Lixiana

Reduction In The Risk Of Stroke And Systemic Embolism In Nonvalvular Atrial Fibrillation

Lixiana is indicated to reduce the risk of stroke and systemic embolism (SE) in patients with nonvalvular atrial fibrillation (NVAF).

Limitation Of Use For NVAF

Lixiana should not be used in patients with CrCL > 95 mL/min because of an increased risk of ischemic stroke compared to warfarin.

Treatment Of Deep Vein Thrombosis And Pulmonary Embolism

Lixiana is indicated for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) following 5 to 10 days of initial therapy with a parenteral anticoagulant.

Nonvalvular Atrial Fibrillation

The recommended dose of Lixiana is 60 mg taken orally once daily. Assess creatinine clearance, as calculated using the Cockcroft-Gault equation*, before initiating therapy with Lixiana. Do not use Lixiana in patients with CrCL > 95 mL/min.

Reduce Lixiana dose to 30 mg once daily in patients with CrCL 15 to 50 mL/min.

*Cockcroft-Gault CrCL = (140-age) x (weight in kg) x (0.85 if female) / (72 x creatinine in mg/dL).

Treatment Of Deep Vein Thrombosis And Pulmonary Embolism

The recommended dose of Lixiana is 60 mg taken orally once daily following 5 to 10 days of initial therapy with a parenteral anticoagulant.

The recommended dose of Lixiana is 30 mg once daily in patients with CrCL 15 to 50 mL/min, patients who weigh less than or equal to 60 kg, or patients who are taking certain concomitant P-gp inhibitor medications based on clinical study data in this indication.

Administration Information

If a dose of Lixiana is missed, the dose should be taken as soon as possible on the same day. Dosing should resume the next day according to the normal dosing schedule. The dose should not be doubled to make up for a missed dose.

Lixiana can be taken without regard to food.

Transition To Or From Lixiana

Transition To Lixiana

Transition from Lixiana

Discontinuation For Surgery And Other Interventions

Discontinue Lixiana at least 24 hours before invasive or surgical procedures because of the risk of bleeding.

If surgery cannot be delayed, there is an increased risk of bleeding. This risk of bleeding should be weighed against the urgency of intervention.

Lixiana can be restarted after the surgical or other procedure as soon as adequate hemostasis has been established noting that the time to onset of pharmacodynamic effect is 1-2 hours. Administer a parenteral anticoagulant and then switch to oral Lixiana, if oral medication cannot be taken during or after surgical intervention.

Administration Options

For patients who are unable to swallow whole tablets, Lixiana tablets may be crushed and mixed with 2 to 3 ounces of water and immediately administered by mouth or through a gastric tube. The crushed tablets may also be mixed into applesauce and immediately administered orally.

Lixiana is contraindicated in patients with:

• Active pathological bleeding.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Reduced Efficacy In Nonvalvular Atrial Fibrillation Patients With CrCL > 95 mL/min

Lixiana should not be used in patients with CrCL > 95 mL/min. In the randomized ENGAGE AF-TIMI 48 study, NVAF patients with CrCL > 95 mL/min had an increased rate of ischemic stroke with Lixiana 60 mg daily compared to patients treated with warfarin. In these patients another anticoagulant should be used.

Increased Risk Of Stroke With Discontinuation of Lixiana in Patients with Nonvalvular Atrial Fibrillation

Premature discontinuation of any oral anticoagulant in the absence of adequate alternative anticoagulation increases the risk of ischemic events. If Lixiana is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant as described in the transition guidance.

Risk Of Bleeding

Lixiana increases the risk of bleeding and can cause serious and potentially fatal bleeding. Promptly evaluate any signs or symptoms of blood loss.

Discontinue Lixiana in patients with active pathological bleeding.

Concomitant use of drugs affecting hemostasis may increase the risk of bleeding. These include aspirin and other antiplatelet agents, other antithrombotic agents, fibrinolytic therapy, chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs), selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors.

