Low Molecular Weight Heparins and Anti-Xa agents

INDICATIONS AND USAGE
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FRAGMIN Injection is indicated for the prophylaxis of ischemic complications in unstable angina and non-Q-wave myocardial infarction, when concurrently administered with aspirin therapy (as described in CLINICAL TRIALS, Prophylaxis of Ischemic Complications in Unstable Angina and Non-Q-Wave Myocardial Infarction).
FRAGMIN is also indicated for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE):

In patients undergoing hip replacement surgery; In patients undergoing abdominal surgery who are at risk for thromboembolic complications; In medical patients who are at risk for thromboembolic complications due to severely restricted mobility during acute illness.

DOSAGE AND ADMINISTRATION
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UNSTABLE ANGINA AND NON-Q-WAVE MYOCARDIAL INFARCTION:
In patients with unstable angina or non-Q-wave myocardial infarction, the recommended dose of FRAGMIN Injection is 120 IU/kg of body weight, but not more than 10,000 IU, subcutaneously (s.c.) every 12 hours with concurrent oral aspirin (75 to 165 mg once daily) therapy. Treatment should be continued until the patient is clinically stabilized. The usual duration of administration is 5 to 8 days. Concurrent aspirin therapy is recommended except when contraindicated.
Table 11 lists the volume of FRAGMIN, based on the 9.5 mL multiple-dose vial (10,000 IU/mL), to be administered for a range of patient weights.

ABDOMINAL SURGERY:
In patients undergoing abdominal surgery with a risk of thromboembolic complications, the recommended dose of FRAGMIN is 2500 IU administered by s.c. injection once daily, starting 1 to 2 hours prior to surgery and repeated once daily postoperatively. The usual duration of administration is 5 to 10 days.
In patients undergoing abdominal surgery associated with a high risk of thromboembolic complications, such as malignant disorder, the recommended dose of FRAGMIN is 5000 IU s.c. the evening before surgery, then once daily postoperatively. The usual duration of administration is 5 to 10 days. Alternatively, in patients with malignancy, 2500 IU of FRAGMIN can be administered s.c. 1 to 2 hours before surgery followed by 2500 IU s.c. 12 hours later, and then 5000 IU once daily postoperatively. The usual duration of administration is 5 to 10 days.
Dosage adjustment and routine monitoring of coagulation parameters are not required if the dosage and administration recommendations specified above are followed.

MEDICAL PATIENTS WITH SEVERELY RESTRICTED MOBILITY DURING ACUTE ILLNESS:
In medical patients with severely restricted mobility during acute illness, the recommended dose of FRAGMIN is 5000 IU administered by s.c. injection once daily. In clinical trials, the usual duration of administration was 12 to 14 days.

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Renal dosing:

In patients with severely impaired renal function (CrCl ≤ 30 mL/min), monitoring for anti-Xa levels is recommended to determine the appropriate FRAGMIN dose. Target anti-Xa range is 0.5-1.5 IU/mL. When monitoring anti-Xa in these patients, sampling should be performed 4-6 hrs after FRAGMIN dosing and only after the patient has received 3-4 doses.

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DVT prophylaxis, abdominal surgery: 2,500 units 1-2 hours preop and once daily postop x 5-10 days (High risk patients (e.g. malignancy): 5000 units SC 1-2 hrs prior to surgery and then qd x 5-10 days.)
Prophylaxis (hip replacement): 2500 units 4-8 hrs postop, then 5000 units qd x 5-10 days (up to 14 days). Start at least 6hr after postop dose. Alternatively: 5000 units 10-14hrs preop and 4-8hrs postop. Maint: 5000 units qd up to 14 days.

Unstable angina, non-Q-wave MI: 120 units/kg up to 10,000 units SC every 12 hours with aspirin (75-165mg) until stable.
DVT treatment (not FDA approved): Dosing: 200 IU/kg SC qd (Max: 18,000 units/day)

DOSAGE AND ADMINISTRATION
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All patients should be evaluated for a bleeding disorder before administration of Lovenox, unless the medication is needed urgently. Since coagulation parameters are unsuitable for monitoring Lovenox activity, routine monitoring of coagulation parameters is not required.

