NOROMBY HP SOLUTION

Canada - English - Health Canada

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Active ingredient:
ENOXAPARIN SODIUM
Available from:
JUNO PHARMACEUTICALS CORP.
ATC code:
B01AB05
INN (International Name):
ENOXAPARIN
Dosage:
150MG
Pharmaceutical form:
SOLUTION
Composition:
ENOXAPARIN SODIUM 150MG
Administration route:
INTRAVENOUS
Units in package:
100
Prescription type:
Prescription
Therapeutic area:
HEPARINS
Product summary:
Active ingredient group (AIG) number: 0131860002; AHFS: 20:12.04.16
Authorization status:
APPROVED
Authorization number:
02506513
Authorization date:
2020-10-14

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NOROMBY

Page 1 of 78

PRODUCT MONOGRAPH

INCLUDING PATIENT MEDICATION INFORMATION

NOROMBY

TM

Enoxaparin sodium

Solution for injection, 100 mg/mL

20 mg/0.2 mL

30 mg/0.3 mL

40 mg/0.4 mL

60 mg/0.6 mL

80 mg/0.8 mL

100 mg/mL

(Subcutaneous or Intravenous Use Only)

NOROMBY

TM

HP

Enoxaparin sodium

Solution for injection, 150 mg/mL

120 mg/0.8 mL

150 mg/mL

(Subcutaneous or Intravenous Use Only)

ATC Code: B01AB05

Anticoagulant/Antithrombotic Agent

Juno Pharmaceuticals Corp.

402-2233 Argentia Road

Mississauga, Ontario

L5N 2X7

Date of Initial Approval:

October 14, 2020

Date of Revision:

February 12, 2021

Submission Control No: 233058

NOROMBY

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TABLE OF CONTENTS

PART I: HEALTH PROFESSIONAL INFORMATION ...............................................................4

1

INDICATIONS ..............................................................................................................4

Pediatrics ............................................................................................................4

Geriatrics ............................................................................................................4

2

CONTRAINDICATIONS................................................................................................4

3

DOSAGE AND ADMINISTRATION...............................................................................5

Dosing Considerations.........................................................................................5

Recommended Dose and Dosage Adjustment .....................................................5

Administration .....................................................................................................8

Missed Dose .....................................................................................................10

4

OVERDOSAGE ..........................................................................................................10

5

DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.......................11

6

DESCRIPTION ...........................................................................................................13

7

WARNINGS AND PRECAUTIONS .............................................................................13

Special Populations ...........................................................................................18

7.1.1

Pregnant Women .......................................................................................... 18

7.1.2

Breast-feeding............................................................................................... 19

7.1.3

Pediatrics ...................................................................................................... 19

7.1.4

Geriatrics ...................................................................................................... 19

7.1.5

Patients with Prosthetic Heart Valves............................................................. 19

7.1.6

Acute Coronary Disease................................................................................ 19

7.1.7

Medical Patients............................................................................................ 19

8

ADVERSE REACTIONS .............................................................................................20

Adverse Reaction Overview...............................................................................20

Clinical Trial Adverse Reactions.........................................................................20

Other Clinically Relevant Adverse Reactions......................................................23

Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other

Quantitative Data ........................................................................................................23

Clinical Trial Adverse Reactions (Pediatrics) ......................................................24

Post-Market Adverse Reactions .........................................................................24

9

DRUG INTERACTIONS ..............................................................................................25

Drug-Drug Interactions ......................................................................................25

Drug-Food Interactions ......................................................................................26

Drug-Herb Interactions ......................................................................................26

Drug-Laboratory Test Interactions......................................................................26

Drug-Lifestyle Interactions .................................................................................26

10

ACTION AND CLINICAL PHARMACOLOGY .............................................................26

10.1

Mechanism of Action ......................................................................................26

10.2

Pharmacokinetics...........................................................................................27

11

STORAGE, STABILITY AND DISPOSAL ...................................................................28

NOROMBY

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12

SPECIAL HANDLING INSTRUCTIONS ......................................................................28

PART II: SCIENTIFIC INFORMATION ...................................................................................29

13

PHARMACEUTICAL INFORMATION .........................................................................29

14

COMPARATIVE CLINICAL TRIALS ...........................................................................30

14.1

Comparative Trial Design and Study Demographics........................................30

14.2

Comparative Study Results ............................................................................31

14.2.1

Comparative Bioavailability Studies............................................................ 31

14.2.1.1

Pharmacodynamics ................................................................................ 31

14.2.2

Comparative Safety and Efficacy................................................................ 32

14.2.2.1

Efficacy .................................................................................................. 32

14.2.2.2

Safety .................................................................................................... 32

15

CLINICAL TRIALS – REFERENCE BIOLOGIC DRUG ...............................................33

16

NON-CLINICAL TOXICOLOGY – REFERENCE BIOLOGIC DRUG ............................55

17

SUPPORTING PRODUCT MONOGRAPHS................................................................60

PATIENT MEDICATION INFORMATION ...............................................................................61

PATIENT MEDICATION INFORMATION ...............................................................................70

NOROMBY

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NOROMBY and NOROMBY HP (enoxaparin sodium) is a biosimilar biologic drug (biosimilar) to

Lovenox and Lovenox HP.

PART I: HEALTH PROFESSIONAL INFORMATION

1

INDICATIONS

Indications have been granted on the basis of similarity between NOROMBY and NOROMBY HP

and the reference biologic drug Lovenox and Lovenox HP.

NOROMBY (enoxaparin sodium) is indicated for:

The prophylaxis of thromboembolic disorders (deep vein thrombosis) in patients undergoing:

orthopedic surgery of the hip or knee. In addition, NOROMBY is indicated in hospital or

after hospital discharge for long-term prevention of venous thromboembolic diseases

following hip replacement surgery.

high risk abdominal, gynecological, or urological surgeries;

colorectal surgery.

The prophylaxis of deep vein thrombosis (DVT) in medical patients who are at moderate risk

of DVT and who are bedridden due to moderate to severe acute cardiac insufficiency (NYHA

Class III or IV heart failure), acute respiratory failure revealing or complicating chronic

respiratory insufficiency not requiring ventilatory support and acute respiratory infections

(excluding septic shock), who require short-term prophylaxis of deep vein thrombosis.

The prevention of thrombus formation in the extra-corporeal circulation during hemodialysis.

NOROMBY is also indicated for:

The treatment of deep vein thrombosis, with or without pulmonary embolism.

The treatment of unstable angina or non-Q-wave myocardial infarction, concurrently with ASA.

Treatment of acute ST-segment Elevation Myocardial Infarction (STEMI), including patients to

be managed medically or with subsequent Percutaneous Coronary Intervention (PCI).

1.1

Pediatrics

No data are available to Health Canada; therefore, Health Canada has not authorized an

indication for pediatric use.

1.2

Geriatrics

Evidence from clinical studies and experience suggests that use in the geriatric population is

associated with differences in safety and a brief discussion can be found in WARNINGS AND

PRECAUTIONS, under Special Populations, Geriatrics.

In the clinical study for treatment of acute STEMI, with adjustment in dose for patients ≥75 years of

age, 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).

2

CONTRAINDICATIONS

Enoxaparin sodium is contraindicated in patients who are hypersensitive to this drug or to any

NOROMBY

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ingredient in the formulation, including any non-medicinal ingredient, component of the container,

or to other low molecular weight heparins and/or heparin. For a complete listing, see Dosage

Forms, Strengths, Composition and Packaging.

History of confirmed or suspected immunologically-mediated heparin-induced

thrombocytopenia (delayed-onset severe thrombocytopenia), within the past 100 days, or in

patients in whom an in vitro platelet-aggregation test in the presence of enoxaparin is positive

(circulating antibodies) (see WARNINGS AND PRECAUTIONS, Heparin-induced

thrombocytopenia)

Acute or subacute bacterial endocarditis

Active bleeding

Major blood clotting disorders

Active gastric or duodenal ulcer

Hemorrhagic cerebrovascular accident (except if there are systemic emboli)

Severe uncontrolled hypertension

Diabetic or hemorrhagic retinopathy

Other conditions or diseases involving an increased risk of hemorrhage

Injuries to and operations on the brain, spinal cord, eyes and ears

Spinal/epidural anesthesia is contraindicated where repeated treatment doses of Enoxaparin

sodium (1 mg/kg every 12 hours or 1.5 mg/kg once daily) are required, due to an increased

risk of bleeding

3

DOSAGE AND ADMINISTRATION

3.1

Dosing Considerations

NOROMBY must not be administered by the intramuscular route.

Subcutaneous injection

NOROMBY is administered by subcutaneous injection for the prevention of venous

thromboembolic disease, treatment of deep vein thrombosis, treatment of unstable angina and

non-Q-wave myocardial infarction and treatment of acute ST-segment Elevation Myocardial

Infarction.

For subcutaneous use NOROMBY should not be mixed with other injections or infusions.

IV bolus injection

For acute ST-segment Elevation Myocardial Infarction, treatment is to be initiated with a single IV

bolus injection immediately followed by a subcutaneous injection.

3.2

Recommended Dose and Dosage Adjustment

Prophylaxis in patients at risk of venous thromboembolism following hip or knee surgery (e.g.

orthopedic surgery)

The recommended dose of NOROMBY is 30 mg (3000 IU) every 12 hours administered by

subcutaneous injection. Provided that hemostasis has been established, the initial dose should be

given 12 to 24 hours after surgery. The usual duration of treatment is from 7 to 14 days.

NOROMBY

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Treatment should be continued for as long as the risk of DVT persists. Continued therapy with

NOROMBY 40 mg once daily for 3 weeks following the initial phase of thromboprophylaxis in hip

replacement surgery patients has been proven to be beneficial.

Prophylaxis in patients at risk of thromboembolism following abdominal or colorectal surgery

In patients undergoing abdominal surgery who are at risk for thromboembolic complications, the

recommended dose of NOROMBY is 40 mg (4000 IU) once daily administered by subcutaneous

injection, with the initial dose given 2 hours prior to surgery (see WARNINGS AND

PRECAUTIONS, General, Selection of General Surgery Patients). The usual duration of treatment

is from 7 to 10 days for a maximum of 12 days.

Patients at high risk for thromboembolic complications following high risk abdominal, gynecological

or urological and colorectal surgery, for cancer, who are not at risk of bleeding may benefit from an

extended prophylaxis up to 4 weeks.

Prophylaxis in Medical Patients

In medical patients at risk for deep vein thrombosis due to severely restricted mobility during acute

illness (see WARNINGS AND PRECAUTIONS, General, Selection of Medical Patients), the

recommended dose of NOROMBY is 40 mg (4000 IU) once daily by subcutaneous injection. The

usual duration of administration is 6 to 11 days.

Treatment of Deep Vein Thrombosis, with or without Pulmonary Embolism

NOROMBY can be administered subcutaneously either as 1.5 mg/kg once daily or as twice daily

injections of 1 mg/kg. The 1.5 mg/kg once daily dose is the equivalent of 150 IU/kg and should be

given at the same time every day. The single daily dose should not exceed 18,000 IU. The

expected plasma anti-Xa levels during subcutaneous treatment, when enoxaparin is used as the

reference standard, would be <0.3 IU anti-Xa/mL before injection and <1.7 IU anti-Xa/mL 3 - 4

hours post injection. The measurement of plasma anti-Xa circulating activities depends on the

experimental conditions of the assay, particularly on the reference standard used.

In patients with complicated thromboembolic disorders (i.e. with increased risk of recurrent VTE

such as obese patients, cancer patients or patients with symptomatic PE), a dose of 1 mg/kg

administered twice daily is recommended. This is the equivalent of 100 IU/kg. The expected

plasma anti-Xa levels during subcutaneous treatment, when enoxaparin is used as the reference

standard, would be <0.3 IU anti-Xa/mL before injection and <1.15 IU anti-Xa/mL 3 - 4 hours post

injection.

Oral anticoagulant therapy should be initiated as soon as possible, and NOROMBY should be

continued until a therapeutic anticoagulant effect has been achieved (INR: 2 to 3), in general for

approximately 7 days.

Treatment of Unstable Angina or non-Q-wave Myocardial Infarction

The recommended dose of NOROMBY is 1 mg/kg every 12 hours by subcutaneous injection. This

is the equivalent of 100 IU/kg. The maximum dose should not exceed 10,000 IU / 12 hours. The

expected plasma anti-Xa levels during subcutaneous treatment would be <0.3 IU anti- Xa/mL

before injection and <1.15 IU anti-Xa/mL 3 - 4 hours after injection. Treatment should continue for

a minimum of 2 days until clinical stabilization has been achieved, in general, for up to 8 days. The

effect of the short-term treatment was sustained over a one-year period.

NOROMBY

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Concomitant therapy with ASA (100 to 325 mg once daily) is recommended (see WARNINGS

AND PRECAUTIONS, Peri-Operative considerations-Percutaneous coronary revascularisation

procedures).

Treatment of acute ST-segment Elevation Myocardial Infarction

In patients with acute-ST-segment elevation myocardial infarction, the recommended dose of

NOROMBY injection 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 each of the first two SC doses only,

followed by 1 mg/kg SC dosing for the remaining doses). For dosage in patients ≥75 years of age,

see section below entitled Geriatrics. When administered in conjunction with a thombolytic (fibrin

specific or non-fibrin specific), NOROMBY injection 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. The recommended duration of NOROMBY injection treatment is 8

days or until hospital discharge, whichever comes first.

For patients managed with Percutaneous Coronary Intervention (PCI):

If the last NOROMBY SC administration was given less than 8 hours before balloon inflation, no

additional dosing is needed. If the last NOROMBY SC administration was given more than 8 hours

before balloon inflation, an IV bolus of 0.3 mg/kg of NOROMBY injection should be administered

(see WARNINGS AND PRECAUTIONS, Peri-Operative considerations - Percutaneous coronary

revascularisation procedures).

Prevention of thrombus formation in the extra corporeal circulation during hemodialysis

In patients with chronic renal failure, undergoing hemodialysis and that are not at high risk of

hemorrhage, the following dosage is recommended:

Optimization of dosage is required for each individual patient (different clotting stimuli are

produced by different dialysis circuits and membranes, and there is inter-patient variability).

A starting dose of enoxaparin, ranging from 0.5-1.0 mg/kg, can be administered into the

arterial line of the circuit at the beginning of the dialysis session. The effect of this dose range

is usually sufficient for a 4-hour session. This dose range recommendation stem from results

in published clinical studies (see CLINICAL TRIALS).

Doses in subsequent dialysis session can be adjusted, based on the outcome of the previous

dialysis.

Geriatrics (≥75 years of age):

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 each of the first two SC doses only, followed by 0.75 mg/kg SC

dosing for the remaining doses). No dose adjustment is necessary for other indications in geriatric

patients unless kidney function is impaired.

Use in Patients with Renal Impairment

All patients with renal impairment treated with low molecular weight heparins should be monitored

carefully.

Exposure to enoxaparin increases with degree of renal impairment. In patients with renal

impairment, the increased exposure to enoxaparin has been shown to increase risk of bleeding

NOROMBY

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(see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Renal

Insufficiency).

For the prevention of thrombus formation in the extra corporeal circulation during hemodialysis,

see DOSAGE AND ADMINISTRATION, Prevention of thrombus formation in the extra corporeal

circulation during hemodialysis.

A dosage adjustment is required for patients with severe renal impairment (creatinine clearance

<30 mL/min) since enoxaparin exposure is significantly increased in this patient population. The

following dosage adjustments are recommended for prophylaxis and treatment in patients with

severe renal impairment:

For prophylaxis in conjunction with hip or knee orthopedic surgery, the recommended

dosage is 30 mg (3,000 IU) once daily

For prophylaxis in conjunction with abdominal or colorectal surgery, or for prophylaxis in

medical patients at risk of DVT, the recommended dosage is 20 mg (2,000 IU) or 30 mg

(3,000 IU) once daily based on individual risk/benefit assessment

For treatment of deep vein thrombosis, with or without pulmonary embolism, the

recommended dosage is 1 mg/kg once daily

For treatment of unstable angina or non-Q-wave myocardial infarction, the recommended

dosage is 1 mg/kg once daily.