Reversal Of Anticoagulant Effect

There is no established way to reverse the anticoagulant effects of Lixiana, which can be expected to persist for approximately 24 hours after the last dose. The anticoagulant effect of Lixiana cannot be reliably monitored with standard laboratory testing. A specific reversal agent for edoxaban is not available. Hemodialysis does not significantly contribute to edoxaban clearance. Protamine sulfate, vitamin K, and tranexamic acid are not expected to reverse the anticoagulant activity of Lixiana. The use of prothrombin complex concentrates (PCC), or other procoagulant reversal agents such as activated prothrombin complex concentrate (APCC) or recombinant factor VIIa (rFVIIa) may be considered but has not been evaluated in clinical outcome studies. When PCCs are used, monitoring for anticoagulation effect of edoxaban using clotting test (PT, INR, or aPTT) or anti-FXa activity is not useful and is not recommended.

Spinal/Epidural Anesthesia Or Puncture

When neuraxial anesthesia (spinal/epidural anesthesia) or spinal/epidural puncture is employed, patients treated with antithrombotic agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma, which can result in long-term or permanent paralysis.

The risk of these events may be increased by the postoperative use of indwelling epidural catheters or the concomitant use of medicinal products affecting hemostasis. Indwelling epidural or intrathecal catheters should not be removed earlier than 12 hours after the last administration of Lixiana. The next dose of Lixiana should not be administered earlier than 2 hours after the removal of the catheter. The risk may also be increased by traumatic or repeated epidural or spinal puncture.

Monitor patients frequently for signs and symptoms of neurological impairment (e.g., numbness or weakness of the legs, bowel, or bladder dysfunction). If neurological compromise is noted, urgent diagnosis and treatment is necessary. Prior to neuraxial intervention the physician should consider the potential benefit versus the risk in anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis.

Patients With Mechanical Heart Valves Or Moderate To Severe Mitral Stenosis

The safety and efficacy of Lixiana has not been studied in patients with mechanical heart valves or moderate to severe mitral stenosis. The use of Lixiana is not recommended in these patients.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Advise patients of the following:

• they may bleed more easily, may bleed longer, or bruise more easily when treated with Lixiana
• to report any unusual bleeding immediately to their healthcare provider
• to take Lixiana exactly as prescribed
• to not discontinue Lixiana without talking to the healthcare provider who prescribed it
• to inform their healthcare providers that they are taking Lixiana before any surgery, medical, or dental procedure is scheduled
• to inform their healthcare providers and dentists if they plan to take, or are taking any prescription medications, over-the-counter drugs or herbal products
• to inform their healthcare provider immediately if they become pregnant or intend to become pregnant during treatment with Lixiana
• to not breastfeed if they are taking Lixiana
• for patients who cannot swallow the tablet whole, crush Lixiana and combine with 2 to 3 ounces of water or applesauce and ingest immediately.
• for patients who require a gastric tube, crush the Lixiana tablet and mix it with 2 to 3 ounces of water before administering immediately via the gastric feeding tube.
• that if a dose is missed, take Lixiana as soon as possible the same day, and resume the normal dosing schedule the following day. The dose should not be doubled to make up for a missing dose
• that if they are having neuraxial anesthesia or spinal puncture, advise patients to watch for signs and symptoms of spinal or epidural hematoma, such as back pain, tingling, numbness (especially in the lower limbs), muscle weakness, and stool or urine incontinence. If any of these symptoms occur, advise the patient to contact his or her physician immediately

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Edoxaban was not carcinogenic when administered daily to mice and rats by oral gavage for up to 104 weeks. The highest dose tested (500 mg/kg/day) in male and female mice was 3 and 6 times, respectively, the human exposure (AUC) at the human dose of 60 mg/day, and the highest doses tested in male (600/400 mg/kg/day) and female (200 mg/kg/day) rats were 8 and 14 times, respectively, the human exposure at the human dose of 60 mg/day.

Edoxaban and its human-specific metabolite, M-4, were genotoxic in in vitro chromosomal aberration tests but were not genotoxic in the in vitro bacterial reverse mutation (Ames test), in in vitro human lymphocytes micronucleus test, in in vivo rat bone marrow micronucleus test, in in vivo rat liver micronucleus test, and in in vivo unscheduled DNA synthesis tests.

Edoxaban showed no effects on fertility and early embryonic development in rats at doses of up to 1000 mg/kg/day (162 times the human dose of 60 mg/day normalized to body surface area).

