Lovenox

• Lovenox does not cross the placenta and shows no evidence of effects on the fetus. It often is used during pregnancy as an alternative to oral anticoagulants such as warfarin (Coumadin), which cannot be safely used during pregnancy.
• Lovenox multiple-dose vials contain benzyl alcohol as a preservative. Benzyl alcohol has been associated with a fatal "gasping syndrome" in premature neonates. Lovenox vials preserved with benzyl alcohol should be used with caution in pregnant women and only if clearly needed because benzyl alcohol may cross the placenta.
• It is not known if Lovenox is excreted in breast milk. Since most medicines are excreted in breast milk, it is recommended that women receiving Lovenox should not breastfeed.

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Blood disease or bleeding problems or
• Blood vessel problems or
• Catheter insertion in the spine or
• Diabetic retinopathy (eye problem) or
• Heart infection or
• Heart valves, prosthetic or
• Hypertension (high blood pressure), uncontrolled or
• Septic shock or
• Stomach or intestinal ulcer or bleeding, active or
• Stroke, recent or history of or
• Surgery (e.g., eye, brain, or spine), recent or history of or
• Thrombocytopenia, heparin-induced, or history of or
• Threatened miscarriage
• Weight of less than 99 pounds in women or 126 pounds in men—Use with caution. The risk of bleeding may be increased.

• Major bleeding, active or
• Thrombocytopenia (low platelet count in the blood)—Should not use in patients with these conditions.

• Kidney disease—Use with caution. The effects may be increased because of slower removal from the body.

The dose your healthcare provider recommends will depend upon several factors such as:

• your weight
• how well your kidneys function
• the medical condition being treated
• whether you are treating or preventing blood clots
• other medical conditions you have

Take Lovenox exactly as prescribed by your doctor. Follow the directions on your prescription label carefully.

If you take too much Lovenox or you suspect you are given too much, call your healthcare provider or local Poison Control Center, or seek emergency medical attention right away.

• Importance of advising patients who have had neuraxial anesthesia or spinal puncture to monitor for manifestations of spinal or epidural hematoma (e.g., tingling or numbness in lower limbs, muscle weakness), particularly if they are receiving concomitant NSAIAs, platelet-aggregation inhibitors (e.g., clopidogrel), or other anticoagulants; importance of immediately contacting a clinician if any of these symptoms occur.1

• If therapy is to continue after hospital discharge, importance of instructing patient on proper injection technique of enoxaparin.1

• Importance of informing patients that they may bruise and/or bleed more easily and that a longer than normal time may be required to stop bleeding when taking enoxaparin.1 Importance of patients reporting any unusual bleeding, bruising, or signs of thrombocytopenia (e.g., dark red spots under skin) to clinician.1

• Importance of patients informing clinicians (including dentists) that they are receiving enoxaparin therapy before scheduling any invasive procedures.1

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.1

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

• Importance of informing patients of other important precautionary information. (See Cautions.)

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

All products:

• It is given as a shot into the fatty part of the skin on the right or left side of the belly.
• This medicine must not be given into a muscle.
• If you will be giving yourself the shot, your doctor or nurse will teach you how to give the shot.
• Follow how to use as you have been told by the doctor or read the package insert.
• To gain the most benefit, do not miss doses.
• Keep using Lovenox as you have been told by your doctor or other health care provider, even if you feel well.
• Wash your hands before and after use.
• Do not use if the solution is cloudy, leaking, or has particles.
• This medicine is colorless to a faint yellow. Do not use if the solution changes color.
• Move the site where you give the shot with each shot.
• Throw away needles in a needle/sharp disposal box. Do not reuse needles or other items. When the box is full, follow all local rules for getting rid of it. Talk with a doctor or pharmacist if you have any questions.

Single-dose container:

• If using prefilled syringe, do not get rid of air bubble from syringe before giving.

What do I do if I miss a dose?

• Take a missed dose as soon as you think about it.
• If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses.

All products:

• Store at room temperature.
• Store in a dry place. Do not store in a bathroom.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

Multi-dose container:

• After opening, throw away any part not used after 28 days.

Pregnancy

Pregnancy Category B

All pregnancies have a background risk of birth defect, loss, or other adverse outcome regardless of drug exposure. The fetal risk summary below describes the potential of Lovenox to increase the risk of developmental abnormalities above the background risk.

Fetal Risk Summary

Lovenox does not cross the placenta, and is not expected to result in fetal exposure to the drug. Human data from a retrospective cohort study, which included 693 live births, suggest that Lovenox does not increase the risk of major developmental abnormalities. Based on animal data, enoxaparin is not predicted to increase the risk of major developmental abnormalities (see Data).