For treatment of acute ST-segment Elevation Myocardial Infarction, the recommended

dosage is 30 mg-single IV bolus plus a 1 mg/kg SC dose followed by 1 mg/kg

administered SC once daily. (Maximum 100 mg for first SC dose only)

For treatment of acute ST-segment Elevation Myocardial Infarction in geriatric patients ≥75

years of age, the recommended dosage is 1 mg/kg administered SC once daily (no

initial bolus). (Maximum 100 mg for first SC dose only)

Dosage adjustment may also need to be considered in patients who have renal characteristics

close to those of patients with severe renal impairment.

Spinal/epidural anesthesia

For patients receiving spinal/epidural anesthesia see WARNINGS AND PRECAUTIONS- Peri-

Operative considerations section.

Health Canada has not authorized an indication for pediatric use.

3.3

Administration

Subcutaneous Injection Technique

The subcutaneous injection of NOROMBY should be carried out with the patient sitting or lying

down in a comfortable position. Inject in the subcutaneous tissue of the anterolateral and

posterolateral abdominal girdle, alternatively on the left and right sides. With the thickness of skin

held between the operator's thumb and finger, introduce the entire length of the needle vertically

into the skin.

Arterial line injection:

NOROMBY is administered through the arterial line of a dialysis circuit for the prevention of

thrombus formation in the extra-corporeal circulation during hemodialysis.

NOROMBY

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It must not be administered by the intramuscular route.

The NOROMBY pre-filled disposable syringe is ready for immediate use.

Intravenous (Bolus) Injection Technique

NOROMBY should be administered through an intravenous line. NOROMBY should not be mixed

or co-administered with other medications. To avoid the possible mixture of NOROMBY with other

drugs, the intravenous access chosen should be flushed with a sufficient amount of saline or

dextrose solution prior to and following the intravenous bolus administration of NOROMBY to clear

the port of drug. NOROMBY may be safely administered with normal saline solution (0.9%) or 5%

dextrose in water.

Initial 30-mg bolus

The initial 30-mg bolus can be administered using Enoxaparin sodium pre-filled syringes. When

graduated pre-filled syringes are used, expel the excessive volume if needed, to retain only 30 mg

(0.3 ml) in the syringe. The 30-mg dose can then be directly injected into the intravenous line.

Additional bolus for PCI when last SC administration was given more than 8 hours before balloon

inflation

For patients being managed with Percutaneous Coronary Intervention (PCI), an additional IV bolus

of 0.3 mg/kg is to be administered if last SC administration was given more than 8 hours before

balloon inflation (see DOSAGE AND ADMINISTRATION: Recommended Dose and Dosage

Adjustment- For patients managed with Percutaneous Coronary Intervention (PCI)).

In order to assure the accuracy of the small volume to be injected, it is recommended to dilute the

drug.

For example, to obtain a 3-mg/ml solution, using a 60-mg Enoxaparin sodium pre-filled syringe, it

is recommended to use a 50-ml infusion bag (i.e. using either normal saline solution (0.9%) or 5%

dextrose in water) as follows:

Withdraw 30 ml from the infusion bag with a syringe and discard the liquid. Inject the complete

contents of the 60-mg Enoxaparin sodium pre-filled syringe into the 20 ml remaining in the bag.

Gently mix the contents of the bag. Withdraw the required volume of diluted solution with a syringe

for administration into the intravenous line.

After dilution is completed, the volume to be injected can be calculated using the following formula

[Volume of diluted solution (ml) = Patient weight (kg) x 0.1] or using the table below. The dilution

should be prepared immediately before use.

Table 1 – Volume to be injected through intravenous line after dilution is completed

Weight

[kg]

Required dose

(0.3 mg/kg)

[mg]

Volume to inject when diluted to a final

concentration of 3 mg/ml

[ml]

13.5

16.5

NOROMBY

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Weight

[kg]

Required dose

(0.3 mg/kg)

[mg]

Volume to inject when diluted to a final

concentration of 3 mg/ml

[ml]

19.5

22.5

25.5

28.5

Care should be taken to ensure use of the correct formulation, either NOROMBY

(100 mg/mL concentration) or NOROMBY HP (150 mg/mL concentration), when using these

products.

Important: When the NOROMBY dose to be given is equivalent to the full amount of the pre- filled

syringe, no attempt should be made to expel air prior to giving the injection. If the graduated

syringes (60 mg/0.6 mL, 80 mg/0.8 mL, 100 mg/mL, 120 mg/0.8 mL, 150 mg/mL) are used and the

dose of NOROMBY has to be adjusted, it is necessary to expel the air bubble and any excess

drug solution.

Under normal conditions of use, enoxaparin sodium does not modify global clotting tests of

activated partial thromboplastin time (aPTT), prothrombin time (PT) and thrombin clotting time

(TT). Therefore, treatment cannot be monitored with these tests. The plasma levels of the drug

can be verified by measuring anti-Xa and anti-IIa activities.

3.4

Missed Dose

If you miss a dose of this medication by a few hours, take it as soon as you remember. However, if

you are close to the time of the next dose, skip the missed dose and proceed with the regular

dosing schedule. Do not double doses. If you are unsure about how to proceed contact your

doctor or your pharmacist.

4

OVERDOSAGE

Accidental overdosage following administration of NOROMBY (enoxaparin sodium) may lead to

hemorrhagic complications. NOROMBY should be immediately discontinued, at least temporarily,

in cases of significant excess dosage. In more serious cases, protamine should be administered.

The anticoagulant effect of enoxaparin sodium is inhibited by protamine. This effect may be largely

neutralized by slow intravenous injection of protamine sulfate. However, even with higher doses of

protamine, the aPTT may remain prolonged to a greater extent than usually seen with

unfractionated heparin. Anti-factor Xa activity is never completely neutralized (maximum about

60%).

In the event that prompt reversal of the anticoagulant effects of enoxaparin is required at any time

NOROMBY

Page 11 of 78

after NOROMBY dosing, the following table is provided as a guide for initial use of protamine.

Attending physicians confronted with a potential overdosage of enoxaparin should always use

their best clinical judgment in determining the appropriate dosing regimen of protamine to be

administered.

Table 2 - Neutralization of enoxaparin by protamine

Protamine dose

Time Since NOROMBY Dose

< 8 hours

> 8 hours and

12 hours

>12 hours

1 mg protamine per 1 mg enoxaparin

0.5 mg protamine per 1 mg enoxaparin

may not be required

A second infusion of 0.5 mg protamine per 1 mg NOROMBY may be administered if the aPTT

measured 2 to 4 hours after the first infusion remains prolonged.

Particular care should be taken to avoid overdosage with protamine sulfate. Administration of

protamine sulfate can cause severe hypotensive and anaphylactoid reactions. Because fatal

reactions, often resembling anaphylaxis, have been reported with protamine sulfate, it should be

given only when resuscitation equipment and treatment of anaphylactic shock are readily

available.

5

DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

To help ensure the traceability of biologic products, including biosimilars, health professionals

should recognise the importance of recording both the brand name and the non-proprietary (active

ingredient) name as well as other product-specific identifiers such as the Drug Identification

Number (DIN) and the batch/lot number of the product supplied.

Table 3 – Dosage Forms, Strengths, Composition and Packaging

For management of a suspected drug overdose, contact your regional poison control centre.

Route of

Administration

Dosage Form /

Strength/Composition

Non-medicinal Ingredients

Subcutaneous

injection &

Intravenous injection

Enoxaparin sodium solution for

injection - 100 mg/mL

Pre-filled syringes with protective

shield:

20 mg/0.2 mL

30 mg/0.3 mL

40 mg/0.4 mL

60 mg/0.6 mL

80 mg/0.8 mL

100 mg/mL

Enoxaparin sodium solution for

injection (HP)-150 mg/mL Pre-filled

syringes with protective shield:

120 mg/0.8 mL

150 mg/ mL

The pre-filled syringes contain

water for injection.

For composition, see the Dosage

Forms, Composition and

Packaging section of the Product

Monograph.

NOROMBY

Page 12 of 78

NOROMBY (Enoxaparin sodium solution for injection) 100 mg/mL is available in pre-filled syringes

offered with a system that shields the needle after injection:

Single dose 20 mg/0.2 mL pre-filled syringes 27 ½ G in packs of 2, 6, 10, or 12 syringes

per carton, 2 pre filled syringes with protective shield per blister, each in individual blister

pack.

Single dose 30 mg/0.3 mL pre-filled syringes 27 ½ G in packs of 2, 6, 10, or 12 syringes

per carton, 2 pre filled syringes with protective shield per blister, each in individual blister

pack.

Single dose 40 mg/0.4 mL pre-filled syringes 27 ½ G in packs of 2, 6, 10, or 12 syringes

per carton, 2 pre- filled syringes with protective shield per blister, each in individual blister

pack.

Single dose 60 mg/0.6 mL pre-filled syringes 27 ½ G in packs of 2, 6, 10, or 12 syringes

per carton, 2 pre- filled syringes with protective shield per blister, each in individual blister

pack.

Single dose 80 mg/0.8 mL pre-filled syringes 27 ½ G in packs of 2, 6, 10, or 12 syringes

per carton, 2 pre filled syringes with protective shield per blister, each in individual blister

pack.

Single dose 100 mg/mL pre-filled syringes 27 ½ G in packs of 2, 6, 10, or 12 syringes per

carton, 2 pre- filled syringes with protective shield per blister, each in individual blister pack.

The 60 mg/0.6 mL, 80 mg/0.8 mL, and the 100 mg/mL syringes are imprinted with a graduation

scale of 1.0 mL with major increments of 0.1 mL and minor increments of 0.025 mL.

NOROMBY HP (Enoxaparin sodium solution for injection) 150 mg/mL (High Potency) is available

in pre-filled syringes offered with a system that shields the needle after injection:

Single dose 120 mg/0.8 mL pre-filled syringes 27 ½ G in packs of 2, 6, 10, or 12 syringes

per carton, 2 pre- filled syringes with protective shield per blister, each in individual blister

pack.

Single dose 150 mg/mL pre-filled syringes 27 ½ G in packs of 2, 6, 10, or 12 syringes per

carton, 2 pre-filled syringes with protective shield per blister, each in individual blister pack.

The 120 mg/0.8 mL, and the 150 mg/mL syringes are imprinted with a graduation scale of 1.0 mL

with major increments of 0.1 mL and minor increments of 0.02 mL.

Each enoxaparin sodium presentation has a solution pH of 5.5 - 7.5 with an approximate anti-

Factor Xa activity of 100 IU per 1 mg of drug (with reference to the W.H.O. First International Low

Molecular Weight Heparin Reference Standard).

Composition

NOROMBY (Enoxaparin sodium solution for injection) pre-filled syringe: each syringe contains 100

mg/mL of Enoxaparin sodium in water for injection. The solution in the pre-filled syringe is

preservative-free and intended for use as a single-dose injection.

NOROMBY HP (Enoxaparin sodium solution for injection) pre-filled syringe: each syringe contains

150 mg/mL of Enoxaparin sodium in water for injection. The solution in the pre-filled syringe is

preservative-free and intended for use as a single-dose injection.

NOROMBY

Page 13 of 78

The pH of the syringe solution is 5.5 - 7.5 with an approximate anti-Factor Xa activity of 100 IU per

1 mg of drug (with reference to the W.H.O. First International Low Molecular Weight Heparin

Reference Standard). Nitrogen is used in the headspace to inhibit oxidation.

6

DESCRIPTION

NOROMBY is a low molecular weight heparin fragment, which is obtained by controlled

depolymerization of natural heparin from porcine intestinal mucosa. It possesses antithrombotic

action. Enoxaparin is composed of molecules with and without a specially characterized

pentasaccharide, the antithrombin binding site that is essential for high affinity binding to the

plasma protein antithrombin (formerly referred to as antithrombin III). With a molecular weight

range of 3,800 - 5,000 daltons (versus 15,000 daltons for heparin), the enoxaparin molecule is too

small to bind simultaneously to thrombin and antithrombin, the primary anticoagulant factor in

blood.

7

WARNINGS AND PRECAUTIONS

General

NOROMBY (enoxaparin sodium) must NOT be administered by the intramuscular route.

NOROMBY cannot be used interchangeably (unit for unit) with unfractionated heparin

(UFH) or other low molecular weight heparins (LMWHs) as they differ in their manufacturing

process, molecular weight distribution, anti-Xa and anti-IIa activities, units and dosages.

Special attention and compliance with instructions for use of each specific product is

required during any change in treatment.

Determination of anti-Xa levels in plasma is the only method available for monitoring enoxaparin

sodium activity. The effect of enoxaparin sodium on global clotting tests such as aPTT, PT and TT

is dose-dependent. At lower doses, used in prophylaxis, enoxaparin sodium does not prolong

these tests. At higher doses, aPTT prolongation is observed but treatment cannot be monitored

with these tests.

Measurement of peak anti-Xa levels at about 4 hours post-dose should be considered in patients

at higher risk of bleeding and receiving NOROMBY, such as the elderly, patients with renal

impairment or the extremes of body weight, during pregnancy, or for children. At treatment doses,

peak anti-Xa levels should generally be maintained at no more than 1.5 IU/mL in these patients

(see ACTION AND CLINICAL PHARMACOLOGY, and WARNINGS AND PRECAUTIONS,

Monitoring and Laboratory Tests).

Selection of General Surgery Patients

Risk factors associated with postoperative venous thromboembolism following general surgery

include history of venous thromboembolism, varicose veins, obesity, heart failure, malignancy,

previous long bone fracture of a lower limb, bed rest for more than 5 days prior to surgery,

predicted duration of surgery of more than 30 minutes, age 60 years or above.

NOROMBY

Page 14 of 78

Selection of Orthopedic Surgery Patients

Major orthopedic surgery carried out on the lower extremities is associated with a higher risk of

VTE, and a notable percentage of patients will develop a thrombosis if they are not given

prophylaxis. Factors shown to predispose patient to VTE following major orthopedic surgery

include a history of VTE, current obesity, delayed mobilization advanced age or cancer. Other risk

factors that might be clinically important include congestive heart failure, chronic obstructive

pulmonary disease (COPD) as well as female gender.

High risk period for VTE lasts up to 3 months after hip surgery, therefore thromboprophylaxis

should start as soon as possible and continue for up to 28 to 35 days after surgery. (ACCP

guidelines 2004)

Selection of Medical Patients

The risk factors for the development of thrombosis in the individual medical patient are important in

determining whether thromboprophylaxis is appropriate. In one clinical trial, enoxaparin sodium 40

mg once daily reduced the risk of the development of deep vein thrombosis (DVT) from 14.9% to

5.5% during the short term risk period in bedridden patients. Careful consideration should be given

to the selection of patients. Patients at high risk of developing DVT or other thrombosis (such as

patients with a malignant disease, a history of thrombophilia and known deficiency in antithrombin

III, protein C or protein S, or APC resistance) are not candidates for therapy with NOROMBY 40

mg once daily because this dose may be inadequate for those patients. Furthermore, NOROMBY

should not be given for thromboprophylaxis in medical patients who are bedridden due to

infections with septic shock. Medical patients who require short term thromboprophylaxis for the

risk of DVT due to severely restricted mobility during acute illness including moderate to severe

heart failure, acute respiratory failure revealing or complicating chronic respiratory insufficiency not

requiring ventilatory support, and acute respiratory infections may be selected for

thromboprophylaxis with NOROMBY 40 mg once daily.

The safety and efficacy of enoxaparin sodium 40 mg once daily following hospital discharge has

not been established in the medical patient population. In the clinical trial mentioned above,

thromboembolic events were not common following discontinuation of enoxaparin sodium 40 mg

at discharge. However, a significant number of patients did require antithrombotic therapy

following discharge; specifically 13.63%. During the 3-month period following discharge, less than

1% of events were serious and included deep vein thrombosis, pulmonary embolism and death

which is considered to be thromboembolic in origin. Therefore, the physician should consider

whether thromboprophylaxis post-discharge would be necessary for the individual patient.

Gastrointestinal

NOROMBY should be used with caution in patients with gastrointestinal ulceration.

Hematologic

Hemorrhage

Bleeding may occur in conjunction with unfractionated heparin or low molecular weight heparin

use. As with other anticoagulants, NOROMBY should be used with extreme caution in patients at

increased risk of hemorrhage. Bleeding can occur at any site during therapy with enoxaparin

sodium. An unexpected drop in hematocrit or blood pressure should lead to a search for a

bleeding site (see ADVERSE REACTIONS, Bleeding).