Use In Specific Populations

Pregnancy

Risk Summary

Available data about Lixiana use in pregnant women are insufficient to determine whether there are drug-associated risks for adverse developmental outcomes. In animal developmental studies, no adverse developmental effects were seen when edoxaban was administered orally to pregnant rats and rabbits during organogenesis at up to 16-times and 8-times, respectively, the human exposure, when based on body surface area and AUC, respectively (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Disease-Associated Maternal And/Or Embryo/Fetal Risk

Pregnancy confers an increased risk of thromboembolism that is higher for women with underlying thromboembolic disease and certain high-risk pregnancy conditions. Published data describe that women with a previous history of venous thrombosis are at high risk for recurrence during pregnancy.

Fetal/Neonatal Adverse Reactions

Use of anticoagulants, including edoxaban, may increase the risk of bleeding in the fetus and neonate. Monitor neonates for bleeding.

Labor Or Delivery

All patients receiving anticoagulants, including pregnant women, are at risk for bleeding. Lixiana use during labor or delivery in women who are receiving neuraxial anesthesia may result in epidural or spinal hematomas. Consider use of a shorter acting anticoagulant as delivery approaches ].

Data

Animal Data

Embryo-fetal development studies were conducted in pregnant rats and rabbits during the period of organogenesis. In rats, no malformation was seen when edoxaban was administered orally at doses up to 300 mg/kg/day, or 49 times the human dose of 60 mg/day normalized to body surface area. Increased post-implantation loss occurred at 300 mg/kg/day, but this effect may be secondary to the maternal vaginal hemorrhage seen at this dose. In rabbits, no malformation was seen at doses up to 600 mg/kg/day (49 times the human exposure at a dose of 60 mg/day when based on AUC). Embryo-fetal toxicities occurred at maternally toxic doses, and included absent or small fetal gallbladder at 600 mg/kg/day, and increased post-implantation loss, increased spontaneous abortion, and decreased live fetuses and fetal weight at doses equal to or greater than 200 mg/kg/day, which is equal to or greater than 20 times the human exposure.

In a rat pre-and post-natal developmental study, edoxaban was administered orally during the period of organogenesis and through lactation day 20 at doses up to 30 mg/kg/day, which is up to 3 times the human exposure when based on AUC. Vaginal bleeding in pregnant rats and delayed avoidance response (a learning test) in female offspring were seen at 30 mg/kg/day.

Lactation

Risk Summary

There are no data on the presence of edoxaban in human milk, or its effects on the breastfeeding infant or on milk production. Edoxaban was present in rat milk. Because of the potential for serious adverse reactions in nursing infants, including hemorrhage, advise patients that breastfeeding is not recommended during treatment with Lixiana.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Of the total patients in the ENGAGE AF-TIMI 48 study, 5182 (74%) were 65 years and older, while 2838 (41%) were 75 years and older. In Hokusai VTE, 1334 (32%) patients were 65 years and older, while 560 (14%) patients were 75 years and older. In clinical trials the efficacy and safety of Lixiana in elderly (65 years or older) and younger patients were similar.

Renal Impairment

Renal clearance accounts for approximately 50% of the total clearance of edoxaban. Consequently, edoxaban blood levels are increased in patients with poor renal function compared to those with higher renal function. Reduce Lixiana dose to 30 mg once daily in patients with CrCL 15-50 mL/min. There are limited clinical data with Lixiana in patients with CrCL < 15 mL/min; Lixiana is therefore not recommended in these patients. Hemodialysis does not significantly contribute to Lixiana clearance.

As renal function improves and edoxaban blood levels decrease, the risk for ischemic stroke increases in patients with NVAF.

Hepatic Impairment

The use of Lixiana in patients with moderate or severe hepatic impairment (Child-Pugh B and C) is not recommended as these patients may have intrinsic coagulation abnormalities. No dose reduction is required in patients with mild hepatic impairment (Child-Pugh A).

Low Body Weight Consideration For Patients Treated For DVT And/Or PE

Based on the clinical experience from the Hokusai VTE study, reduce Lixiana dose to 30 mg in patients with body weight less than or equal to 60 kg.

The following serious adverse reactions are discussed in greater detail in other sections of the prescribing information.

