodialysis , except nonvalvular atrial fibrillation patients who meet the criteria for dosage adjustment [ see Dosage and Administration ( 2.1 ) in full Prescribing Information ]. Patients with ESRD ( CrCl < 15 mL / min ) receiving or not receiving hemodialysis were not studied in clinical efficacy and safety studies with ELIQUIS ; therefore , the dosing recommendations are based on pharmacokinetic and pharmacodynamic ( anti-Factor Xa activity ) data in subjects with ESRD maintained on dialysis [ see Clinical Pharmacology ( 12.3 ) in full Prescribing Information ].

Hepatic Impairment

No dose adjustment is required in patients with mild hepatic impairment ( Child-Pugh class A ). Because patients with moderate hepatic impairment ( Child-Pugh class B ) may have intrinsic coagulation abnormalities and there is limited clinical experience with ELIQUIS in these patients , dosing recommendations cannot be provided [ see Clinical Pharmacology ( 12.2 ) in full Prescribing Information ]. ELIQUIS is not recommended in patients with severe hepatic impairment ( Child-Pugh class C ) [ see Clinical Pharmacology ( 12.2 ) in full Prescribing Information ].

OVERDOSAGE

There is no antidote to ELIQUIS . Overdose of ELIQUIS increases the risk of bleeding [ see Warnings and Precautions ].

In controlled clinical trials , orally administered apixaban in healthy subjects at doses up to 50 mg daily for 3 to 7 days ( 25 mg twice daily for 7 days or 50 mg once daily for 3 days ) had no clinically relevant adverse effects .

In healthy subjects , 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 . Thus , administration of activated charcoal may be useful in the management of apixaban overdose or accidental ingestion .

PATIENT COUNSELING INFORMATION See FDA-approved patient labeling ( Medication Guide ). Advise patients of the following :

• They should not discontinue ELIQUIS without talking to their physician first .

• They should be informed that it might take longer than usual for bleeding to stop , and they may bruise or bleed more easily when treated with ELIQUIS . Advise patients about how to recognize bleeding or symptoms of hypovolemia and of the urgent need to report any unusual bleeding to their physician .

• They should tell their physicians and dentists they are taking ELIQUIS , and / or any other product known to affect bleeding ( including nonprescription products , such as aspirin or NSAIDs ), before any surgery or medical or dental procedure is scheduled and before any new drug is taken .

• If the patient is having neuraxial anesthesia or spinal puncture , inform the patient to watch for signs and symptoms of spinal or epidural hematomas , such as numbness or weakness of the legs , or bowel or bladder dysfunction [ see Warnings and Precautions ]. If any of these symptoms occur , the patient should contact his or her physician immediately .

• They should tell their physicians if they are pregnant or plan to become pregnant or are breastfeeding or intend to breastfeed during treatment with ELIQUIS [ see Use in Specific Populations ].

• If a dose is missed , the dose should be taken as soon as possible on the same day and twice-daily administration should be resumed . The dose should not be doubled to make up for a missed dose .

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1356615A0 / 1356514A0 Rev September 2015 432US1501679-06-01