NOROMBY

Page 15 of 78

Thrombocytopenia

Thrombocytopenia of any degree should be monitored closely.

Heparin-induced thrombocytopenia (HIT)

Heparin-induced thrombocytopenia can occur with the administration of enoxaparin sodium. Its

incidence is unknown at present.

Use of NOROMBY in patients with a history of immune mediated HIT within the past 100 days or

in the presence of circulating antibodies is contraindicated (see CONTRAINDICATIONS).

Circulating antibodies may persist several years.

Enoxaparin sodium is to be used with extreme caution in patients with a history (more than 100

days) of heparin-induced thrombocytopenia without circulating antibodies. The decision to use

enoxaparin sodium in such a case must be made only after a careful benefit risk assessment and

after non-heparin alternative treatments are considered.

Platelets

Platelet counts should be determined prior to the commencement of treatment with NOROMBY

and, subsequently, twice weekly for the duration of therapy.

Caution is recommended when administering NOROMBY to patients with congenital or drug

induced thrombocytopenia, or platelet defects.

Hepatic/Biliary/Pancreatic

NOROMBY should be used with caution in patients with hepatic insufficiency.

Immune

During NOROMBY administration, special caution is necessary in rapidly developing

thrombocytopenia and severe thrombocytopenia (<100,000/µL). A positive or indeterminate result

obtained from in vitro tests for antiplatelet antibody in the presence of enoxaparin or other low

molecular weight heparins and/or heparin would contraindicate enoxaparin sodium.

Monitoring and Laboratory Tests

Enoxaparin sodium has only a moderate prolonging effect on clotting time assays such as aPTT or

thrombin time. For lab monitoring of effect, anti-Xa methods are recommended. Prolongation of

aPTT during therapy with Enoxaparin sodium to the same extent as with unfractionated heparin

should only be used as a criteria of overdose. Dose increases aimed at prolonging aPTT to the

same extent as with unfractionated heparin could cause overdose and bleeding.

Enoxaparin sodium is administered subcutaneously, and therefore, the individual patient’s

antifactor Xa activity level will not remain within the range that would be expected with

unfractionated heparin by continuous IV infusion throughout the entire dosing interval. In patients

treated with enoxaparin 1 mg/kg twice daily for proximal deep vein thrombosis, mean peak plasma

anti-Xa levels were 0.91 IU/mL. In patients given enoxaparin 1 mg/kg twice daily for acute

treatment of unstable angina, peak anti-Xa activity levels were 1 - 1.1 IU/mL. At steady-state in

patients given a 1.5 mg/kg qd regimen for treatment of DVT, mean peak activity was 1.7 IU anti-

Xa/mL. The steady-state is practically achieved at the second or the third dose depending on the

dosage regimen, once or twice daily, respectively. NOROMBY should be administered as directed

(see DOSAGE AND ADMINISTRATION).

NOROMBY

Page 16 of 78

As with all anti-thrombotic agents, there is a risk of systemic bleeding with Enoxaparin sodium

administration. Consequently, therapy should not be started before primary hemostasis has been

established and preferably no sooner than 12 hours after surgery (see DOSAGE AND

ADMINISTRATION). Care should be taken with Enoxaparin sodium use in high dose treatment of

newly operated patients.

After treatment is initiated, patients should be carefully monitored for bleeding complications. This

may be done by regular physical examination of the patients, close observation of the surgical

drain and periodic measurements of hemoglobin, and anti-factor Xa determinations. With normal

prophylactic doses, Enoxaparin sodium does not modify global clotting tests of activated partial

thromboplastin time (aPTT), prothrombin time (PT) and thrombin clotting time (TT). Therefore,

treatment cannot be monitored with these tests.

At higher doses, increases in aPTT (activated partial thromboplastin time) and ACT (activated

clotting time) may occur. Increases in aPTT and ACT are not linearly correlated with increasing

enoxaparin antithrombotic activity and therefore are unsuitable and unreliable for monitoring

enoxaparin activity.

Patients with Extreme Body Weight

Safety and efficacy of low molecular weight heparins in high weight (eg.> 120 kg) and low weight

(eg. < 45kg) patients have not been fully determined. Individualised clinical and laboratory

monitoring is recommended in these patients (see also ACTION AND CLINICAL

PHARMACOLOGY, Special Population and Conditions, Low-Weight Patients).

Low-weight patients – prophylactic treatment

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), which may lead

to a higher risk of bleeding. Therefore, careful clinical monitoring is advised in these patients (see

ACTION AND CLINICAL PHARMACOLOGY, Special Population and Conditions, Low-Weight

Patients).

Obese patients – prophylactic treatment

Obese patients are at higher risk for thromboembolism. The safety and efficacy of prophylactic

doses in obese patients (BMI >30 kg/m

) 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.

Peri-Operative Considerations

Spinal/Epidural Hematomas

There have been cases of epidural hematomas reported with the use of low molecular weight

heparins (LMWH) and spinal/epidural anesthesia or spinal puncture procedures, resulting in long

term or permanent paralysis. The risk of these events is greater with higher NOROMBY dosage

regimens, use of post-operative indwelling catheters or the concomitant use of additional drugs

affecting hemostasis such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, or

other drugs affecting coagulation including glycoprotein IIb/IIIa antagonists. The risk of spinal

hematoma appears to be increased by traumatic or repeated epidural or spinal puncture, history of

spinal surgery or spinal deformity. NOROMBY should be given after spinal/epidural anesthesia

only if the anesthesiologist considers the spinal/epidural puncture as uncomplicated.

NOROMBY

Page 17 of 78

Consideration should be given to delaying the next dose for 24 hours if the puncture induced

trauma.

The concomitant use of a neuraxial blockade and of an anticoagulant therapy is a clinical

decision that should be made after careful assessment of the benefits and risks to the

individual patient, in the following situations:

In patients already treated with anticoagulants, the benefits of a neuraxial blockade must

be carefully balanced against the risks

In patients planned to undergo elective surgery with neuraxial blockade, the benefits of

anticoagulant therapy must be carefully balanced against the risks

To reduce the potential risk of bleeding associated with the concurrent use of NOROMBY and

epidural or spinal anesthesia/analgesia, or spinal puncture procedures, the pharmacokinetic profile

of the drug should be considered (see ACTION AND CLINICAL PHARMACOLOGY section).

Placement and removal of the catheter is best performed when the anticoagulant effect of

enoxaparin is low; however, the exact timing to reach a sufficiently low anticoagulant effect in each

patient is not known. In the case of patients with spinal lumbar puncture, spinal anesthesia or

epidural anesthesia, a minimum of 12 hours should elapse between the NOROMBY injection at

prophylactic doses or for 24 hours at treatment doses, and the insertion or removal of the

spinal/epidural catheter or needle. A specific recommendation for timing of a subsequent LMWH

dose after catheter removal cannot be made. The timing of the next dose must be based on a

benefit-risk assessment considering both the risk for thrombosis and the risk for bleeding in the

context of the procedure and patient risk factors.

If anticoagulation is administered in the setting of epidural/spinal anesthesia or spinal puncture

procedures, continuous monitoring must be exercised to detect any signs and symptoms of

neurological impairment such as midline back pain, sensory and motor deficits (numbness or

weakness in lower limbs), bowel and/or bladder dysfunction (see ADVERSE REACTIONS

section). Patients should be instructed to inform their physician immediately if they experience an y

of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected, urgent

diagnosis and treatment including spinal cord decompression should be initiated immediately.

For patients with creatinine clearance <30 mL/minute, additional clinical considerations are

necessary, given that elimination of enoxaparin is more prolonged; consideration should be given

to doubling the timing of removal of a catheter.

Percutaneous coronary revascularisation procedures

To minimize the risk of bleeding following the vascular instrumentation during the treatment of

unstable angina, non-Q-wave myocardial infarction, and acute ST-segment elevation myocardial

infarction, adhere precisely to the intervals recommended between NOROMBY injection doses. It

is important to achieve hemostasis at the puncture site after PCI. In case a closure device is used,

the sheath can be removed immediately. If a manual compression method is used, it is

recommended to remove the sheath 6 hours after the last IV/SC injection. If the treatment with

Enoxaparin sodium is to be continued, the next scheduled dose should be given no sooner than 6

to 8 hours after sheath removal. The site of the procedure should be observed for signs of

bleeding or hematoma formation (see DOSAGE AND ADMINISTRATION, Recommended Dose

and Dosage Adjustment- Treatment of Unstable Angina or non-Q-wave Myocardial Infarction and

Treatment of acute ST-segment Elevation Myocardial Infarction).

NOROMBY

Page 18 of 78

Renal

NOROMBY should be used with caution in patients with renal insufficiency.

NOROMBY dosage should be reduced in patients with severely impaired renal function (see

ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Renal

Insufficiency, and DOSAGE AND ADMINISTRATION, Use in Patients with Renal Impairment).

Patients with impaired renal function should be carefully monitored because half-life for anti-Xa

activity after administration of low molecular weight heparin may be prolonged in this patient

population (see DOSAGE AND ADMINISTRATION, Use in Patients with Renal Impairment).

In patients with renal impairment, there is an increase in exposure to enoxaparin which increases

the risk of bleeding. Since exposure to enoxaparin is significantly increased in patients with severe

renal impairment (creatinine clearance <30 mL/min), a dosage adjustment is recommended for

both therapeutic and prophylactic dosage ranges (see ACTION AND CLINICAL

PHARMACOLOGY, Special Populations and conditions, Renal Insufficiency, and DOSAGE AND

ADMINISTRATION, Use in Patients with Renal Impairment).

7.1

Special Populations

7.1.1

Pregnant Women

Teratogenic effects: As with other low molecular weight heparins, NOROMBY should not be used

in pregnant women unless the therapeutic benefits to the patients outweigh the possible risks.

There have been reports of congenital anomalies in infants born to women who received low

molecular weight heparin during pregnancy including cerebral anomalies, limb anomalies,

hypospadias, peripheral vascular malformation, fibrotic dysplasia and cardiac defects. A causal

relationship has not been established nor has the incidence been shown to be higher than in the

general population.

Non-teratogenic effects: There have been post-marketing reports of fetal death when pregnant

women received low molecular weight heparins. Causality for these cases has not been

established. Pregnant women receiving anticoagulants, including enoxaparin sodium, are at

increased risk for bleeding. Hemorrhage can occur at any site and may lead to death of mother

and/or fetus. Pregnant women receiving NOROMBY should be carefully monitored. Pregnant

women and women of child-bearing potential should be informed of the potential hazard to the

fetus and the mother if NOROMBY is administered during pregnancy.

There are also post-marketing reports of prosthetic valve thrombosis in pregnant women with

prosthetic heart valves while receiving low molecular weight heparins for thromboprophylaxis.

These events led to maternal death or surgical interventions.

Pregnant women with prosthetic heart valves appear to be at exceedingly high risk of

thromboembolism. An incidence of thromboembolism approaching 30% has been reported in

these patients, in some cases even with apparent adequate anticoagulation at treatment doses of

low molecular weight heparins or unfractionated heparin. Any attempt to anticoagulate such

patients should normally only be undertaken by medical practitioners with documented expertise

and experience in this clinical area.

NOROMBY

Page 19 of 78

7.1.2

Breast-feeding

It is not known whether enoxaparin sodium is excreted in human milk. Because many drugs are

excreted in human milk, caution should be exercised when NOROMBY is administered to nursing

women.

7.1.3

Pediatrics

No data are available to Health Canada; therefore, Health Canada has not authorized an

indication for pediatric use.

7.1.4

Geriatrics

Elderly patients (especially patients eighty years of age and older) receiving low molecular weight

heparins are at increased risk of bleeding. Careful attention to dosing and concomitant

medications, especially anti-platelet preparations, is advised. Close monitoring of elderly patients

with low body weight (eg. <45 kg) and those predisposed to decreased renal function is

recommended.

For treatment of acute ST-segment Elevation Myocardial Infarction in geriatric patients, the

incidence of bleeding complications was higher in patients ≥65 years of age as compared to

younger patients (<65 years). 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 - Recommended Dose and Dosage Adjustment, Treatment of

acute ST-segment Elevation Myocardial Infarction, Geriatrics (≥75 years of age).

7.1.5

Patients with Prosthetic Heart Valves

Cases of prosthetic valve thrombosis have been reported in patients who have received low

molecular weight heparins for thromboprophylaxis. Some of these patients were pregnant women

in whom thrombosis led to maternal and/or fetal deaths. Pregnant women are at higher risk of

thromboembolism (see WARNINGS AND PRECAUTIONS, Use in Pregnant Women).

7.1.6

Acute Coronary Disease

When thrombolytic treatment is considered appropriate in patients with unstable angina, non -Q-

wave myocardial infarction and acute ST-segment Elevation Myocardial Infarction, the

concomitant use of an anticoagulant such as Enoxaparin sodium may increase the risk of

bleeding.

7.1.7

Medical Patients

Enoxaparin sodium at a dose of 40 mg once daily should not be given for thromboprophylaxis

other than deep vein thrombosis (DVT) prevention or in medical patients who, in the opinion of the

attending physician, would be at a higher risk of thromboembolism (such as patients with a

malignant disease, a history of thrombophilia and known deficiency in antithrombin III, protein C or

protein S, or APC resistance). Furthermore, Enoxaparin sodium should not be given for

NOROMBY

Page 20 of 78

thromboprophylaxis in medical patients who are bedridden due to infections with septic shock.

Patients with severe COPD complicated by right heart failure are candidates for another form of

thromboprophylaxis. Enoxaparin sodium at a dose of 40 mg once daily has been studied in

medical patients who require short term thromboprophylaxis to prevent the development of DVT

while they are bedridden (6 to 11 days). If, in the opinion of the attending physician, longer

thromboprophylaxis is necessary, then consideration should be given to a thromboprophylactic

agent, which has been proven effective.

8

ADVERSE REACTIONS

The adverse drug reaction profiles reported in clinical studies that compared NOROMBY to the

reference biologic drug were comparable. The description of adverse reactions in this section is

based on clinical experience with the reference biologic drug.

8.1

Adverse Reaction Overview

Bleeding

As with any antithrombotic treatment, hemorrhagic manifestations can occur (also see ADVERSE

REACTIONS, Local Reactions).

The incidence of major hemorrhagic complications during enoxaparin sodium treatment has been

low and generally did not differ from that observed with unfractionated heparin. Patients taking

NOROMBY are at risk for major bleeding complications when the plasma anti-factor Xa levels

approach 2.0 IU/mL. Other risk factors associated with bleeding on therapy with heparins include a

serious concurrent illness, chronic heavy alcohol consumption, use of platelet inhibiting drugs,

renal failure, age and possibly, the female gender. Petechiae or easy bruising may precede frank

hemorrhage. Bleeding may range from minor local hematoma to major hemorrhage. The early

signs of bleeding may include epistaxis, hematuria, or melena. Bleeding may occur at any site and

may be difficult to detect; such as retroperitoneal bleeding. Bleeding may also occur from surgical

sites.

Major hemorrhage, including retroperitoneal and intracranial bleeding, has been reported in

association with enoxaparin sodium use, in some cases leading to fatality.

Local Reactions

Pain and mild local irritation may follow the subcutaneous injection of Enoxaparin sodium. Rarely,

hard inflammatory nodules have been observed at the injection site. Injection site hematomas are

a common side effect with enoxaparin sodium occurring at a frequency of 5% or less with lower

(prophylaxis) doses to 10% or more with higher (treatment) doses.

8.2

Clinical Trial Adverse Reactions

Because clinical trials are conducted under very specific conditions, the adverse reaction rates

observed in the clinical trials may not reflect the rates observed in practice and should not be

compared to the rates in the clinical trials of another drug. Adverse reaction information from

clinical trials is useful for identifying drug-related adverse events and for approximating rates.

NOROMBY

Page 21 of 78

The following rates of major bleeding events have been reported during clinical trials with

enoxaparin sodium.

Table 4 - Major Bleeding Episodes Following Abdominal and Colorectal Surgery

1

Indications

Dosing Regimen

Enoxaparin Sodium

40 mg qd SC

Heparin

5000 U q8h SC

Abdominal Surgery

2

Colorectal Surgery

2

n = 555

23 (4%)

n = 673

28 (4%)

n = 560

16 (3%)

n = 674

21 (3%)

Bleeding complications were considered major: (1) if the hemorrhage caused a significant clinical

event, or (2) if accompanied by a hemoglobin decrease ≥ 2 g/dL or transfusion of 2 or more units

of blood products. Retroperitoneal, intraocular, and

intracranial hemorrhages were always considered major.