• Increased risk of stroke with discontinuation of Lixiana in patients with NVAF
• Spinal/epidural anesthesia or puncture

The most serious adverse reactions reported with Lixiana were related to bleeding.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of Lixiana was evaluated in the ENGAGE AF-TIMI 48 and Hokusai VTE studies including 11,130 patients exposed to Lixiana 60 mg and 7002 patients exposed to Lixiana 30 mg once daily.

The ENGAGE AF-TIMI 48 Study

In the ENGAGE AF-TIMI 48 study, the median study drug exposure for the Lixiana and warfarin treatment groups was 2.5 years.

Bleeding was the most common reason for treatment discontinuation. Bleeding led to treatment discontinuation in 3.9% and 4.1% of patients in the Lixiana 60 mg and warfarin treatment groups, respectively.

In the overall population, Major Bleeding was lower in the Lixiana group compared to the warfarin group [HR 0.80 (0.70, 0.91), p<0.001]. Table 6.1 shows Major Bleeding events (percentage of patients with at least one bleeding event, per year) for the indicated population (CrCL ≤ 95 mL/min).

Table 6.1: Adjudicated Bleeding Events for NVAF Patients with CrCL ≤ 95 mL/min*

The most common site of a Major Bleeding event was the gastrointestinal (GI) tract. Table 6.2 shows the number of and the rate at which patients experienced GI bleeding in the Lixiana 60 mg and warfarin treatment groups.

Table 6.2: Gastrointestinal Bleeding Events for NVAF Patients with CrCL ≤ 95 mL/min*

The rate of anemia-related adverse events was greater with Lixiana 60 mg than with warfarin (9.6% vs. 6.8%).

The comparative rates of Major Bleeding on Lixiana and warfarin were generally consistent among subgroups (see Figure 6.1). Bleeding rates appeared higher in both treatment arms (Lixiana and warfarin) in the following subgroups of patients: those receiving aspirin, those in the United States, those more than 75 years old and those with reduced renal function.

Figure 6.1: Adjudicated Major Bleeding in the ENGAGE AF-TIMI 48* Study

*During or within 2 days of stopping study treatment Note: The figure above presents effects in various subgroups all of which are baseline characteristics and most of which were pre-specified. The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.

Other Adverse Reactions

The most common non-bleeding adverse reactions (≥ 1%) for Lixiana 60 mg versus warfarin were rash (4.2% vs. 4.1%), and abnormal liver function tests (4.8% vs. 4.6%), respectively.

Interstitial Lung Disease (ILD) was reported as a serious adverse event on treatment for Lixiana 60 mg and warfarin in 15 (0.2%) and 7 (0.1%) patients, respectively. Many of the cases in both treatment groups were confounded by the use of amiodarone, which has been associated with ILD, or by infectious pneumonia. In the overall study period, there were 5 and 0 fatal ILD cases in the Lixiana 60 mg and warfarin groups, respectively.

The Hokusai VTE Study

In the Hokusai VTE study, the duration of drug exposure for Lixiana was ≤ 6 months for 1561 (37.9%) of patients, > 6 months for 2557 (62.1%) of patients and 12 months for 1661 (40.3%) of patients.

Bleeding was the most common reason for treatment discontinuation and occurred in 1.4% and 1.4% of patients in the Lixiana and warfarin arms, respectively.

Bleeding In Patients With DVT And/Or PE In The Hokusai VTE Study

The primary safety endpoint was Clinically Relevant Bleeding, defined as the composite of Major and Clinically Relevant Non-Major (CRNM) Bleeding that occurred during or within three days of stopping study treatment. The incidence of Clinically Relevant Bleeding was lower in Lixiana than warfarin [HR (95% CI): 0.81 (0.71, 0.94); p =0.004].

Table 6.3 shows the number of patients experiencing bleeding events in the Hokusai VTE Study.

Table 6.3: Bleeding Events in the Hokusai VTE Study

Patients with low body weight (≤ 60 kg), CrCL ≤ 50 mL/min, or concomitant use of select P-gp inhibitors were randomized to receive Lixiana 30 mg or warfarin. As compared to all patients who received Lixiana or warfarin in the 60 mg cohort, all patients who received Lixiana or warfarin in the 30 mg cohort (n= 1452, 17.6% of the entire study population) were older (60.1 vs 54.9 years), more frequently female (66.5% vs 37.7%), more frequently of Asian race (46.0% vs 15.6%) and had more co-morbidities (e.g., history of bleeding, hypertension, diabetes, cardiovascular disease, cancer). Clinically relevant bleeding events occurred in 58/733 (7.9%) of the Lixiana patients receiving 30 mg once daily and 92/719 (12.8%) of warfarin patients meeting the above criteria.