Clinical Considerations

Pregnancy alone confers an increased risk for thromboembolism that is even higher for women with thromboembolic disease and certain high risk pregnancy conditions. While not adequately studied, pregnant women with mechanical prosthetic heart valves may be at even higher risk for thrombosis [see Warnings and Precautions (5.7) and Use in Specific Populations (8.6)]. Pregnant women with thromboembolic disease, including those with mechanical prosthetic heart valves and those with inherited or acquired thrombophilias, have an increased risk of other maternal complications and fetal loss regardless of the type of anticoagulant used.

All patients receiving anticoagulants, including pregnant women, are at risk for bleeding. Pregnant women receiving enoxaparin should be carefully monitored for evidence of bleeding or excessive anticoagulation. Consideration for use of a shorter acting anticoagulant should be specifically addressed as delivery approaches [see Boxed Warning]. Hemorrhage can occur at any site and may lead to death of mother and/or fetus. Pregnant women should be apprised of the potential hazard to the fetus and the mother if enoxaparin is administered during pregnancy.

It is not known if monitoring of anti-Factor Xa activity and dose adjustment (by weight or anti-Factor Xa activity) of Lovenox affect the safety and the efficacy of the drug during pregnancy.

Cases of "gasping syndrome" have occurred in premature infants when large amounts of benzyl alcohol have been administered (99–405 mg/kg/day). The multiple-dose vial of Lovenox contains 15 mg benzyl alcohol per 1 mL as a preservative [see Warnings and Precautions (5.8)].

Data

• Human Data - There are no adequate and well-controlled studies in pregnant women. A retrospective study reviewed the records of 604 women who used enoxaparin during pregnancy. A total of 624 pregnancies resulted in 693 live births. There were 72 hemorrhagic events (11 serious) in 63 women. There were 14 cases of neonatal hemorrhage. Major congenital anomalies in live births occurred at rates (2.5%) similar to background rates.
  
  There have been postmarketing reports of fetal death when pregnant women received Lovenox. Causality for these cases has not been determined. Insufficient data, the underlying disease, and the possibility of inadequate anticoagulation complicate the evaluation of these cases.
  
  A clinical study using enoxaparin in pregnant women with mechanical prosthetic heart valves has been conducted [see Warnings and Precautions (5.7)].
   
• Animal Data - Teratology studies have been conducted in pregnant rats and rabbits at SC doses of enoxaparin up to 15 times the recommended human dose (by comparison with 2 mg/kg as the maximum recommended daily dose). There was no evidence of teratogenic effects or fetotoxicity due to enoxaparin. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

It is not known whether Lovenox is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Lovenox, a decision should be made whether to discontinue nursing or discontinue Lovenox, taking into account the importance of Lovenox to the mother and the known benefits of nursing.

Pediatric Use

Safety and effectiveness of Lovenox in pediatric patients have not been established.

Geriatric Use

Prevention of Deep Vein Thrombosis in Hip, Knee and Abdominal Surgery; Treatment of Deep Vein Thrombosis, Prevention of Ischemic Complications of Unstable Angina and Non-Q-wave Myocardial Infarction

Over 2800 patients, 65 years and older, have received Lovenox in pivotal clinical trials. The efficacy of Lovenox in the geriatric (≥65 years) was similar to that seen in younger patients (<65 years). The incidence of bleeding complications was similar between geriatric and younger patients when 30 mg every 12 hours or 40 mg once a day doses of Lovenox were employed. The incidence of bleeding complications was higher in geriatric patients as compared to younger patients when Lovenox was administered at doses of 1.5 mg/kg once a day or 1 mg/kg every 12 hours. The risk of Lovenox-associated bleeding increased with age. Serious adverse events increased with age for patients receiving Lovenox. Other clinical experience (including postmarketing surveillance and literature reports) has not revealed additional differences in the safety of Lovenox between geriatric and younger patients. Careful attention to dosing intervals and concomitant medications (especially antiplatelet medications) is advised. Lovenox should be used with care in geriatric patients who may show delayed elimination of enoxaparin. Monitoring of geriatric patients with low body weight (<45 kg) and those predisposed to decreased renal function should be considered [see Warnings and Precautions (5.9) and Clinical Pharmacology (12.3)].

Treatment of Acute ST-Segment Elevation Myocardial Infarction

In the clinical study for treatment of acute ST-segment elevation myocardial infarction, there was no evidence of difference in efficacy between patients ≥75 years of age (n = 1241) and patients less than 75 years of age (n=9015). Patients ≥75 years of age did not receive a 30 mg IV bolus prior to the normal dosage regimen and had their SC dose adjusted to 0.75 mg/kg every 12 hours [see Dosage and Administration (2.3)]. The incidence of bleeding complications was higher in patients ≥65 years of age as compared to younger patients (<65 years).