Enoxaparin Sodium 40 mg qd SC initiated two hours prior to surgery and continued for up to 12

days after surgery.

Table 5 - Major Bleeding Episodes Following Hip or Knee Replacement Surgery

1

Indications

Dosing Regimen

Enoxaparin Sodium

30 mg q12h SC

Heparin

15,000 U/24h SC

Hip Replacement Surgery

2

Knee Replacement Surgery

2

n = 786

31 (4%)

n = 294

3 (1%)

=541

32 (6%)

=225

3 (1%)

Bleeding complications were considered major: (1) if the hemorrhage caused a significant clinical

event, or (2) if accompanied by a hemoglobin decrease ≥ 2 g/dL or transfusion of 2 or more units

of blood products. Retroperitoneal and intracranial hemorrhages were always considered major. In

the knee replacement surgery trials, intraocular hemorrhages were also

considered major hemorrhages.

Enoxaparin Sodium 30 mg every 12 hours SC initiated 12 to 24 hours after surgery and continued

for up to 14 days after surgery.

NOTE: At no time point were the 40 mg once a day pre-operative and the 30 mg every 12 hours

post-operative hip replacement surgery prophylactic regimens compared in clinical trials.

Table 6 - Major Bleeding Episodes Following Hip or Knee Replacement Surgery With

Extended Prophylaxis

1

Dosing Regimen

Initial Prophylaxis

2

Extended Prophylaxis

3

Indications

Enoxaparin sodium

30 mg q12h SC

Enoxaparin

sodium

40 mg qd

Enoxaparin

sodium

40 mg qd

Placebo

qd SC

Hip Replacement Surgery

n =475

8 (1.7%)

N = 288

3 (1.0%)

n = 445

0 (0%)

N = 431

0 (0%)

Knee Replacement Surgery

4

n = 493

8 (1.6%)

n = 217

0 (0%)

N = 221

1 (0%)

NOROMBY

Page 22 of 78

Bleeding complications were considered major: (1) if the hemorrhage caused a significant clinical

event, or (2) if accompanied by a hemoglobin decrease ≥ 2 g/dL or transfusion of 2 or more units

of blood products. Retroperitoneal and intracranial hemorrhages were always considered major.

Initial Prophylaxis hospital phase: In the multicentre study 307, Enoxaparin sodium 30 mg q12h

SC for 7-10 days, initiated within 12- 24 hours postoperatively; in the single-centre study PK537,

Enoxaparin sodium 40 mg qd SC initiated 12 ± 2 hours before surgery, repeated on the day of the

surgery and continued for 9 ± 2 days.

Extended Prophylaxis outpatient phase: In the multicentre study 307, Enoxaparin sodium 40 mg

qd SC for 18-21 days; in the single-centre studies PK537 and ENX491001, Enoxaparin sodium 40

mg qd SC 21 ± 2 days.

Initial Prophylaxis hospital phase: In the multicentre study 307, Enoxaparin sodium 30 mg q12h

SC for 7-10 days, initiated within 12- 24 hours postoperatively; Extended Prophylaxis outpatient

phase: In the multicentre study 307.

Table 7 - Major Bleeding Episodes in Medical Patients With Severely Restricted Mobility

During Acute Illness

1

Indication

Dosing Regimen

Enoxaparin Sodium

2

40 mg qd SC

Placebo

2

Medical Patients During Acute Illness

3

n = 360

3 (<1%)

n = 362

2 (<1%)

Bleeding complications were considered major: (1) if the hemorrhage caused a significant clinical

event, (2) if the hemorrhage caused a decrease in hemoglobin of ≥ 2 g/dL or transfusion of 2 or

more units of blood products. Retroperitoneal and intracranial hemorrhages were always

considered major although none were reported during the trial.

The rates represent major bleeding on study medication up to 24 hours after last dose.

Usual duration of treatment 6 to 11 days.

Table 8 - Major Bleeding Episodes in Unstable Angina and Non-Q-Wave Myocardial

Infarction

Indication

Dosing Regimen

Enoxaparin Sodium

1

1 mg/kg q12h SC

Heparin

1

aPTT Adjusted

IV Therapy

Unstable Angina and Non-Q-Wave MI

2, 3

n = 1578

17 (1%)

n = 1529

18 (1%)

The rates represent major bleeding on study medication up to 12 hours after last dose with

treatment for up to 8 days.

Aspirin therapy was administered concurrently (100 to 325 mg per day).

Bleeding complications were considered major: (1) if the hemorrhage caused a significant clinical

event, or (2) if accompanied by a hemoglobin decrease by ≥3 g/dL or transfusion of 2 or more

units of blood products. Intraocular, retroperitoneal, and intracranial hemorrhages were always

considered major.

Table 9 - Major Bleeding Episodes in Treatment of Deep Vein Thrombosis With or Without

Pulmonary Embolism Treatment

1

Dosing Regimen

2

NOROMBY

Page 23 of 78

Indication

Enoxaparin Sodium

1.5 mg/kg qd SC

Enoxaparin Sodium

1 mg/kg q12h SC

Heparin

aPTT Adjusted

IV Therapy

Treatment of DVT, with or without

PE

n = 298

5 (2%)

n = 559

9 (2%)

n = 554

9 (2%)

Bleeding complications were considered major: (1) if the hemorrhage caused a significant clinical

event, or (2) if accompanied by a hemoglobin decrease ≥ 2 g/dL or transfusion of 2 or more units

of blood products. Retroperitoneal, intraocular, and intracranial hemorrhages were always

considered major.

All patients also received warfarin (dose-adjusted according to PT to achieve an INR of 2.0 to 3.0)

commencing within 72 hours of ENOXAPARIN SODIUM or standard heparin therapy and

continuing for up to 90 days. ENOXAPARIN SODIUM or standard heparin therapy was

discontinued after a therapeutic oral anticoagulant effect was achieved in general about 7 days

after treatment initiation.

Table 10 - Major Bleeding Episodes in acute ST-segment Elevation Myocardial Infarction

Indication

Dosing Regimen

Enoxaparin Sodium

Initial 30-mg IV bolus follow ed

by 1 mg/kg q12h SC*

Heparin

aPTT

Adjusted IV

Therapy

Acute ST-segment Elevation Myocardial

Infarction

n = 10176

n = 10151

Major bleeding (including ICH)

211 (2.1%)

138 (1.4%)

Intracranial hemorrhages (ICH)

84 (0.8%)

66 (0.7%)

The rates represent major bleeding (including ICH) up to 30 days.

Bleedings were considered major if the hemorrhage caused a significant clinical event associated

with a hemoglobin decrease by

≥ 5 g/dL. ICH were always considered major.

*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.

8.3

Other Clinically Relevant Adverse Reactions

Other adverse reactions commonly reported in clinical trials with enoxaparin sodium were

thrombocytosis, allergic reactions, hepatic enzymes increase, urticaria, pruritus, erythema, and

injection site reactions.

Adverse Reactions in enoxaparin sodium Injection Treated Patients With acute ST-segment

Elevation Myocardial Infarction

In a clinical trial in patients with acute ST-segment elevation myocardial infarction, the only

additional possibly related adverse reaction that occurred at a rate of at least 0.5% in the

enoxaparin sodium group was thrombocytopenia (1.5%).

8.4

Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other

Quantitative Data

See WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests.

NOROMBY

Page 24 of 78

8.5

Clinical Trial Adverse Reactions (Pediatrics)

Not applicable.

8.6

Post-Market Adverse Reactions

Blood and Lymphatic System Disorders

Heparin-induced Thrombocytopenia

Severe immunologically-mediated thrombocytopenia has been observed rarely with

enoxaparin sodium use, resulting in arterial and/or venous thrombosis or thromboembolism

(see WARNINGS AND PRECAUTIONS, Hematologic, Thrombocytopenia, Platelets and

WARNINGS AND PRECAUTIONS, Immune). In some cases thrombosis was complicated

by organ infarction or limb ischemia.

Thrombocytopenia

Hemorrhagic anemia

Eosinophilia

Hepatobiliary disorders

Liver

Transient, asymptomatic elevations of liver transaminases (AST and ALT) to greater than

three times the upper limit of normal has been observed in up to 6% of patients taking

enoxaparin sodium. This is a consistent finding with all members of the LMWH class, as

well as with unfractionated heparin. The mechanism associated with the increased levels of

liver transaminases has not been elucidated. No consistent irreversible liver damage has

been observed. Transaminase levels returned to normal within 3 to 7 days after

discontinuation of enoxaparin.

Hepatocellular injury

Cholestatic liver injury

Immune System Disorders

Hypersensitivity

Hypersensitivity reactions, including angioedema and anaphylactic/anaphylactoid reaction

including shock have been observed rarely with unfractionated heparin and low molecular

weight heparins including enoxaparin.

Metabolism and nutrition disorders

Hyperkalemia

Cases of hyperkalemia have been reported with heparins and Low Molecular Weight

Heparins.

NOROMBY

Page 25 of 78

Musculoskeletal and connective tissue disorders

Skeletal Effects

Use of low molecular weight heparins over extended periods has been reported to be

associated with development of osteopenia.

Osteoporosis following long-term therapy (greater than 3 months)

Nervous System Disorders

Headache

Skin and subcutaneous tissue disorders

Skin rash (including bullous eruptions), purpura, and allergic reactions occur with all low

molecular weight heparins. Skin necrosis is rare, usually occurring at the injection site and

preceded by purpura or erythematous plaques, infiltrated and painful. In case such reaction

is observed, treatment with Enoxaparin sodium must be discontinued. Very rare cases of

hypersensitivity cutaneous vasculitis have been reported. These cases may include

leukocytoclastic vasculitis. Enoxaparin sodium should be discontinued in patients showing

local or systemic allergic responses.

Alopecia

Vascular Disorders

Cases of spinal hematoma (or neuraxial hematoma) have been reported with the

concurrent use of Enoxaparin sodium as well as spinal/epidural anesthesia or spinal

puncture. These reactions have resulted in varying degrees of neurologic injuries including

long-term or permanent paralysis (see WARNINGS AND PRECAUTIONS, Peri-Operative

considerations, Spinal/Epidural Hematomas).

9

DRUG INTERACTIONS

9.1

Drug-Drug Interactions

It is recommended that agents which affect hemostasis should be discontinued prior to

NOROMBY therapy unless strictly indicated. If the combination is indicated, NOROMBY should be

used with careful clinical and laboratory monitoring when appropriate.

NOROMBY should be used with caution in patients receiving oral anticoagulants, platelet

inhibitors, non-steroidal anti-inflammatories and thrombolytic agents because of increased risk of

bleeding. Aspirin, unless contraindicated, is recommended in patients treated for unstable angina

or non-Q-wave myocardial infarction and acute ST-segment Elevation Myocardial Infarction (see

DOSAGE AND ADMINISTRATION).

NOROMBY

Page 26 of 78

9.2

Drug-Food Interactions

Not applicable.

9.3

Drug-Herb Interactions

Not applicable.

9.4

Drug-Laboratory Test Interactions

Since enoxaparin sodium use may be associated with a rise in hepatic transaminases, this

observation should be considered when liver function tests are assessed (see ADVERSE

REACTIONS, Post Market Adverse Drug Reactions, and Liver).

9.5

Drug-Lifestyle Interactions

Not applicable.

10

ACTION AND CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

The mechanism of action of enoxaparin is antithrombin-dependent. It acts mainly by accelerating

the rate of the neutralization of certain activated coagulation factors by antithrombin, but other

mechanisms may also be involved. Enoxaparin potentiates preferentially the inhibition of

coagulation factors Xa and IIa and only slightly affects other hemostatic mechanisms such as

clotting time. The antithrombotic effect of enoxaparin is well correlated to the inhibition of factor Xa.

The ratio of anti-Xa/anti-IIa activity is greater than 4 with enoxaparin (whereas this ratio is equal to

1 with heparin). This dissociation between anti-Xa and anti-IIa activities has been shown in

experimental models with an antithrombotic activity comparable to that of heparin while the

bleeding effect is reduced. In man, clinical trials have not shown a causal relationship between the

ratio of anti-Xa/anti-IIa activity and clinical/pharmacological effect.

Enoxaparin sodium cannot be measured directly in the bloodstream. Rather the effect on clotting

mechanisms is measured. Heparin dosage is monitored by both prolongation of aPTT and by anti-

Xa activity. For enoxaparin, the aPTT may not be significantly prolonged relative to unfractionated

heparin at prophylactic doses, and at therapeutic doses aPTT prolongation is not used to measure

the therapeutic effect of enoxaparin sodium. Enoxaparin potency is described in international anti-

Xa units (e.g., 1 mg of enoxaparin is equivalent to 100 IU of anti-Xa).

In the in vitro purified system, Enoxaparin sodium has a high anti-Xa activity (approximately 100

IU/mg) and low anti-IIa or anti thrombin activity (approximately 28 IU/mg). These anticoagulant

activities are mediated through anti-thrombin III (ATIII) resulting in anti- thrombotic activities in

humans.

NOROMBY

Page 27 of 78

Beyond its anti-Xa/IIa activity, further anti-thrombotic and anti-inflammatory properties of

enoxaparin have been identified in healthy subjects and patients as well as in non-clinical models.

These include ATIII-dependent inhibition of other coagulation factors like factor VIIa, induction of

endogenous Tissue Factor Pathway Inhibitor (TFPI) release as well as a reduced release of von

Willebrand factor (vWF) from the vascular endothelium into the blood circulation. These factors are

known to contribute to the overall anti-thrombotic effect of enoxaparin.

10.2 Pharmacokinetics

Absorption: The pharmacokinetics of enoxaparin have been studied on the basis of plasma levels

of anti-Xa activity. The mean absolute bioavailability of enoxaparin, when given subcutaneously, is

about 92% in healthy volunteers.

The mean peak plasma anti-Xa activity is observed 3 to 5 hours after subcutaneous injection.

Levels of approximately 0.2, 0.4, 1.0 and 1.3 anti-Xa IU/mL were seen in healthy volunteers,

following a single subcutaneous administration of 20 mg, 40 mg, 1 mg/kg and 1.5 mg/kg,

respectively.

Enoxaparin pharmacokinetics appear to be linear over the recommended dosage ranges. After

repeated subcutaneous administration of the 1 mg/kg twice daily regimen, the steady-state is

reached from Day 3 to 4 with mean exposure about 65% higher than after a single dose. Mean

peak and trough levels of about 1.2 and 0.52 IU/mL respectively were seen with this regimen.

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 88% of steady-

state levels. Steady state is achieved on the second day of treatment.

Distribution:

The volume of distribution of enoxaparin is about 5 liters. Following subcutaneous

dosing, the apparent clearance of enoxaparin is approximately 15 mL/min.

Information from a clinical trial with a very small number of volunteers indicates that enoxaparin, as

detected by anti-factor Xa activity, does not appear to cross the placental barrier, at least during

the second trimester of pregnancy.

Metabolism: Enoxaparin is metabolized in the liver by desulfation and depolymerization.

Elimination:

Elimination appears monophasic with a half-life of about 4 hours after a single

subcutaneous dose and about 7 hours after repeated dosing, in healthy volunteers.

The main route of elimination is via the kidney. 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.

Pharmacokinetic interaction: No pharmacokinetic interaction was observed between enoxaparin

and thrombolytics when administered concomitantly.

Special Populations and Conditions

NOROMBY

Page 28 of 78

Pediatrics: The safety and effectiveness of NOROMBY in children has not been established.

Geriatrics:

Based on the results of a population pharmacokinetic analysis, the enoxaparin kinetic

profile is not different in elderly subjects compared to younger subjects when renal function is

normal. However, since renal function is known to decline with age, elderly patients may show

reduced elimination of enoxaparin (see WARNINGS AND PRECAUTIONS, Renal and Special

Populations, Geriatrics).

Low-Weight Patients: When non-weight-adjusted dosing was administered, after a single-

subcutaneous 40 mg dose, anti-Xa exposure was observed to be 52% higher in low-weight

women (<45 kg) and 27% higher in low-weight men (<57 kg) when compared to normal weight

control subjects, which may lead to a higher risk of bleeding (see WARNINGS AND

PRECAUTIONS, Special Populations, Patients with Extreme Body Weight).