For subcutaneous use, Lovenox should not be mixed with other injections or infusions. For intravenous use (i.e., for treatment of acute STEMI), Lovenox can be mixed with normal saline solution (0.9%) or 5% dextrose in water.

Lovenox is not intended for intramuscular administration.

Adult Dosage
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Abdominal Surgery: In patients undergoing abdominal surgery who are at risk for thromboembolic complications, the recommended dose of Lovenox is 40 mg once a day administered by SC injection with the initial dose given 2 hours prior to surgery. The usual duration of administration is 7 to 10 days; up to 12 days administration has been administered in clinical trials.

Hip or Knee Replacement Surgery: In patients undergoing hip or knee replacement surgery, the recommended dose of Lovenox is 30 mg every 12 hours administered by SC injection. Provided that hemostasis has been established, the initial dose should be given 12 to 24 hours after surgery. For hip replacement surgery, a dose of 40 mg once a day SC, given initially 12 (±3) hours prior to surgery, may be considered. Following the initial phase of thromboprophylaxis in hip replacement surgery patients, it is recommended that continued prophylaxis with Lovenox 40 mg once a day is administered by SC injection for 3 weeks. The usual duration of administration is 7 to 10 days; up to 14 days administration has been administered in clinical trials.

Medical Patients During Acute Illness: In medical patients at risk for thromboembolic complications due to severely restricted mobility during acute illness, the recommended dose of Lovenox is 40 mg once a day administered by SC injection. The usual duration of administration is 6 to 11 days; up to 14 days of Lovenox has been administered in the controlled clinical trial.

Treatment of Deep Vein Thrombosis With or Without Pulmonary Embolism:
In outpatient treatment, patients with acute deep vein thrombosis without pulmonary embolism who can be treated at home, the recommended dose of Lovenox is 1 mg/kg every 12 hours administered SC.
In inpatient (hospital) treatment, patients with acute deep vein thrombosis with pulmonary embolism or patients with acute deep vein thrombosis without pulmonary embolism (who are not candidates for outpatient treatment), the recommended dose of Lovenox is 1 mg/kg every 12 hours administered SC or 1.5 mg/kg once a day administered SC at the same time every day. In both outpatient and inpatient (hospital) treatments, warfarin sodium therapy should be initiated when appropriate (usually within 72 hours of Lovenox). Lovenox should be continued for a minimum of 5 days and until a therapeutic oral anticoagulant effect has been achieved (International Normalization Ratio 2.0 to 3.0). The average duration of administration is 7 days; up to 17 days of Lovenox administration has been administered in controlled clinical trials.

Unstable Angina and Non-Q-Wave Myocardial Infarction: In patients with unstable angina or non-Q-wave myocardial infarction, the recommended dose of Lovenox is 1 mg/kg administered SC every 12 hours in conjunction with oral aspirin therapy (100 to 325 mg once daily). Treatment with Lovenox should be prescribed for a minimum of 2 days and continued until clinical stabilization. The usual duration of treatment is 2 to 8 days; up to 12.5 days of Lovenox has been administered in clinical trials.

Treatment of acute ST-segment Elevation Myocardial Infarction: In patients with acute ST-segment Elevation Myocardial Infarction, the recommended dose of Lovenox is a single IV bolus of 30 mg plus a 1 mg/kg SC dose followed by 1 mg/kg administered SC every 12 hours (maximum 100 mg for the first two doses only, followed by 1 mg/kg dosing for the remaining doses). Dosage adjustments are recommended in patients ≥75 years of age.

When administered in conjunction with a thrombolytic (fibrin-specific or non-fibrin specific), Lovenox should be given between 15 minutes before and 30 minutes after the start of fibrinolytic therapy. All patients should receive acetylsalicylic acid (ASA) as soon as they are identified as having STEMI and maintained with 75 to 325 mg once daily unless contraindicated. In the pivotal clinical study, the Lovenox treatment duration was 8 days or until hospital discharge, whichever came first. An optimal duration of treatment is not known, but it is likely to be longer than 8 days.