Patients with Mechanical Prosthetic Heart Valves

The use of Lovenox has not been adequately studied for thromboprophylaxis in patients with mechanical prosthetic heart valves and has not been adequately studied for long-term use in this patient population. Isolated cases of prosthetic heart valve thrombosis have been reported in patients with mechanical prosthetic heart valves who have received enoxaparin for thromboprophylaxis. Some of these cases were pregnant women in whom thrombosis led to maternal and fetal deaths. Insufficient data, the underlying disease and the possibility of inadequate anticoagulation complicate the evaluation of these cases. Pregnant women with mechanical prosthetic heart valves may be at higher risk for thromboembolism [see Warnings and Precautions (5.7)].

Renal Impairment

In patients with renal impairment, there is an increase in exposure of enoxaparin sodium. All such patients should be observed carefully for signs and symptoms of bleeding. Because exposure of enoxaparin sodium is significantly increased in patients with severe renal impairment (creatinine clearance <30 mL/min), a dosage adjustment is recommended for therapeutic and prophylactic dosage ranges. No dosage adjustment is recommended in patients with moderate (creatinine clearance 30–50 mL/min) and mild (creatinine clearance 50–80 mL/min) renal impairment [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]. In patients with renal failure, treatment with enoxaparin has been associated with the development of hyperkalemia [see Adverse Reactions (6.2)].

Hepatic Impairment

The impact of hepatic impairment on enoxaparin's exposure and antithrombotic effect has not been investigated. Caution should be exercised when administering enoxaparin to patients with hepatic impairment.

Low-Weight Patients

An increase in exposure of enoxaparin sodium with prophylactic dosages (non-weight adjusted) has been observed in low-weight women (<45 kg) and low-weight men (<57 kg). All such patients should be observed carefully for signs and symptoms of bleeding [see Clinical Pharmacology (12.3)].

Obese Patients

Obese patients are at higher risk for thromboembolism. The safety and efficacy of prophylactic doses of Lovenox in obese patients (BMI >30 kg/m2) has not been fully determined and there is no consensus for dose adjustment. These patients should be observed carefully for signs and symptoms of thromboembolism.

Mechanism of Action

Enoxaparin is a low molecular weight heparin which has antithrombotic properties.

Pharmacodynamics

In humans, enoxaparin given at a dose of 1.5 mg/kg subcutaneously (SC) is characterized by a higher ratio of anti-Factor Xa to anti-Factor IIa activity (mean ± SD, 14.0 ± 3.1) (based on areas under anti-Factor activity versus time curves) compared to the ratios observed for heparin (mean±SD, 1.22 ± 0.13). Increases of up to 1.8 times the control values were seen in the thrombin time (TT) and the activated partial thromboplastin time (aPTT). Enoxaparin at a 1 mg/kg dose (100 mg/mL concentration), administered SC every 12 hours to patients in a large clinical trial resulted in aPTT values of 45 seconds or less in the majority of patients (n = 1607). A 30 mg IV bolus immediately followed by a 1 mg/kg SC administration resulted in aPTT post-injection values of 50 seconds. The average aPTT prolongation value on Day 1 was about 16% higher than on Day 4.

Pharmacokinetics

Absorption: Pharmacokinetic trials were conducted using the 100 mg/mL formulation. Maximum anti-Factor Xa and anti-thrombin (anti-Factor IIa) activities occur 3 to 5 hours after SC injection of enoxaparin. Mean peak anti-Factor Xa activity was 0.16 IU/mL (1.58 mcg/mL) and 0.38 IU/mL (3.83 mcg/mL) after the 20 mg and the 40 mg clinically tested SC doses, respectively. Mean (n = 46) peak anti-Factor Xa activity was 1.1 IU/mL at steady state in patients with unstable angina receiving 1 mg/kg SC every 12 hours for 14 days. Mean absolute bioavailability of enoxaparin, after 1.5 mg/kg given SC, based on anti-Factor Xa activity is approximately 100% in healthy subjects.

A 30 mg IV bolus immediately followed by a 1 mg/kg SC every 12 hours provided initial peak anti-Factor Xa levels of 1.16 IU/mL (n=16) and average exposure corresponding to 84% of steady-state levels. Steady state is achieved on the second day of treatment.