In the Hokusai VTE study, among all patients the most common bleeding adverse reactions (≥ 1%) are shown in Table 6.4.

Table 6.4: Adverse Reactions Occurring in ≥ 1% of Patients Treated in Hokusai VTE

A specific reversal agent for edoxaban is not available. Overdose of Lixiana increases the risk of bleeding.

The following are not expected to reverse the anticoagulant effects of edoxaban: protamine sulfate, vitamin K, and tranexamic acid.

Hemodialysis does not significantly contribute to edoxaban clearance.

As a result of FXa inhibition, edoxaban prolongs clotting time tests such as prothrombin time (PT), and activated partial thromboplastin time (aPTT). Changes observed in PT, INR, and aPTT at the expected therapeutic dose, however, are small, subject to a high degree of variability and not useful in monitoring the anticoagulant effect of edoxaban. Following oral administration, peak pharmacodynamic effects are observed within 1-2 hours, which correspond with peak edoxaban concentrations (Cmax).

Cardiac Electrophysiology

In a thorough QT study in healthy men and women aged 19-45 years, no QTc interval prolongation was observed with edoxaban (90 mg and 180 mg).

Effect Of PCCs On Pharmacodynamics Of Lixiana

There is no systematic evaluation of bleeding reversal by 4-factor prothrombin complex concentrate (PCC) products in patients who have received Lixiana.

Effects of PCC (50 IU/kg) on the pharmacodynamics of edoxaban were studied in healthy subjects following a punch biopsy. Following administration of a single dose of edoxaban, endogenous thrombin potential (ETP) returned to pre-edoxaban baseline levels in 0.5 hours after the initiation of a 15 minute infusion of 50 IU/kg PCC, compared to more than 24 hours with placebo. Mean ETP levels continued to increase and exceeded pre-edoxaban baseline, reaching maximum elevations (~40% over pre-edoxaban levels) at 22 hours after initiating PCC dose, which was the last observation of ETP. The clinical relevance of this ETP increase is unknown.

Pharmacodynamic Interactions

Aspirin

Co-administration of aspirin (100 mg or 325 mg) and edoxaban increased bleeding time relative to that seen with either drug alone.

NSAID (Naproxen)

Co-administration of naproxen (500 mg) and edoxaban increased bleeding time relative to that seen with either drug alone.

Edoxaban displays approximately dose-proportional pharmacokinetics for doses of 15 to 150 mg and 60 to 120 mg following single and repeat doses, respectively, in healthy subjects.

Absorption

Following oral administration, peak plasma edoxaban concentrations are observed within 1-2 hours. Absolute bioavailability is 62%. Food does not affect total systemic exposure to edoxaban. Lixiana was administered with or without food in the ENGAGE AF-TIMI 48 and Hokusai VTE trials.

Administration of a crushed 60 mg tablet, either mixed into applesauce or suspended in water and given through a nasogastric tube, showed similar exposure compared to administration of an intact tablet.

Distribution

Disposition is biphasic. The steady-state volume of distribution (Vdss) is 107 (19.9) L [mean (SD)]. In vitro plasma protein binding is approximately 55%. There is no clinically relevant accumulation of edoxaban (accumulation ratio 1.14) with once daily dosing.

Steady-state concentrations are achieved within 3 days.

Metabolism

Unchanged edoxaban is the predominant form in plasma. There is minimal metabolism via hydrolysis (mediated by carboxylesterase 1), conjugation, and oxidation by CYP3A4.

The predominant metabolite M-4, formed by hydrolysis, is human-specific and active and reaches less than 10% of the exposure of the parent compound in healthy subjects. Exposure to the other metabolites is less than 5% of exposure to edoxaban.

Elimination

Edoxaban is eliminated primarily as unchanged drug in the urine. Renal clearance (11 L/hour) accounts for approximately 50% of the total clearance of edoxaban (22 L/hour). Metabolism and biliary/intestinal excretion account for the remaining clearance. The terminal elimination half-life of edoxaban following oral administration is 10 to 14 hours.