For patients managed with Percutaneous Coronary Intervention (PCI): If the last Lovenox SC administration was given less than 8 hours before balloon inflation, no additional dosing is needed. If the last Lovenox SC administration was given more than 8 hours before balloon inflation, an IV bolus of 0.3 mg/kg of Lovenox should be administered.

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Renal Impairment
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Although no dose adjustment is recommended in patients with moderate (creatinine clearance 30–50 mL/min) and mild (creatinine clearance 50–80 mL/min) renal impairment, all such patients should be observed carefully for signs and symptoms of bleeding.

The recommended prophylaxis and treatment dosage regimens for patients with severe renal impairment (creatinine clearance <30 mL/min) are described in Table below.

Geriatric patients with acute ST-segment Elevation Myocardial Infarction
For treatment of acute ST-segment Elevation Myocardial Infarction in geriatric patients ≥75 years of age, do not use an initial IV bolus. Initiate dosing with 0.75 mg/kg SC every 12 hours (maximum 75 mg for the first two doses only, followed by 0.75 mg/kg dosing for the remaining doses).   No dose adjustment is necessary for other indications in geriatric patients unless kidney function is impaired.

Prevention of deep vein thrombosis, general surgery: 3500 units anti-Xa SC qd x 5-10 days.
Prevention of deep vein thrombosis, orthopedic surgery: 50 units anti-Xa/kg SC qd.
Treatment of deep vein thrombosis / PE: 175 units anti-Xa/kg SC qd for at least 6 days and until the patient is adequately anticoagulated with warfarin (INR of 2 for at least 2 days)

Initial U.S. Approval:  2012

Mechanism of Action: Apixaban is a selective inhibitor of FXa. It does not require antithrombin III for antithrombotic activity. Apixaban inhibits free and clot-bound FXa, and prothrombinase activity. Apixaban has no direct effect on platelet aggregation, but indirectly inhibits platelet aggregation induced by thrombin. By inhibiting FXa, apixaban decreases thrombin generation and thrombus development.

INDICATIONS AND USAGE:
ELIQUIS is a factor Xa inhibitor indicated:
to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. (1.1)
for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE), in patients who have undergone hip or knee replacement surgery. (1.2)
for the treatment of DVT and PE, and for the reduction in the risk of recurrent DVT and PE following initial therapy. (1.3, 1.4, 1.5)

DOSAGE AND ADMINISTRATION
Reduction of risk of stroke and systemic embolism in nonvalvular atrial fibrillation:
The recommended dose is 5 mg orally twice daily. (2.1)

In patients with at least 2 of the following characteristics: age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL, the recommended dose is 2.5 mg orally twice daily. (2.1)

Prophylaxis of DVT following hip or knee replacement surgery:
The recommended dose is 2.5 mg orally twice daily. (2.1)

Treatment of DVT and PE:
The recommended dose is 10 mg taken orally twice daily for 7 days, followed by 5 mg taken orally twice daily. (2.1)

Reduction in the risk of recurrent DVT and PE following initial therapy:
The recommended dose is 2.5 mg taken orally twice daily. (2.1)

HOW SUPPLIED:Tablets: 2.5 mg and 5 mg

WARNINGS:  WARNING: DISCONTINUING ELIQUIS IN PATIENTS WITHOUT ADEQUATE CONTINUOUS ANTICOAGULATION INCREASES RISK OF STROKE
See full prescribing information for complete boxed warning.

Discontinuing ELIQUIS places patients at an increased risk of thrombotic events. An increased rate of stroke was observed following discontinuation of ELIQUIS in clinical trials in patients with nonvalvular atrial fibrillation. If anticoagulation with ELIQUIS must be discontinued for a reason other than pathological bleeding, coverage with another anticoagulant should be strongly considered.

WARNINGS AND PRECAUTIONS:
ELIQUIS can cause serious, potentially fatal bleeding. Promptly evaluate signs and symptoms of blood loss.
Prosthetic heart valves: ELIQUIS use not recommended.