Enoxaparin pharmacokinetics appear to be linear over the recommended dosage ranges [see Dosage and Administration (2)]. After repeated subcutaneous administration of 40 mg once daily and 1.5 mg/kg once-daily regimens in healthy volunteers, the steady state is reached on day 2 with an average exposure ratio about 15% higher than after a single dose. Steady-state enoxaparin activity levels are well predicted by single-dose pharmacokinetics. After repeated subcutaneous administration of the 1 mg/kg twice daily regimen, the steady state is reached from day 4 with mean exposure about 65% higher than after a single dose and mean peak and trough levels of about 1.2 and 0.52 IU/mL, respectively. Based on enoxaparin sodium pharmacokinetics, this difference in steady state is expected and within the therapeutic range.

Although not studied clinically, the 150 mg/mL concentration of enoxaparin sodium is projected to result in anticoagulant activities similar to those of 100 mg/mL and 200 mg/mL concentrations at the same enoxaparin dose. When a daily 1.5 mg/kg SC injection of enoxaparin sodium was given to 25 healthy male and female subjects using a 100 mg/mL or a 200 mg/mL concentration the following pharmacokinetic profiles were obtained [see Table 13].

Distribution: The volume of distribution of anti-Factor Xa activity is about 4.3 L.

Elimination: Following intravenous (IV) dosing, the total body clearance of enoxaparin is 26 mL/min. After IV dosing of enoxaparin labeled with the gamma-emitter, 99mTc, 40% of radioactivity and 8 to 20% of anti-Factor Xa activity were recovered in urine in 24 hours. Elimination half-life based on anti-Factor Xa activity was 4.5 hours after a single SC dose to about 7 hours after repeated dosing. Significant anti-Factor Xa activity persists in plasma for about 12 hours following a 40 mg SC once a day dose.

Following SC dosing, the apparent clearance (CL/F) of enoxaparin is approximately 15 mL/min.

Metabolism: Enoxaparin sodium is primarily metabolized in the liver by desulfation and/or depolymerization to lower molecular weight species with much reduced biological potency. Renal clearance of active fragments represents about 10% of the administered dose and total renal excretion of active and non-active fragments 40% of the dose.

Special Populations

Gender: Apparent clearance and Amax derived from anti-Factor Xa values following single SC dosing (40 mg and 60 mg) were slightly higher in males than in females. The source of the gender difference in these parameters has not been conclusively identified; however, body weight may be a contributing factor.

Geriatric: Apparent clearance and Amax derived from anti-Factor Xa values following single and multiple SC dosing in geriatric subjects were close to those observed in young subjects. Following once a day SC dosing of 40 mg enoxaparin, the Day 10 mean area under anti-Factor Xa activity versus time curve (AUC) was approximately 15% greater than the mean Day 1 AUC value [see Dosage and Administration (2.3) and Use in Specific Populations (8.5)].

Renal Impairment: A linear relationship between anti-Factor Xa plasma clearance and creatinine clearance at steady state has been observed, which indicates decreased clearance of enoxaparin sodium in patients with reduced renal function. Anti-Factor Xa exposure represented by AUC, at steady state, is marginally increased in mild (creatinine clearance 50–80 mL/min) and moderate (creatinine clearance 30–50 mL/min) renal impairment after repeated subcutaneous 40 mg once-daily doses. In patients with severe renal impairment (creatinine clearance <30 mL/min), the AUC at steady state is significantly increased on average by 65% after repeated subcutaneous 40 mg once-daily doses [see Dosage and Administration (2.2) and Use in Specific Populations (8.7)].

Hemodialysis: In a single study, elimination rate appeared similar but AUC was two-fold higher than control population, after a single 0.25 or 0.5 mg/kg intravenous dose.

Hepatic Impairment: Studies with enoxaparin in patients with hepatic impairment have not been conducted and the impact of hepatic impairment on the exposure to enoxaparin is unknown [see Use in Specific Populations (8.8)].

Weight: After repeated subcutaneous 1.5 mg/kg once daily dosing, mean AUC of anti-Factor Xa activity is marginally higher at steady state in obese healthy volunteers (BMI 30–48 kg/m2) compared to non-obese control subjects, while Amax is not increased.

When non-weight adjusted dosing was administered, it was found after a single-subcutaneous 40 mg dose, that anti-Factor Xa exposure is 52% higher in low-weight women (<45 kg) and 27% higher in low-weight men (<57 kg) when compared to normal weight control subjects [see Use in Specific Populations (8.9)].

Pharmacokinetic interaction: No pharmacokinetic interaction was observed between enoxaparin and thrombolytics when administered concomitantly.

Lovenox is available in two concentrations [see Tables 26 and 27]:

Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature].