Renal Insufficiency:

A linear relationship between anti-Xa plasma clearance and creatinine

clearance at steady-state has been observed, indicating decreased clearance of enoxaparin in

patients with reduced renal function.

Anti-Xa exposure at steady-state, represented by AUC, is increased about 34% in mild renal

impairment (creatinine clearance 50-80 mL/min), about 72% in moderate renal impairment

(creatinine clearance 30-50 mL/min), and about 95% in severe renal impairment (creatinine

clearance <30 mL/min) upon administration of enoxaparin 1.5 mg/kg once daily SC for 4 days.

Anti-Xa exposure at steady-state is increased about 33% in mild renal impairment, about 46% in

moderate and about 97% in severe renal impairment upon administration of enoxaparin 1 mg/kg

bid SC for 4 days. When enoxaparin was administered at a fixed, prophylaxis dose of 40 mg once

daily SC for 4 days, the anti-Xa exposure increased by about 20% in mild renal impairment, about

21% in moderate renal impairment, and about 65% in severe renal impairment (see WARNINGS

AND PRECAUTIONS, Renal, and DOSAGE AND ADMINISTRATION, Use in Patients with Renal

Impairment).

The half-life for anti-Xa activity in patients with impaired renal function is much longer than for

people with normal renal function (t½ = 5.12 h in patients with chronic renal failure vs 2.94 h in

young healthy volunteers) when enoxaparin was administered intravenously.

11

STORAGE, STABILITY AND DISPOSAL

Store at room temperature (15-25ºC). Protect from heat and freezing.

12

SPECIAL HANDLING INSTRUCTIONS

Not applicable.

NOROMBY

Page 29 of 78

PART II: SCIENTIFIC INFORMATION

13

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Enoxaparin sodium

Chemical name:

Enoxaparin sodium is the sodium salt of a low molecular weight heparin, obtained by alkaline

depolymerisation of the benzyl ester of heparin sodium from porcine intestinal mucosa. The

average molecular weight of Enoxaparin sodium is one third of unfractionated heparin.

Enoxaparin sodium is a mixture of sulfated polysaccharide chains which vary in length and are

made of repeating disaccharide units; the complex set of oligosaccharides have not yet been

completely characterised. The disaccharide monomer consists of one molecule of uronic acid and

one molecule of D-glucosamine, linked in the 1-4 position. Uronic acid can be either D- glucuronic

acid or L-iduronic acid, and in addition, L-iduronic acid can be sulfated on position 2. Glucosamine

can be N-sulfated, N-acetylated, 6-0-sulfated, or 3-0-sulfated.

Based on current knowledge, the majority of the components have a 4-enopyranose uronate

structure at the non-reducing end of their chain. About 20% of the components contain a

1,6 anhydro derivative on the reducing end of the chain, the range being between 15 and 2 5%.

The mass-average molecular mass ranges between 3,800 and 5,000 daltons with a characteristic

value of about 4,500 daltons. The mass percentage of chains between 2,000 and 8,000 daltons

ranges between 68.0 and 82.0 percent.

Molecular formula and molecular mass:

Relative molecular mass is about 4500 daltons (range: 3,800 - 5,000 daltons).

NOROMBY

Page 30 of 78

X = 15 to 25 %

n = 0

to 20

100 - X

n = 1

to 21

X = Percent of polysaccharide chain containing 1,6 anhydro derivative on the reducing end

Physicochemical properties: Enoxaparin sodium is a fine white to almost white powder.

Enoxaparin sodium is soluble in water, but practically insoluble in ethanol and chloroform.

Aqueous solutions of Enoxaparin sodium (10% aqueous solution) have a pH between 6.2 to 7.7.

14

COMPARATIVE CLINICAL TRIALS

14.1 Comparative Trial Design and Study Demographics

Clinical studies conducted to support similarity between NOROMBY and the reference biologic

drug included:

A Single-Dose, Randomized, Double-Blind, Two-Way Crossover Comparative

Pharmacodynamic (PD) Study in Healthy Volunteers (Study ROV-RO20-2015-01).

An overview of the study designs and demographic characteristics of patients enrolled in each

clinical study is presented in Table 11.

Table 11- Summary of patient demographics for clinical trial

Study

Number

Trial design

Dosage, route

of

administration

and duration

Study

subjects (n)

Mean age

(Range)

Sex

ROV-RO20-

2015-01

Single-dose,

randomized,

double-blind,

two-way

cross-over

study in

healthy

volunteers

assessing

comparative

PD and

safety

Single SC dose

(100 mg/mL) of

either

NOROMBY or

Clexane (EU) in

each of the 2

treatment

periods,

separated by at

least a 7 day

washout period

between periods

Randomized:

46 healthy

volunteer

subjects

Completed:

43 healthy

volunteer

subjects

26 years

(range:

18 to 44

years)

Enrolled:

33 (71.7%)

Males

13 (28.3%)

Females

NOROMBY

Page 31 of 78

Study ROV-RO20-2015-01 was a randomized, double-blind, two way crossover study in healthy

adult volunteers assessing comparative PD and safety of NOROMBY and Clexane (EU)

following a single dose of 100 mg/mL subcutaneous (SC) injection. The study evaluated 46

healthy subjects (N=23 in each treatment sequence NOROMBY/EU-Clexane or EU-

Clexane/NOROMBY). Two subjects from the NOROMBY/EU-Clexane and one from the EU-

Clexane/NOROMBY treatment sequence did not complete the study, which resulted in 43

subjects being included in the statistical comparisons.

The main objective of the study was to assess the pharmacodynamic (PD) comparability of

NOROMBY to the reference biologic drug. The primary PD parameters evaluated were

maximum activity (A

) and area under the effect curve from time 0 to the last measured

activity (T) (AUEC

0–T

) and AUEC from time 0 to infinity (AUEC

0–inf

) of anti-FXa activity, and A

and AUEC

0–T

of anti-FIIa activity

14.2 Comparative Study Results

14.2.1 Comparative Bioavailability Studies

14.2.1.1 Pharmacodynamics

The results of the primary PD comparisons are shown in Tables 12 and 13.

Table 12. Study ROVRO20201501-Statistical Analysis of Primary PD Parameters

Anti-FXa activity

(1 x 100 mg/mL SC)

From measured data

Geometric Mean

Arithmetic Mean (CV %)

Parameter

Test

Reference

% Ratio of

Geometric

Means

95%

Confidence

Interval

AUEC

(h∙IU/mL)

8.05

8.38 (29.2)

7.75

8.00 (25.6)

103.8

99.8-108.0

AUEC

0-inf

(h∙IU/mL)

8.91

9.21 (26.3)

8.55

8.98 (23.0)

104.2

100.0-108.6

(IU/mL)

0.97

0.99 (19.0)

0.97

0.99 (19.7)

100.1

94.6-105.9

4.00

(2.05, 6.02)

4.00

(2.00, 5.00)

NOROMBY

(enoxaparin sodium injection) by Juno Pharmaceuticals Corp.

Clexane (EU) (enoxaparin sodium injection) by sanofi-aventis France (as a suitable proxy for the

reference biologic drug, Lovenox from sanofi-aventis Canada Inc.)

AUEC

= area under the effect curve from time 0 to the last measured activity (T)

AUEC

0-inf

= area under the effect curve from time 0 to infinity

NOROMBY

Page 32 of 78

Amax = maximum activity

*n=40

Expressed as the median (range) only

Acceptance Interval was 80.0% to 125.0%

Table 13. Study ROVRO20201501- Statistical Analysis of Primary PD Parameters

Anti-FIIa activity

(1 x 100 mg/mL SC)

From measured data

Geometric Mean

Arithmetic Mean (CV %)

Parameter

Test

Reference

% Ratio of

Geometric

Means

95%

Confidence

Interval

AUEC

(h∙IU/mL)

1.08

1.21 (55.3)

1.04

1.14 (47.8)

103.5

90.9-117.9

(IU/mL)

0.18

0.19 (29.4)

0.18

0.18 (32.0)

103.3

94.7-112.6

4.50

(2.00, 6.02)

4.50

(2.50, 6.00)

NOROMBY (enoxaparin sodium injection) by Juno Pharmaceuticals Corp.

Clexane (EU) (enoxaparin sodium injection) by sanofi-aventis France (as a suitable proxy for the

reference biologic drug, Lovenox from sanofi-aventis Canada Inc.)

AUEC

= area under the effect curve from time 0 to the last measured activity (T)

AUEC

0-inf

= area under the effect curve from time 0 to infinity

Amax = maximum activity

Expressed as the median (range) only

Acceptance Interval was 80.0% to 125.0%

14.2.2 Comparative Safety and Efficacy

14.2.2.1 Efficacy

See section 14.2.1.1 Pharmacodynamics.

14.2.2.2 Safety

In the single dose two way cross over comparative PD and safety study of NOROMBY and

Clexane (EU) in healthy adult volunteers (Study ROV-RO20-2015-01) the types, frequency and

severity of adverse events were comparable between the biosimilar and the reference biologic

drug.

NOROMBY

Page 33 of 78

15

CLINICAL TRIALS – REFERENCE BIOLOGIC DRUG

Prophylaxis of venous thromboembolic disease following hip or knee surgery

Study demographics and trials design [CPK 0884 P20, CPK 0387/PK523, CPK 0688/

PK527]

The safety and efficacy of enoxaparin sodium in preventing deep vein thrombosis (DVT)

following hip or knee surgery has been evaluated in three large pivotal trials involving 896

patients over 40 years of age. The mean age was 67 years, with 40.2% men and 56.5%

women. All studies were conducted as multi-centre, controlled, double-blind comparison of

enoxaparin sodium with placebo or with calcium heparin in patients undergoing orthopedic

surgery of the hip or knee. Treatment with enoxaparin sodium or the selected drug standard

was initiated the day after or second day after surgery, provided hemostasis was established,

and continued for 14 days or until discharge if sooner. All three studies shared the same

objectives, criteria of evaluation and procedures.

Table 14 - Summary of patient demographics in clinical trials for prophylaxis of venous

thromboembolic disease following hip or knee surgery

Study #

Trial design

Dosage, route of

administration and

duration

Study

subjects

(n=number)

Mean age

(Range)

Gender

(M/F)

CPK 0884 P20

(Hip)

Randomized, double-

blind, parallel group,

To compare

enoxaparin with

placebo in prevention

of DVT in patients

undergoing total hip

replacement

Enoxaparin

30 mg SC injection

twice daily

Placebo

SC injection twice daily

Duration: up to

14 days

Total = 100

67.1 years

(41-84)

45% /55%

CPK 0387/PK523

(Hip)

Randomized, double-

blind, parallel group,

To compare

enoxaparin with

calcium heparin in

prevention of DVT in

patients undergoing

elective hip surgery

Enoxaparin

30 mg SC

injection twice

daily

Calcium heparin

7500 units SC

injection twice daily

Duration: up to

14 days

Total: 665

67 years

(66.2 ± 10.39)

67 years

(66.8 ± 9.09)

45.8% / 54.2%

NOROMBY

Page 34 of 78

Study #

Trial design

Dosage, route of

administration and

duration

Study

subjects

(n=number)

Mean age

(Range)

Gender

(M/F)

CPK 0688/PK527

(Knee)

Randomized, double-

blind, parallel group,

To compare

enoxaparin with

placebo in prevention

of DVT in patients

undergoing major

knee surgery

Enoxaparin

30 mg SC injection

twice daily

Placebo

SC injection twice daily

Duration: up to

14 days

Total: 131

68.1

(42-85)

29.7% /60.3%

Study results

The primary aim of each study was to determine the efficacy and safety of enoxaparin sodium in

the prevention of thromboembolism. Efficacy assessments were based on venography, 125I-

fibrinogen scanning of the lower limbs and impedance plethysmography (IPG). The efficacy

data are provided below.

Table 15 -Incidence of DVT in patients treated with enoxaparin or placebo, following hip

or knee surgery

Study

Incidence of DVT

P value #

ENOXAPARIN

SODIUM

group (%)

Placebo group

(%)

heparin group

(%)

CPK 0884 P20 (Hip)

CPK 0387 (Hip)

0.0002

0.5317

CPK 0688 (Knee)

19.7

60.0

< 0.0001

In patients undergoing total hip replacement (study CPK 0884), postoperative treatment with

enoxaparin sodium 30 mg SC twice daily statistically significantly reduced the incidence of DVT

compared to placebo group (10% vs 46% respectively, p = 0.0002). The odds ratio was 8.34

(95% CI = [2.72, 25.56], p = 0.0002).

In patients undergoing elective hip surgery (study CPK0387), the incidence rate of DVT in the

enoxaparin sodium group was lower than in the calcium heparin group (17% vs 19%

respectively), although the comparison between these groups was not statistically significant.

enoxaparin sodium 30 mg SC twice daily was shown to be at least as efficacious as calcium

heparin 7500 units twice daily.

In patients undergoing major knee surgery (study CPK 0688) enoxaparin sodium 30 mg twice

daily significantly reduced the incidence rate of VTE disease relative to placebo (60% vs 19.7%

respectively, p< 0.0001). The estimated odds for development of VTE disease in the placebo

group was 7.5 times higher than for the enoxaparin sodium group (95% CI = [3.13 – 17.74]).

NOROMBY

Page 35 of 78

Extended Prophylaxis of DVT Following Hip Replacement Surgery

Study demographics and trial design [Study 307]

In the open label phase of the multicentre study 307, patients undergoing elective primary hip

replacement surgery received enoxaparin sodium 30 mg SC twice daily for 7 to 10 days,

initiated within 12 to 24 hours post surgery. Patients who did not require re-operation, had

received appropriate enoxaparin sodium dosing during the open-label phase, did not receive

prohibited concomitant medications and had not developed DVT or PE, or experienced a major

hemorrhage during the hospitalization were entered into the double-blind treatment phase. In

the double-blind phase, 435 patients with unilateral primary hip replacements, revision, or

previous joint replacements were randomized to a post discharge long-term regimen of

enoxaparin sodium 40 mg (n=224) qd SC or matching placebo (n=211) until a total of 28 days of

therapy was administered (mean treatment duration 19 days). Patients ranged in age from 26 to

88 years (mean age 63.4 years) in the placebo group and from 28 to 90 years (mean age 64.4

years) in the enoxaparin sodium group. The majority of patients were Caucasians with 49.9%

men and 50.1% women. The primary endpoint of this study was the incidence of venous

thromboembolism (VTE) during the double-blind treatment period. VTE constituted a treatment

failure.

Table 16 - Summary of patient demographics in clinical trials for extended prophylaxis of

venous thromboembolic disease following hip surgery

Study #

Trial design

Dosage, route of

administration and duration

Study subjects

(n=number)

Mean age

(Range)

Gender

(M/F)

307 (Hip)

Randomised, double-

blind, parallel group,

placebo-controlled,

multicentre study

To evaluate the efficacy

and safety of a

prolonged post-hospital

regimen of enoxaparin

compared to placebo

for the prevention of

venous thromboembolic

disease in patients

undergoing elective,

primary total hip

replacement.

Open label phase

Enoxaparin

30 mg SC b.i.d. initiated

within 12 to 24 hours post

surgery

Duration: for 7 to 10 days.

Double-blind phase

Enoxaparin

40 mg qd SC or

Placebo

qd SC

Duration: until a total of 28

days of therapy was

administered (mean: 19 days).

Total =

Total = 435

(randomized)

64.4 years

(28-90)

63.4 years

(26-88)

49.9% /50.1%

Study Results

Extended prophylaxis with enoxaparin sodium 40 mg qd SC resulted in statistically and clinically

significant reductions in the incidence rates of VTE as compared to placebo treatment. PE was

not observed in the enoxaparin sodium treatment group but 1 patient in the placebo treatment

group experienced both DVT and PE. An evaluation of the anatomic site of DVTs indicated a

clinically and statistically significant reduction of patients who experienced proximal or proximal

NOROMBY

Page 36 of 78

and distal DVTs. The effect was slightly less pronounced in patients with only distal DVT but

remained clinically apparent.