Initial U.S. Approval:  2015

Mechanism of Action: Edoxaban is a selective inhibitor of FXa. It does not require antithrombin III for antithrombotic activity. Edoxaban inhibits free FXa, and prothrombinase activity and inhibits thrombin-induced platelet aggregation. Inhibition of FXa in the coagulation cascade reduces thrombin generation and reduces thrombus formation.

INDICATIONS AND USAGE: 
1.1 Reduction in the Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation
SAVAYSA is indicated to reduce the risk of stroke and systemic embolism (SE) in patients with nonvalvular atrial fibrillation (NVAF).

Limitation of Use for NVAF
SAVAYSA should not be used in patients with CrCL > 95 mL/min because of an increased risk of ischemic stroke compared to warfarin [see Dosage and Administration (2.1), Warnings and Precautions (5.1), Clinical Studies (14.1)].

1.2 Treatment of Deep Vein Thrombosis and Pulmonary Embolism
SAVAYSA 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.

HOW SUPPLIED:
60 mg, yellow round shaped, film-coated tablets, debossed with DSC L60 on one side.
30 mg, pink round shaped, film-coated tablets, debossed with DSC L30 on one side.
15 mg, orange round shaped, film-coated tablets, debossed with DSC L15 on one side.

Synthetic pentasaccharide that causes an antithrombin III-mediated selective inhibition of factor Xa.
DVT prophylaxis: (patients > 50kg): 2.5 mg SC once daily (After hemostasis has been established, the initial dose should be given 6 to 8 hours after surgery. ) Usual duration: 5-9 days (up to 10 days following abdominal surgery or up to 11 days following hip replacement or knee replacement). Extended prophylaxis is recommended following hip fracture surgery.

Acute DVT/PE treatment:
<50 kg: 5 mg once daily
50-100 kg: 7.5 mg once daily
>100 kg: 10 mg once daily
Usual duration: 5-9 days (has been administered up to 26 days)

Renal Dosing:
[crcl 30 - 50 ml/min]: Use caution
[<30 ml/min]: Contraindicated
Supplied: Syringe: 2.5 mg/0.5 ml, 5 mg/0.4ml, 7.5 mg/0.6 ml, 10 mg/0.8 ml

Much more selective inhibitor of factor Xa

Agent	Anti-Xa/anti-IIa ratio
UFH	1:1
LMWH	2-4:1
Danaparoid	22:1
Fondaparinux

(2) for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE) in patients undergoing knee or hip replacement surgery

USE IN SPECIFIC POPULATIONS
Nursing mothers: discontinue drug or discontinue nursing

Renal impairment:
Prophylaxis of DVT: Avoid use in patients with severe impairment (CrCl <30 mL/min).
Use with caution in moderate impairment (CrCl 30 to <50 mL/min)

DOSAGE AND ADMINISTRATION
2.1 Nonvalvular Atrial Fibrillation

For patients with creatinine clearance (CrCl) >50 mL/min, the recommended dose of XARELTO is 20 mg taken orally once daily with the evening meal. For patients with CrCl 15 to 50 mL/min, the recommended dose is 15 mg once daily with the evening meal [see package insert for Use in Specific Populations (8.7)].

Switching from or to Warfarin - When switching patients from warfarin to XARELTO, discontinue warfarin and start XARELTO as soon as the International Normalized Ratio (INR) is below 3.0 to avoid periods of inadequate anticoagulation.

No clinical trial data are available to guide converting patients from XARELTO to warfarin. XARELTO affects INR, so INR measurements made during co-administration with warfarin may not be useful for determining the appropriate dose of warfarin. One approach is to discontinue XARELTO and begin both a parenteral anticoagulant and warfarin at the time the next dose of XARELTO would have been taken.