Do not store the multiple-dose vials for more than 28 days after the first use.

Keep out of the reach of children.

Lovenox is usually given every day until your bleeding condition improves. Follow all directions on your prescription label. Do not use this medicine in larger or smaller amounts or for longer than recommended.

Lovenox is injected under the skin or into a vein through an IV. You may be shown how to use injections at home. Do not self-inject this medicine if you do not fully understand how to give the injection and properly dispose of used needles, IV tubing, and other items used to inject the medicine.

You should be sitting or lying down during the injection. Do not inject Lovenox into a muscle.

Use a different place on your stomach each time you give an injection under the skin. Your care provider will show you the best places on your body to inject the medication. Do not inject into the same place two times in a row.

Prepare your dose in a syringe only when you are ready to give yourself an injection. Do not mix Lovenox with other medications in the same IV. Do not use Lovenox if it has changed colors or has particles in it. Call your pharmacist for new medication.

Use a disposable needle only once. Follow any state or local laws about throwing away used needles and syringes. Use a puncture-proof "sharps" disposal container (ask your pharmacist where to get one and how to throw it away). Keep this container out of the reach of children and pets.

Tell any doctor who treats you that you are using Lovenox. If you need surgery or dental work, tell the surgeon or dentist ahead of time that you are using this medication.

While using Lovenox your blood and your stool (bowel movement) may need to be tested often. Your nerve and muscle function may also need to be tested. Visit your doctor regularly.

Store Lovenox vials (bottles) at room temperature away from moisture and heat. Once you have used a vial for the first time, the medicine will keep at room temperature for up to 28 days. Throw away the vial after 28 days have passed since you first used the vial, even if there is still medicine left in it.

Get emergency medical help if you have any of these signs of an allergic reaction to Lovenox: hives; itching or burning skin; difficulty breathing; swelling of your face, lips, tongue, or throat.

Also seek emergency medical attention if you have symptoms of a spinal blood clot: back pain, numbness or muscle weakness in your lower body, or loss of bladder or bowel control.

Call your doctor at once if you have:

• unusual bleeding (nose, mouth, vagina, or rectum), bleeding from wounds or needle injections, any bleeding that will not stop;

• easy bruising, purple or red pinpoint spots under your skin;

• pale skin, feeling light-headed or short of breath, rapid heart rate, trouble concentrating;

• black or bloody stools, coughing up blood or vomit that looks like coffee grounds;

• sudden weakness, severe headache, confusion, or problems with speech, vision, or balance; or

• trouble breathing.

Common Lovenox side effects may include:

• nausea, diarrhea;

• fever;

• swelling in your hands or feet; or

• mild pain, irritation, redness, or swelling where the medicine was injected.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

You should not use this medicine if you are allergic to enoxaparin, heparin, benzyl alcohol, or pork products, or if you have:

• active or uncontrolled bleeding; or

• if you had decreased platelets in your blood after testing positive for a certain antibody while using enoxaparin within the past 100 days.

Enoxaparin may cause you to bleed more easily, especially if you have:

• a bleeding disorder that is inherited or caused by disease;

• hemorrhagic stroke;

• an infection of the lining of your heart (also called bacterial endocarditis);

• stomach or intestinal bleeding or ulcer; or

• recent brain, spine, or eye surgery.

Enoxaparin can cause a very serious blood clot around your spinal cord if you undergo a spinal tap or receive spinal anesthesia (epidural). This type of blood clot could cause long-term or permanent paralysis, and may be more likely to occur if:

• you have a spinal cord injury;

• you have a spinal catheter in place or if a catheter has been recently removed;

• you have a history of spinal surgery or repeated spinal taps;

• you have recently had a spinal tap or epidural anesthesia;

• you take aspirin or an NSAID (nonsteroidal anti-inflammatory drug)--ibuprofen (Advil, Motrin), naproxen (Aleve), diclofenac, indomethacin, meloxicam, and others; or

• you are using a blood thinner (warfarin, Coumadin) or other medicines to treat or prevent blood clots.

Tell your doctor if you have ever had:

• a bleeding disorder such as hemophilia;

• kidney or liver disease;

• uncontrolled high blood pressure;

• eye problems caused by diabetes;

• a stomach ulcer; or

• low blood platelets after receiving heparin.

Tell your doctor if you are pregnant. If you use enoxaparin during pregnancy, make sure your doctor knows if you have a mechanical heart valve.

You should not breast-feed while using this medicine.

Avoid activities that may increase your risk of bleeding or injury. Use extra care to prevent bleeding while shaving or brushing your teeth.