Table 17 - Efficacy of Enoxaparin sodium 40 mg qd SC in Extended Prophylaxis of DVT

Following Hip Replacement Surgery*

Endpoints

Dosing Regimen

p value

enoxaparin sodium

40 mg q.d. SC

n (% )

placebo qd SC

n (% )

All Treated Hip Replacement Patients

All Failures

DVT location

at least proximal

proximal

distal

proximal + distal

DVT & PE

18 (8.0)

6 (2.7)

4 (1.8)

12 (5.4)

2 (0.9)

0 (0.0% )

49 (23.2)

27 (12.8)

14 (6.6)

22 (10.4)

13 (6.2)

1 (0.5% )

<0.001

<0.001

* Multicentre study

Includes patients with proximal DVT and those with both proximal and distal DVT

Intraabdominal surgery

Two multicenter Phase III clinical trials (PK567 and PK568) were conducted in order to evaluate

the efficacy and safety of enoxaparin sodium in the prevention of deep vein thrombosis (DVT)

and pulmonary embolism (PE) in a total of 2462 patients undergoing colorectal and elective

curative cancer surgery. Both studies were double blind and used standard heparin 5000 units

subcutaneously every 8 hours as control; the study medication was initiated 2 hours

preoperatively and continued for 6 to 12 days.

Study demographics and trial design [PK567]

Abdominal surgery patients at risk include those who are over 40 years of age, obese,

undergoing surgery under general anesthesia lasting longer than 30 minutes or who have

additional risk factors such as malignancy or a history of deep vein thrombosis or pulmonary

embolism.

In a double-blind, parallel group study of patients undergoing elective cancer surgery of the

gastrointestinal, urological, or gynecological tract, a total of 1116 patients were enrolled in the

study, and 1115 patients were treated. Patients ranged in age from 32 to 97 years (mean age

67.1 years) with 52.7% men and 47.3% women. Patients were 98% Caucasian, 1.1% Black,

1.4% Oriental, and 0.4% others.

Table 18 - Summary of patient demographics in clinical trial PK567 for the prophylaxis of

deep vein thrombosis following abdominal surgery

NOROMBY

Page 37 of 78

Study #

Trial design

Dosage, route of

administration

and duration

Study

subjects

(n=number)

Mean

age

(range)

Gender

(M/F)

PK567

Multicentre, randomized,

double- blind, heparin-

controlled

To compare the safety and

efficacy of enoxaparin with

unfractionated

heparin for prevention of DVT in

patients after planned

elective cancer surgery

Enoxaparin

40 mg SC injection

once daily

HEPARIN

5000 units SC

injection three times

daily

Duration: 6 to 12 days

median duration:

enoxaparin 9 days,

heparin 8 days

Total: 1115

67.1

(32-97)

52.7% /47.3%

* In addition, the patients from enoxaparin group received 2 placebo injections

Study results

The primary efficacy variable was the incidence rate of VTE in all treated population. The aim of

the study was to demonstrate that enoxaparin sodium was at least as effective as heparin in

prevention of DVT in abdominal surgery patients. The efficacy data are provided below.

Table 19 - Efficacy of enoxaparin sodium injection in the prophylaxis of deep vein

thrombosis following abdominal surgery

Endpoints

Dosing Regimen

Enoxaparin sodium

40 mg q.d. SC

n (% )

Heparin

5000 U q8h SC

n (% )

All Treated Abdominal Surgery Patients

555 (100)

560 (100)

Treatment Failures

Total VTE

(% )

56 (10.1)

63 (11.3)

(95% CI

: 8 to 13)

(95% CI: 9 to 14)

DVT Only (%)

54 (9.7)

61 (10.9)

(95% CI: 7 to 12)

(95% CI: 8 to 13)

VTE = Venous thromboembolic events which included DVT, PE, and death considered to be thromboembolic in

origin. The observed difference between the heparin and the enoxaparin group was

1.16% [90% CI = -4.20%;

1.88% ]

CI = Confidence Interval

Enoxaparin sodium injection 40 mg SC, administered once a day, beginning 2 hours prior to

surgery and continuing for a maximum of 12 days after elective cancer surgery, was found to be

as effective as heparin 5000 units every 8 hours SC in reducing the risk of deep vein thrombosis

(DVT).

NOROMBY

Page 38 of 78

Study demographics and trial design [PK568]

In a second double-blind, parallel group study, enoxaparin sodium injection 40 mg SC once a

day was compared to heparin 5000 units every 8 hours SC in patients undergoing colorectal

surgery (one- third with cancer). A total of 1347 patients were randomized in the study and all

patients were treated. Patients ranged in age from 18 to 92 years (mean age 50.1 years) with

54.2% men and 45.8% women.

Table 20 - Summary of patient demographics in clinical trial PK568 for the prophylaxis of

deep vein thrombosis following colorectal surgery

Study #

Trial design

Dosage, route of

administration

and duration

Study

subjects

(n=number)

Mean age

(range)

Gender

(M/F)

PK568

Multicentre, randomized,

double-blind

To compare the efficacy

and safety enoxaparin

with calcium heparin for

prevention of DVT in

patients undergoing

colorectal surgery

Enoxaparin

40 mg SC injection

once daily

Heparin

5000 units SC

injection, three times

daily

Duration: 7-10 days

Follow-up: 6 weeks

Total: 1347

50.1

54.2% /45.8%

(18 - 92)

In addition, the patients from enoxaparin group received 2 placebo injections

Study results

Treatment was initiated approximately 2 hours prior to surgery and continued for approximately

7 to 10 days after surgery. The primary efficacy variable was the incidence rate of VTE in the

all-treated population. The primary objective of the study was to demonstrate that enoxaparin

sodium was at least as effective as heparin in preventing of DVT. The efficacy data are provided

below.

Table 21 - Efficacy of Enoxaparin sodium injection in the prophylaxis of deep vein

thrombosis following colorectal surgery

Endpoints

Dosing Regimen

enoxaparin sodium

40 mg q.d. SC

n (% )

Heparin

5000 U q8h SC

n (% )

All Treated Colorectal Surgery Patients

673 (100)

674 (100)

Treatment Failures

Total VTE

(% )

48 (7.1)

45 (6.7)

(95% CI

: 5 to 9)

(95% CI: 5 to 9)

DVT Only (%)

47 (7.0)

44 (6.5)

(95% CI: 5 to 9)

(95% CI: 5 to 8)

In patients undergoing colorectal surgery treated for a maximum of 10 days, enoxaparin sodium

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40 mg once daily was found to be as effective as heparin 5000 units three times daily in the

prevention of VTE disease.

Prophylaxis of Venous Thromboembolism (VTE) In Medical Patients with Severely

Restricted Mobility During Acute Illness

Study demographics and trial design [MEDENOX (ENX395006)]

In a double blind multicenter, parallel group study, enoxaparin sodium injection 20 mg or 40 mg

once a day SC was compared to placebo in the prophylaxis of VTE in medical patients with

severely restricted mobility during acute illness. This study included patients with heart failure

(NYHA Class III or IV); acute respiratory failure or complicated chronic respiratory insufficiency

(not requiring ventilatory support); acute infection (excluding septic shock); or acute rheumatic

disorder [acute lumbar or sciatic pain, vertebral compression (due to osteoporosis or tumor),

acute arthritic episodes of the lower extremities]. A total of 1102 patients were enrolled in the

study, and 1073 patients were treated. A number of 866 patients were assessed for the

incidence of venous thromboembolism. Patients ranged in age from 41 to 97 years (mean age

73.55 years) with 50.35% men and 49.65% women. Treatment continued for a maximum of 14

days (median duration 7 days), and patients were followed-up at day 90.

Table 22 - Summary of patient demographics in clinical trial for the prophylaxis of deep

vein thrombosis in medical patients with severely restricted mobility during acute illness

Study #

Trial design

Dosage, route of

administration

and duration

Study

subjects

(n=number)

Mean age

(range)

Gender

(M/F)

MEDENOX

(ENX395006)

Multicenter,

randomized,

double- blind,

parallel group

To evaluate the

safety and efficacy

of two doses of

enoxaparin for

prevention of VTE

in hospitalized

patient with acute

medical disorders.

40 mg or 20

mg* enoxaparin

or placebo, SC,

once daily

Duration: 6-14 days

Follow-up: 3 months

Total: 866

Enoxaparin

20 mg: 287

40 mg: 291

Placebo: 288

73.55

(41 - 97)

49.65%/50.35%

There were no differences between enoxaparin sodium 20 mg and the placebo groups. Enoxaparin sodium 20

mg is not an approved dose in Canada.

Study results

The primary outcome was venous thromboembolism between days 1 and 14, defined as deep

vein thrombosis detected by bilateral venography (or duplex ultrasonography) between days 6

and 14 (or earlier if clinically indicated) or documented pulmonary embolism. The duration of

follow-up was 3 months. The efficacy data are provided below.

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Table 23 - Efficacy of Enoxaparin sodium injection in the prophylaxis of deep vein

thrombosis in medical patients with severely restricted mobility during acute illness.

Endpoints

Dosing Regimen

enoxaparin sodium

40 mg q.d. SC

n (% )

Placebo

n (% )

Patients randomized and assessed for primary efficacy

291 (100)

288 (100)

Treatment Failure

Total VTE

(% )

16 (5.5)

43 (14.9)

Total DVT (% )

16 (5.5)

40 (13.9)

Proximal DVT (%)

5 (1.7)

14 (4.9)

Treatment failures during therapy, between Days 1 and 14.

VTE = Venous thromboembolic events which included DVT, PE, and death considered to be thromboembolic in origin.

When given at a dose of 40 mg once a day SC, enoxaparin sodium injection significantly

reduced the incidence of DVT as compared to placebo. The relative risk reduction for total VTE

events was 63% (95% CI = [37%; 78%], p= 0.0002). At approximately 3 months following

enrollment, the incidence of venous thromboembolism remained significantly lower in the

enoxaparin sodium injection 40 mg treatment group (19/272, 6.98%) versus the placebo

treatment group (45/263, 17.11%), with a relative risk of 0.41 (95% CI between 0.25 and 0.68,

p=0.0003).

Treatment of Deep Vein Thrombosis (DVT) with or without Pulmonary Embolism (PE)

The safety and efficacy of enoxaparin in the treatment of DVT with or without PE has been

evaluated in 2 clinical trials (PK529 and CPK2091) involving 1401 patients.

Study demographics and trial design [PK529]

In a multicenter, parallel group study, 900 patients with acute lower extremity DVT with or

without PE were randomized to an inpatient (hospital) treatment of either (i) enoxaparin sodium

injection 1.5 mg/kg once a day SC, (ii) enoxaparin sodium injection 1 mg/kg every 12 hours SC,

or (iii) heparin IV bolus (5000 units) followed by a continuous infusion (administered to achieve

an aPTT of 55 to 85 seconds). A total of 900 patients were randomized in the study and all

patients were treated. Patients ranged in age from 18 to 92 years (mean age 60.7 years) with

54.7% men and 45.3% women. All patients also received warfarin sodium (dose adjusted

according to PT to achieve an International Normalization Ratio [INR] of 2.0 to 3.0),

commencing within 72 hours of initiation of enoxaparin sodium injection or standard heparin

therapy, and continuing for 90 days. enoxaparin sodium injection or standard heparin therapy

was administered for a minimum of 5 days and until the targeted warfarin sodium INR was

achieved.

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Table 24 - Summary of patient demographics in clinical trial comparing the efficacy of

enoxaparin sodium with heparin for treatment of venous thromboembolic disease.

Study #

Trial design

Dosage*, route of

administration and

duration

Study

subjects

(n=number)

Mean age (range)

Gender

(M/F)

PK529

Multicenter,

randomized,

controlled, partially

blind, parallel

group

To compare the

efficacy and safety

of enoxaparin with

heparin in the

treatment of DVT

with or without

pulmonary

embolism

Enoxaparin

1 mg/kg SC twice daily or

1.5 mg/kg once daily

Heparin

IV bolus (5000 U) followed

by a continuous infusion

Duration: minimum of

5 days and until the

targeted warfarin sodium

INR was achieved

median duration: 7 days

Total=900

60.7

(18 - 92)

54.7% /45.3%

* All patients also received warfarin sodium

Study results

The primary objective of this study was to demonstrate that enoxaparin sodium was as effective

as heparin in the heparin group and both the once and twice-daily enoxaparin sodium treatment

groups for the incidence of recurrent deep venous thrombosis or pulmonary embolism within 3

month of randomization in all treated patients. The efficacy data are provided below.

Table 25 - Efficacy of enoxaparin sodium injection in treatment of deep vein thrombosis

with or without pulmonary embolism.

Endpoints

Dosing Regimen

1

enoxaparin sodium

1.5 mg/kg q.d. SC

n (%)

enoxaparin sodium

1 mg/kg q12h SC

n (%)

Heparin

aPTT

Adjusted IV

Therapy

n (%)

All Treated DVT Patients with or without PE

298 (100)

312 (100)

290 (100)

Patient Outcome

Total VTE

13 (4.4)

9 (2.9)

12 (4.1)

DVT Only (%)

11 (3.7)

7 (2.2)

8 (2.8)

Proximal DVT (%)

9 (3.0)

6 (1.9)

7 (2.4)

PE (%)

2 (0.7)

2 (0.6)

4 (1.4)

All patients were also treated with warfarin sodium commencing within 72 hours of Enoxaparin sodium

Injection or standard heparin therapy.

VTE = venous thromboembolic event (DVT and/or PE).

The 95% Confidence Intervals for the treatment differences for total VTE were: Enoxaparin sodium Injection

once a day versus heparin (-3.0 to 3.5) Enoxaparin sodium Injection every 12 hours versus heparin (-4.2 to 1.7).

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Enoxaparin sodium administered as a 1 mg/kg twice-daily regimen or a 1.5 mg/kg once-daily

regimen was found to be as effective as the regimen of adjusted-dose, continuous infusion

heparin therapy for the prevention of recurrent VTE disease in patients with acute deep vein

thrombosis with or without pulmonary embolism.

Study demographics and trial design [CPK2091]

Similarly, in a multicenter, open-label, parallel group study, patients with acute proximal DVT

were randomized to enoxaparin sodium injection or heparin. Patients who could not receive

outpatient therapy were excluded from entering the study. Outpatient exclusion criteria included

the following: inability to receive outpatient heparin therapy because of associated co-morbid

conditions or potential for non-compliance and inability to attend follow-up visits as an outpatient

because of geographic inaccessibility. Eligible patients could be treated in the hospital, but

ONLY enoxaparin sodium injection patients were permitted to go home on therapy (72%). A

total of 501 patients were randomized in the study and all patients were treated. Patients ranged

in age from 19 to 96 years (mean age 57.8 years) with 60.5% men and 39.5% women. Patients

were randomized to either enoxaparin sodium injection 1 mg/kg every 12 hours SC or heparin

IV bolus (5000 units) followed by a continuous infusion administered to achieve an aPTT of 60

to 85 seconds (in-patient treatment). All patients also received warfarin sodium as described in

the previous study. Enoxaparin sodium injection or standard heparin therapy was administered

for a minimum of 5 days.

Table 26 - Summary of patient demographics in CPK2091 clinical trial comparing the

efficacy of ENOXAPARIN SODIUM with heparin for treatment of deep vein thrombosis.

Study #

Trial design

Dosage

*

, route of

administration and

duration

Study subjects

(n=number)

Mean age

(range)

Gender

CPK2091

Multicenter,

randomized, open

label, parallel group

To compare the

efficacy and safety of

outpatient

enoxaparin regimen

with standard

inpatient heparin

regimen in reducing

the risk of recurrent

venous

thromboembolism

Enoxaparin

1mg/kg twice daily

Heparin

IV - bolus (5000 U) followed

by a continuous infusion of

20000 U

Duration: 5 days

median duration for all

groups: 6 days

Follow-up: 3 months

Total = 501

(19 - 96)

60.5% /39.5%

All patients also received warfarin sodium

Study results

The primary efficacy endpoint was the incidence of VTE disease in all-treated patients. The

primary objective in patients with acute proximal DVT was to compare the efficacy and safety of

outpatient anticoagulant regimen consisting of fixed-dose subcutaneous enoxaparin sodium

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injection with a standard inpatient anticoagulant regimen consisting of unfractionated heparin

administered by continuous intravenous infusion. The efficacy data are provided below.