Switching from or to Anticoagulants other than Warfarin - For patients currently receiving an anticoagulant other than warfarin, start XARELTO 0 to 2 hours prior to the next scheduled evening administration of the drug (e.g., low molecular weight heparin or non-warfarin oral anticoagulant) and omit administration of the other anticoagulant. For unfractionated heparin being administered by continuous infusion, stop the infusion and start XARELTO at the same time.

For patients currently taking XARELTO and transitioning to an anticoagulant with rapid onset, discontinue XARELTO and give the first dose of the other anticoagulant (oral or parenteral) at the time that the next XARELTO dose would have been taken.

2.2 Prophylaxis of Deep Vein Thrombosis
The recommended dose of XARELTO is 10 mg taken orally once daily with or without food. The initial dose should be taken at least 6 to 10 hours after surgery once hemostasis has been established.

-For patients undergoing hip replacement surgery, treatment duration of 35 days is recommended.
-For patients undergoing knee replacement surgery, treatment duration of 12 days is recommended.

2.3 General Dosing Instructions
Hepatic Impairment:
No clinical data are available for patients with severe hepatic impairment. Avoid use of XARELTO in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy [see Use in Specific Populations (8.8)].

Renal Impairment:
Nonvalvular Atrial Fibrillation:
Avoid the use of XARELTO in patients with CrCl <15 mL/min. Periodically assess renal function as clinically indicated (i.e., more frequently in situations in which renal function may decline) and adjust therapy accordingly. Discontinue XARELTO in patients who develop acute renal failure while on XARELTO [see Use in Specific Populations (8.7)].

Prophylaxis of Deep Vein Thrombosis:
Avoid the use of XARELTO in patients with severe renal impairment (CrCl <30 mL/min) due to an expected increase in rivaroxaban exposure and pharmacodynamic effects in this patient population. Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with moderate renal impairment (CrCl 30 to 50 mL/min). Patients who develop acute renal failure while on XARELTO should discontinue the treatment [see Use in Specific Populations (8.7)].

Surgery and Intervention:
If anticoagulation must be discontinued to reduce the risk of bleeding with surgical or other procedures, XARELTO should be stopped at least 24 hours before the procedure. In deciding whether a procedure should be delayed until 24 hours after the last dose of XARELTO, the increased risk of bleeding should be weighed against the urgency of intervention. XARELTO should be restarted after the surgical or other procedures as soon as adequate hemostasis has been established. If oral medication cannot be taken after surgical intervention, consider administering a parenteral anticoagulant.

Missed Dose:
If a dose of XARELTO is not taken at the scheduled time, administer the dose as soon as possible on the same day.

Use with P-gp and Strong CYP3A4 Inhibitors or Inducers:
Avoid concomitant use of XARELTO with combined P-gp and strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir/ritonavir, and conivaptan) [see Drug Interactions (7.1)].

Avoid concomitant use of XARELTO with drugs that are combined P-gp and strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, St. John's wort)

HOW SUPPLIED
XARELTO (rivaroxaban) Tablets are available in the strengths and packages listed below:

10 mg tablets are round, light red, biconvex film-coated tablets marked with a triangle pointing down above a "10" on one side, and an "Xa" on the other side. The tablets are supplied in the packages listed:
NDC 50458-580-30 Bottle containing 30 tablets
NDC 50458-580-10 Blister package containing 100 tablets (10 blister cards containing 10 tablets each)

15 mg tablets are round, red, biconvex film-coated tablets with a triangle pointing down above a "15" marked on one side and "Xa" on the other side. The tablets are supplied in the packages listed:
NDC 50458-578-30 Bottle containing 30 tablets
NDC 50458-578-90 Bottle containing 90 tablets
NDC 50458-578-10 Blister package containing 100 tablets (10 blister cards containing 10 tablets each)

20 mg tablets are triangle-shaped, dark red film-coated tablets with a triangle pointing down above a "20" marked on one side and "Xa" on the other side. The tablets are supplied in the packages listed:
NDC 50458-579-30 Bottle containing 30 tablets
NDC 50458-579-90 Bottle containing 90 tablets
NDC 50458-579-10 Blister package containing 100 tablets (10 blister cards containing 10 tablets each)