Table 27 - Efficacy of enoxaparin sodium in treatment of deep vein thrombosis

Endpoints

Dosing Regimen

1

Enoxaparin sodium

1 mg/kg q12h SC

n (% )

Heparin

aPTT Adjusted

IV Therapy

n (% )

All Treated DVT Patients

Patient Outcome

Total VTE

(% )

DVT Only (%)

Proximal DVT (%)

PE (% )

247 (100)

13 (5.3)

11 (4.5)

10 (4.0)

2 (0.8)

254 (100)

17 (6.7)

14 (5.5)

12 (4.7)

3 (1.2)

All patients were also treated with warfarin sodium commencing on the evening of the second day of ENOXAPARIN

SODIUM Injection or standard heparin therapy.

VTE = venous thromboembolic event (deep vein thrombosis [DVT] and/or pulmonary embolism [PE]).

The 95% Confidence Intervals for the treatment difference for total VTE was: heparin vs ENOXAPARIN SODIUM injection (-

2.72, 5.58)

In patients with proximal DVT, enoxaparin sodium injection given as a fixed dose of 1 mg/kg SC

twice daily was found to be as effective as standard heparin therapy administered as a

continuous IV infusion in reducing the risk of recurrent VTE.

Prophylaxis of Ischemic Complications in Unstable Angina and Non-Q-Wave Myocardial

Infarction

Study demographics and trial design [ESSENCE - RP54563q-303]

In a multicenter, double-blind, parallel group study, patients who recently experienced unstable

angina or non-Q-wave myocardial infarction were randomized to either enoxaparin sodium

injection 1 mg/kg every 12 hours SC or heparin IV bolus (5000 units) followed by a continuous

infusion (adjusted to achieve an aPTT of 55 to 85 seconds). A total of 3171 patients were

enrolled in the study, and 3107 patients were treated. Patients ranged in age from 25-94 years

(median age years), with 33.6% of patients female and 66.4% male. Race was distributed as

follows: 89.8% Caucasian, 4.8% Black, 2.0% Oriental, and 3.5% other. All patients were also

treated with aspirin 100 to 325 mg per day. Treatment was initiated within 24 hours of the event

and continued until clinical stabilization, revascularization procedures, or hospital discharge,

with a maximal duration of 8 days of therapy.

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Table 28 - Summary of patient demographics for clinical trial of enoxaparin sodium

injection in the prophylaxis of ischemic complications in unstable angina and non -Q-

wave myocardial infarction

Study #

Trial design

Dosage, route of

administration

and duration

Study

subjects

(n=number)

Mean

age

(range)

Gender

(M/F)

ESSENCE (Efficacy

and Safety of

Subcutaneous

Enoxaparin in Non-Q

wave Coronary

Events)

RP54563q-303

Multicenter,

randomized, double-

blind, placebo-

controlled

To compare efficacy

and safety of

enoxaparin with

heparin

in preventing ischemic

complications in

patients with

UA/NQMI

Enoxaparin

1 mg/kg

subcutaneously, twice

daily

Heparin

IV- bolus (5000 U)

followed by a

continuous infusion

Duration: 48 h-8 days

median duration: 2.6

days

Total = 3107

1578

1529

63.7

66.4%/33.6%

(25-94)

All patients were also treated with aspirin 100 to 325 mg per day

Study results

The primary efficacy parameter was the incidence of the composite triple endpoint of death,

myocardial infarction (MI), and recurrent angina at day 14. The efficacy data are provided

below.

Table 29 - Efficacy of enoxaparin sodium injection in the prophylaxis of ischemic

complications in unstable angina and non-Q-wave myocardial infarction (combined

endpoint of death, myocardial infarction, or recurrent angina)

Endpoints

Dosing Regimen

1

Enoxaparin

sodium

1 mg/kg q12h SC

n (%)

Heparin

aPTT

Adjusted IV

Therapy

n (%)

Reduction

p Value

All Treated Unstable Angina and Non-Q-Wave MI

Patients

1578 (100)

1529 (100)

0.120

Timepoint

48 Hours

96 (6.1)

112 (7.3)

14 Days

261 (16.5)

303 (19.8)

0.017

All patients were also treated with aspirin 100 to 325 mg per day.

Evaluation timepoints are after initiation of treatment. Therapy continued for up to 8 days (median duration of 2.6 days).

No capping of dose based on patient weight

The combined incidence of the triple endpoint (death, MI, recurrent angina) was significantly

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lower for enoxaparin sodium injection compared with heparin therapy at 14 days after initiation

of treatment in all-treated patients (16.5% vs 19.8%, p = 0.017). The lower incidence of the triple

endpoint was sustained up to 30 days after initiation of treatment (19.8% in enoxaparin sodium

group vs 23.3% in heparin group, p=0.016). These results were observed in an analysis of both

all- randomized and all-treated patients.

Benefit of enoxaparin sodium beyond 30 days post-treatment period, up to 1 year

The ESSENCE – 1 year follow-up study and TIMI 11B clinical trial evaluated the benefits of

enoxaparin sodium beyond 30 days post-treatment period up to 1 year.

Study demographics and trial design [ESSENCE – 1-year follow-up]

In order to determine whether or not the observed superiority of enoxaparin sodium over

heparin shown in the early phase of ESSENCE trial persisted during long-term follow-up, a one-

year follow-up survey was undertaken in all patients enrolled in the ESSENCE study. The one-

year follow-up period was defined as time of randomization through one-year assessment or

last contact. A retrospective collection of data was organized 1 year after the end of the study,

whereby each site was requested to contact by telephone all randomized patients, and to

provide the appropriate documentation concerning the efficacy endpoints. Complete information

from 2915 patients was finally available, and 2992 patients had information available on their

vital status at one year. Patients not reported as dead after the research were still considered

lost to follow-up for the purpose of the analysis.

Table 30 - Summary of patient demographics for ESSENCE – 1-year follow-up clinical

trial

Study #

Trial design

Dosage, route of

administration and

duration

Study

subjects

(n=number)

Mean

age

(range)

Gender

(M/F)

ESSENCE – 1-

year follow-up

Retrospective

collection of

data

See ESSENCE clinical trial

Total = 2915

enoxaparin : 1469

heparin : 1446

(25-94)

66.1/33.9%

Study results

For this study, the same composite triple end-point of death, MI or recurrent angina was used,

and the time to first composite triple end-point was the primary outcome. The efficacy data are

provided below.

Table 31 - Summary of major event incidence from randomization to 1 year follow-up in

the ESSENCE – 1-year follow-up study

Endpoints

Enoxaparin

sodium

1

n (est.%)

*

Heparin

n (est%)

*

Hazard ratio

Log Rank

P value

Number of patients

1607

1564

0.87

0.0217

Triple endpoint

498 (32.0)

543 (35.7)

Death (including resuscitated)

94 (6.0)

114 (7.5)

0.80

0.0995

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Endpoints

Enoxaparin

sodium

1

n (est.%)

*

Heparin

n (est%)

*

Hazard ratio

Log Rank

P value

Myocardial infarction

106 (7.0)

123 (8.2)

0.83

0.1613

Recurrent angina

394 (25.7)

417 (28.0))

0.90

0.1207

* est.% = percentages obtained from Kaplan-Meyer curves (estimated probabilities taking into account the patients

lost to follow-up) Incidences of the components of triple endpoints are not mutually exclusive.

Deaths include 31 (19 heparin, 12 enoxaparin) resuscitations through 12 months.

No capping of dose based on patient weight

The primary efficacy parameter was significantly lower in patients assigned to enoxaparin

sodium compared to heparin (32% vs 35.7% respectively, p = 0.0217). The rates of cardiac

catheterizations (55.8% vs 59.4%, p=0.036) as well as the rates of revascularizations (35.9%vs

41.2%, p=0.002) were significantly lower in the enoxaparin sodium group than in the heparin

group.

Study demographics and trial design [TIMI 11B]

Study TIMI 11B was a multicenter, randomized, double-blind, double-dummy, parallel group

clinical trial designed to evaluate the efficacy and safety of uninterrupted subcutaneous

treatment with enoxaparin sodium vs heparin in patients with unstable angina/non-Q-wave

myocardial infarction (UA/NQMI). The study consisted of two phases of treatment: (1) an acute

phase – in-hospital treatment of weight-based medication, and (2) a chronic phase, consisted of

out-patient treatment with study medication, for 35 days, starting from hospital discharge or

days 8, whichever came first. The medication consisted of heparin for ≥ 3 days followed by SC

placebo injections or continuous antithrombin therapy with enoxaparin sodium during both the

acute phase (30 mg IV bolus, followed by 1 mg/kg every 12 hours) and outpatient phase (40 –

60 mg every 12 hours). A total number of 3910 were randomized; 3874 patients were treated

during the acute phase and 2364 during the chronic phase. Median age was 64.3 years (range

29-93 years) with 64.8% males and 35.2 % females.

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Table 32 - Summary of patient demographics for TIMI 11B clinical trial

Study #

Trial

design

Dosage, route of administration and

duration

Study

subjects

(n=number)

Mean

age

(range)

*

*

Gender

*

*

(M/F)

TIMI 11B

(Thrombolysi

In Myocardial

Infarction)

Multicenter,

randomized,

double-blind,

double-

dummy,

parallel

group

To assess the

effect of

enoxaparin

compared to

HEPARIN

in the

management

of patients

with

UA/NQMI

Acute Phase

(Weight Adjusted treatment)

IV boluses

injection

infusion

Enox aparin

E noxaparin

30 mg

Placebo 70

U/kg

Enoxaparin

1.0 mg/kg

q 12 h

Matching

placebo

HEPARIN*

HEPARIN

70 U/kg

Placebo 30

Matching

placebo

HEPARIN

15 U/kg/h

*Adjusted to an aPTT of 1.5-2.5 x control

Duration: until hospital discharge or day 8

Median duration:

enoxaparin: 4.63 days, heparin 3.02 days

Total = 3874

1938

1936

64.3

(29-93)

64.8%/35.2%

Chronic Phase

(Fixed-dose treatment)

SC injection

Enox aparin

Enoxaparin

≥ 65 kg – 60 mg q 12 h

< 65 kg – 40 mg q 12 h

HEPARIN*

Matching placebo

*Adjusted to an aPTT of 1.5-2.5 x control

Duration: 35 days

Total = 2364

1179

1185

Median duration:

enoxaparin 34.4 days, heparin 34.5 days

Follow-up: 3 months, 1 year

* Both treatment groups received 100-325 mg aspirin daily

** All-randomized patients

Study results

The primary study objective was to demonstrate that a strategy of uninterrupted aspirin and SC

administration of weight-adjusted enoxaparin sodium, followed by fixed-dose enoxaparin sodium

for up to 43 days was superior to a strategy of short-term heparin and aspirin for the prevention

of death, nonfatal (re)infarction, and severe recurrent ischemia requiring urgent

revascularization in patients with unstable angina and non-Q-wave myocardial infarction. The

efficacy data are provided below.

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Table 33 - Summary of efficacy data of enoxaparin sodium injection in patients with

unstable angina and non-Q-wave myocardial infarction (TIMI 11B clinical trial)

1

Endpoints

Enoxaparin

sodium

4

N=1953 n

(% )

Heparin

N=1957

n (% )

Odds Ratio

(95% CI)

Triple endpoint

337 (17.3)

385 (19.7)

0.85 (0.72; 1.00)

Death

75 (3.8)

78 (4.0)

0.96 (0.69; 1.33)

107 (5.5)

129 (6.6)

0.82 (0.63; 1.07)

Recurrent angina leading to urgent

revascularization

208 (10.7)

247 (12.6)

0.82 (0.67; 1.00)

All-randomized population

Through day 43

p = 0.048

No capping of dose based on patient weight

Table 34 - Incidence of triple endpoint at different timepoints in patients with unstable

angina and non-Q-wave myocardial infarction (TIMI 11B clinical trial).

Timepoint

enoxaparin sodium

N=1953

n (% )

Heparin

N=1957

n (% )

Odds ratio

95% CI for

odds ratio

P value

48 hours

108 (5.5)

142 (7.3)

0.75

(0.58, 0.97)

0.026

Day 8

242 (12.4)

284 (14.5)

0.83

(0.69, 1.00)

0.048

Day 14

277 (14.2)

326 (16.7)

0.82

(0.69, 0.98)

0.029

Day 43

337 (17.3)

385 (19.7)

0.85

(0.72, 1.00)

0.048

At 43 days, the incidence of the triple endpoint (death, MI or severe recurrent ischemia requiring

urgent revascularization) was lower with enoxaparin sodium than with heparin (17.3% vs 19.7%

respectively), representing a 12.3% relative risk reduction (p=0.048). A significant reduction in

the incidence of triple endpoint was also consistently observed at 48 hours, 8 days and 14 days.

The double endpoint (death or MI) was also consistently reduced at all timepoints, although the

reduction did not achieve statistical significance.

Treatment of acute ST-segment Elevation Myocardial Infarction (STEMI)

Study demographics and trial design [XRP4563B/3001 ExTRACT-TIMI 25]

In a multicenter, double-blind, double-dummy, parallel group study (XRP4563B/3001 ExTRACT-

TIMI 25), patients with STEMI who were eligible to receive fibrinolytic therapy were randomized

in a 1:1 ratio to receive either enoxaparin sodium or unfractionated heparin. All patients were

also treated with aspirin for a minimum of 30 days. Study medication was administered between

15 minutes before and 30 minutes after the initiation of fibrinolytic therapy. Unfractionated

heparin was administered beginning with an IV bolus of 60 U/kg (maximum 4000 U) and

followed with an infusion of 12 U/kg per hour (initial maximum 1000 U per hour) that was

adjusted to maintain an aPTT of 1.5 to 2.0 times the control value. The IV infusion was to be

given for at least 48 hours. The enoxaparin dosing strategy was adjusted according to the

patient’s age and renal function. For patients younger than 75 years of age, enoxaparin was

given as a single 30-mg intravenous bolus plus a 1 mg/kg SC dose followed by an SC injection

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of 1.0 mg/kg every 12 hours. For patients at least 75 years of age, the IV bolus was not given

and the SC dose was reduced to 0.75 mg/kg every 12 hours. For patients with severe renal

insufficiency (estimated creatinine clearance of less than 30 ml per minute), the dose was to be

modified to 1.0 mg per kilogram every 24 hours. The SC injections of enoxaparin were given

until hospital discharge or for a maximum of eight days (whichever came first).

When percutaneous coronary intervention was performed during study medication period,

patients were to receive antithrombotic support with blinded study drug. Therefore, for patients

on enoxaparin, the PCI was to be performed on enoxaparin (no switch) using the regimen

established in previous studies, i.e. no additional dosing, if the last SC administration given less

than 8 hours before balloon inflation, IV bolus of 0.3 mg/kg enoxaparin-if the last SC

administration given more than 8 hours before balloon inflation.

A total of 20,506 patients were enrolled in the study, and 20,479 patients were included in the

ITT population. Patients ranged in age from 20-99 years (mean age 59.8 years), with 23.5 % of

patients female and 76.5 % male. Race was distributed as follows: 87.2% Caucasian, 0.2%

Black, 9.8% Asian, and 2.8 % other. A fibrinolytic agent was administered to all but 4 patients,

with 79.8% receiving a fibrin-specific agent and 20.2% receiving streptokinase. 4,716 patients

underwent percutaneous coronary interventions.

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Table 35 - Summary of patient demographics for the treatment of acute ST-segment

Elevation Myocardial Infarction (STEMI)

Study #

Trial design

Dosage, route of administration and duration

Study subjects

(n=number)

Mean age

(Range)

Gender

(M/F)

XRP4563B/3001

ExTRACT -TIMI

Randomized,

double-blind,

double-dummy,

parallel group,

multinational

study.

To evaluate the

efficacy and

safety of

enoxaparin versus

HEPARIN in

patients with

acute STEMI

receiving

fibrinolytic therapy

Enoxaparin

Patients <75 Years of Age

Initial 30 mg IV bolus, followed by 1.0

mg/kg SC injection (maximum 100

mg/injection for first 2 injections) Q12h

(first SC dose to be given within 15 min

of IV bolus)

Patients

75 Years of Age

(No bolus)

0.75 mg/kg SC injection (maximum

75 mg/injection for first 2 injections)

Q12h

Patients with CrCl <30 mL/min

ab

Initial 30 mg IV bolus, followed by1.0

mg/kg SC injection Q24h (first SC dose to

be given within 15 min of IV bolus)

Duration of treatment: 8 days

HEPARIN

All patients:

Initial 60 U/kg IV bolus (maximum 4000

U), followed by continuous infusion

(initially at 12 U/kg per h) maximum

1000 U/h with adjustment as per aPTT

(start of infusion within 15 min of IV

bolus)

Duration of treatment: 48 hours

Total = 20 479

10 256

10 223

59.8

(20- 99)

59.9

(20- 98)

7841/2415

7855/2368

a

Subjects with known severe renal impairment at baseline were excluded from the study.

b

In subjects ≥75 years of age, no IV bolus was to be administered.

STEMI = ST-segment elevation myocardial infarction; IV = intravenous; SC = subcutaneous; PCI =

percutaneous intervention; CrCl = creatinine clearance; NA = not applicable

Study Results

The primary efficacy end point was the composite of death from any cause or myocardial re-

infarction in the first 30 days after randomization.

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The efficacy data provided below, show that the rate of the primary efficacy end point (death or

myocardial re-infarction) was 9.9% in the enoxaparin group, as compared with 12.0% in the

unfractionated heparin group, that is a 2.1% reduction in the absolute risk, representing a 17%

reduction in the relative risk, (P<0.001).

Table 36 Efficacy of enoxaparin sodium Injection in the treatment of acute ST-segment

Elevation Myocardial Infarction

Primary Endpoints

Enoxaparin

(N=10,256)

n (% )

HEPARIN

(N=10,223)

n (% )

Reduction in

Absolute Risk

(% )

Relative Risk

(95% CI)

P

Value

Outcome at 48 hours

478 (4.7)

531 (5.2)

0.90 (0.80 to 1.01)

0.08

Death or Myocardial Re-

infarction

Death

383 (3.7)

390 (3.8)

0.98 (0.85 to 1.12)

0.76

Myocardial Re-infarction

102 (1.0)

156 (1.5)

0.65 (0.51 to 0.84)

<0.001

Urgent Revascularization

74 (0.7)

96 (0.9)

0.77 (0.57 to 1.04)

0.09

Death or Myocardial Re-

548 (5.3)

622 (6.1)

0.88 (0.79 to 0.98)

0.02

infarction or Urgent

Revascularization

Outcome at 8 Days

740 (7.2)

954 (9.3)

0.77 (0.71 to 0.85)

<0.001

Death or Myocardial Re-

infarction

Death

559 (5.5)

605 (5.9)

0.92 (0.82 to 1.03)

0.15

Myocardial Re-infarction

204 (2.0)

379 (3.7)

0.54 (0.45 to 0.63)

<0.001

Urgent Revascularization

145 (1.4)

247 (2.4)

0.59 (0.48 to 0.72)

<0.001

Death or Myocardial Re-

874 (8.5)

1181 (11.6)

0.74 (0.68 to 0.80)

<0.001

infarction or Urgent

Revascularization

Outcome at 30 Days

1017 (9.9)

1223 (12.0)

2.1

0.83 (0.77 to 0.90)

<0.001

Primary efficacy endpoint

(Death or Myocardial Re-

infarction)

Death

708 (6.9)

765 (7.5)

0.92 (0.84 to 1.02)

0.11

Myocardial Re-infarction

352 (3.4)

508 (5.0)

0.69 (0.60 to 0.79)

<0.001

Urgent Revascularization

213 (2.1)

286 (2.8)

0.74 (0.62 to 0.88)

<0.001

Death or Myocardial Re-

1199 (11.7)

1479 (14.5)

0.81 (0.75 to 0.87)

<0.001

infarction or Urgent

Revascularization

Note: Urgent revascularization denotes episodes of recurrent myocardial ischemia (without infarction)

leading to the clinical decision to perform coronary revascularization during the same hospitalization. CI

denotes confidence intervals.

The treatment benefits of enoxaparin, evident for a number of efficacy outcomes, emerged at 48

hours, at which time there was a 35% reduction in the relative risk of myocardial re- infarction,

representing an absolute risk reduction of 0.5%, as compared with treatment with unfractionated

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heparin (p < 0.0001). The beneficial effect of enoxaparin on the primary end point was

consistent across key subgroups including age, gender, infarct location, history of diabetes,

history of prior myocardial infarction, fibrinolytic administered, and time to treatment with study

drug (see figure 1).

Figure 1. Relative Risks of and Absolute Event Rates for the Primary End Point at 30

Days in Various Subgroups.

The primary efficacy end point was the composite of death from any cause or myocardial re-

infarction in the first 30 days. The overall treatment effect of enoxaparin as compared to the

unfractionated heparin is shown at the bottom of the figure. For each subgroup, the circle is

proportional to the number and represents the point estimate of the treatment effect and the

horizontal lines represent the 95 percent confidence intervals. Fibrin-specific fibrinolytic agents

included alteplase, tenecteplase and reteplase. Time to treatment indicates the time from the

onset of symptoms to the administration of study drug (median, 3.2 hours). Although there was

some variation in the estimate of the treatment effect of enoxaparin on the primary endpoint

across the subgroups shown, all P values in tests for interaction were non significant.

There was a significant treatment benefit of enoxaparin, as compared with unfractionated

heparin, in patients who underwent percutaneous coronary intervention within 30 days after

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randomization (23% relative risk reduction, representing an absolute risk reduction of 3.1%) or

who were treated medically (15 % relative risk reduction, representing an absolute risk reduction

of 1.7%, P = 0.27 for interaction).

The rate of the 30-day composite endpoint of death, myocardial re-infarction or ICH (a measure

of net clinical benefit) was significantly lower (p<0.0001) in the enoxaparin group (10.1%) as

compared to the heparin group (12.2%), representing a 2.1% absolute risk reduction and a 17%

relative risk reduction in favor of treatment with enoxaparin sodium.

Benefit of ENOXAPARIN SODIUM beyond 30 days post-treatment period, up to 1 year for

the treatment of acute STEMI

The ExTRACT – 1 year follow-up study evaluated the benefits of enoxaparin sodium beyond 30

days post-treatment period up to 1 year.

Study demographics and trial design [ExTRACT – 1-year follow-up]

In order to determine whether or not the clinical benefits of enoxaparin sodium shown in the

early phase of ExTRACT trial persisted over-time, a one-year follow-up survey was undertaken

in all patients enrolled in the ExTRACT study. The main objective of the follow-up period was to

assess the subject status at 6-months and 12-months (mortality, myocardial re-infarction,

disabling stroke, or re- hospitalization). The one-year follow-up period was defined as time of

randomization through one-year assessment or last contact (documented by phone contact or

patient record). Complete 1 year information from 18 160 (88.7%) patients was available. Two

thousand three hundred and twelve (11.3%) patients discontinued from the study. The primary

reasons for discontinuation are: death 2115 (10.3%), discontinuation for other reasons 90

(0.4%), lost to follow-up 107 (0.5 %).

Table 37 - Summary of patient demographics for ExTRACT – 1-year follow-up

Study #

Trial design

Dosage, route of administration

and duration

Study subjects

(n=number)

Mean age

(range)

Gender

(M/F)

ExTRACT – 1-

year follow-up

1 year

collection of

data

See table 28 above for

ExTRACT Dosage, route of

administration and duration

During the additional follow-up

period subjects were off study

medication.

Total: 20 479

18 160

(with long

term follow-

enoxaparin : 9098

heparin : 9062

58.8

(20-99)

58.9

(20-92)

7102/1996

7160/1902

Study results

There was a statistically significant difference (p = 0.0111, log-rank test, hazard ratio [HR] =

0.92) in favor of the enoxaparin group compared with the UFH group with respect to time to

death or myocardial re-infarction at 12 months as assessed by survival analysis (log-rank test).

The beneficial effect of enoxaparin on the composite primary end point (death or myocardial re -

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infarction) observed during the first 30 days was maintained over a 12 month follow-up period

(see Figure 2). The relative risk reduction in the composite endpoint of death from any cause or

myocardial re-infarction observed in the first 30 days after randomization and at 12 months was

17% and 8% respectively.

Table 38 – Results from Cox Regression and Kaplan Meir over 12 months – ITT

population

Parameter

Enoxaparin

UFH

Enox vs UFH

hazard ratio

b

95% CI of HR

p-value

a

N

n

N

n

Main Clinical endpoint

10256

10223

Death or myocardial re-

infarction

1614

1732

0.92

[0.86-0.98]

0.0111

Additional component endpoints

10256

10223

Death or myocardial re-

infarction, or disabling stroke

1638

1765

0.91

[0.85-0.98]

0.0069

Individual component endpoints

10 256

10223

Death

1075

1085

0.98

[0.90 – 1.07]

0.7145

Myocardial re-infarction

0.84

[0.76 - 0.94]

0.0013

Disabling stroke

0.97

[0.75 – 1.26]

0.8121

Re-hospitalization

2873

2742

1.05

[0.99 – 1.10]

0.0849

Note: Re-hospitalization was for a cardiac/vascular reason.

a

log-rank test

b

unadjusted Cox Regression

ITT = intent to treat population; UFH = unfractionated heparin; Enox = enoxaparin, vs = versus, N = population size; n =

number of subjects with events

CI = confidence interval; HR = hazard ratio

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Figure 2. Kaplan-Meier plot - death or myocardial re-infarction at 30 days and at 1 year -

ITT population

Prevention of thrombus formation in the extracorporeal circulation during hemodialysis

Information to support the safety and efficacy of enoxaparin sodium in the prevention of

thrombus formation in the extracorporeal circulation during hemodialysis comes from three

published studies.

16

NON-CLINICAL TOXICOLOGY – REFERENCE BIOLOGIC DRUG

Acute Toxicity

Acute toxicity studies in enoxaparin sodium were carried out with both sexes of several animal

species. The results are tabulated below:

Species

Route

LD

50

(mg/kg)

Mouse (NMRI

strain)

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Species

Route

LD

50

(mg/kg)

M (N=40)

6700 (5027-8930)

F (N=40)

8100 (6326-10371)

M (N=35)

2340 (2066-2650)

F (N=30)

2340 (2122-2580)

Rat (Sprague-Daw ley strain)

M (N=40)

>46.4*

F (N=40)

>46.4*

M (N=35)

1660 (1518-1816)

F (N=30)

1810 (1625-2017)

Dog (Beagle)

(N=3)

>2150

*Mortality not linearly related.

Acute signs of toxicity in mice and rats following IV dosing of enoxaparin included ataxia,

dyspnea with slight mydriasis, short tonic convulsions and death. Following SC dosing, acute

signs of toxicity included ataxia, dyspnea, cyanosis and, occasionally, ventral decubitus, coma

and death. In dogs, signs of toxicity included polypnea, tachycardia, mild agitation, sedation,

lateral decubitus, ptyalism, mydriasis and loss of oculopalpebral reflex; all dogs recovered

completely.

Local Tolerance and Sensitization

Single high dose subcutaneous injections of 0.6 mL enoxaparin injection solution (equivalent to

an anti-Xa activity of approximately 100 mg) were well tolerated by 6 Beagle dogs, with no signs

of local irritation or allergic potential. Likewise, single intradermal injections of up to 50%

enoxaparin for 1 to 3 weeks, followed by epicutaneous application of the drug, revealed no

allergenic potential or local intolerance in 40 male Pirbright white guinea pigs.

Long Term Toxicity

Subacute and chronic toxicity studies were conducted in rats, dogs and monkeys. There were

no species differences in the toxicity of enoxaparin; in all animals there were changes in

hematology values and organ weights, reflecting the physiological adaptation of animals to long

term anticoagulant treatment and resulting hemorrhage. In subacute studies, the highest non-

toxic SC doses over 13 weeks were 3 mg/kg/day in rats and 6.5 mg/kg/day in dogs. In 26-week

studies, the highest non-toxic dose was 3 mg/kg/day in both rats and monkeys.

In the Rat

13-Week, Subcutaneous Administration

Wistar rats received enoxaparin in doses of 3, 6.5 or 15 mg/kg/day for 13 weeks (30 rats per

dose). Hematology values remained within the normal limits during the first 6 weeks, but after

13 weeks of treatment, animals in the highest dose group showed moderate decreases in

hemoglobin, red cell count, packed cell volume and small increases in WBC and platelets. With

the highest dose, there were slight increases in LDH, alpha hydroxy butyric dehydrogenase

(HBDH) and slight decreases in alkaline phosphatase, sodium ion and chloride ion.

Histopathological examination revealed dose-related hemorrhage and hematomas at the

injection site.

26-Week, Subcutaneous Administration

Groups of Sprague-Dawley rats (30 animals per group) received 0, 3, 10 and 30 mg/kg/day SC

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for 26 weeks.

Mortality rates of about 30% occurred among animals taking the two highest doses (versus 2%

of control animals and 3% of animals on the lowest dose).

Animals receiving the highest dose exhibited decreased concentrations of hemoglobin,

hematocrit and RBC and a higher incidence of prothrombin consumption times of less than 100

seconds. Platelet counts were elevated in all treated animals, but normalized during a post-

treatment recovery period. These hematology responses were considered normal sequelae of

anticoagulant activity, rather than toxic manifestations.

Cholesterol levels in all males and in high dose females were elevated above control values in

both treatment and recovery phases.

Terminal absolute and relative organ weights for the spleen and liver were elevated in dose -

related manner. Histomorphological examinations revealed bleeding at the injection site, but no

toxicopathological effects.

26-Week, Intravenous Administration

Sprague-Dawley rats (25-30 animals per dose) initially received 0, 1, 10, 30 and 90 mg/kg/day,

but after 4 weeks, the two highest doses were reduced to 20 and 40 mg/kg/day because of

excessive anticoagulation and toxicity.

In all animals, inflammation, hemorrhage and necrosis were observed at the injection site.

Mortality was dose related, death being due to internal hemorrhaging, particularly into the

abdominal cavity.

Chronic enoxaparin administration induced decreases in hemoglobin, hematocrit and RBC and

increases in platelet and reticulocyte counts, the latter in the highest dose group only. All values

normalized during the post-treatment recovery period. With the highest doses, serum urea was

elevated, which was likely a result of tubular nephrosis of the kidney and renal capsular

hemorrhage seen at autopsy. In addition, organ weights of the spleen, adrenal gland, kidney,

heart and liver were increased. Autopsy revealed tubular nephrosis of the kidney and renal

capsular hemorrhage.

In the Dog

13-Week, Subcutaneous Administration

Beagle dogs (6 animals per dose) received enoxaparin for 13 weeks in doses of 0, 3, 6.5 and 15

mg/kg/day SC.

There were no deaths and no drug related effects on body weight, food consumption, ocular

examination, plasma parathormone (PTH) levels or terminal organ weights.

Mild dose-related local hemorrhaging occurred at the injection site, but almost no subcutaneous

hemorrhaging.

Hematology and biochemistry values remained normal throughout the study and

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histopathological findings at necropsy revealed only mild parathyroid hyperplasia in dogs given

the highest dose.

In the Monkey

26-Week, Subcutaneous Administration

Cynomolgus monkeys (7 animals/sex/group) were given enoxaparin in doses of 0, 3, 10 and

20 mg/kg/day SC for 26 weeks. After 6 months, 2 animals/sex/group were selected for 6 weeks

of observation of recovery.

Two high dose males died spontaneously after 10 and 172 days. Another high dose male and 3

high dose females were killed in extremis. All deaths were the result of hemorrhaging.

Dose-related inflammation of the injection site was observed, but symptoms generally

disappeared by the end of the recovery period.

Among surviving animals, body weight and food consumption remained normal. Hematology

values of RBC, hemoglobin and hematocrit, prothrombin time decreased, while thrombin time

and eosinophilic sedimentation rates were elevated in mid- and high dose animals. Urinalysis

and biochemistry values remained within normal limits.

Organ weights for the kidney, liver and spleen were elevated in the mid- and high dose animals

and remained elevated in the male animals of the high dose group after the recovery period.

26-Week, Intravenous Administration

Cynomolgus monkeys (4-5 animals per dose) were given 0, 5, 10 or 20 mg/kg enoxaparin IV for

26 weeks. One animal in each group was retained for 4 weeks for observation of recovery.

One monkey in the high dose group died, although it had had no excessive bleeding or

abnormal histopathological signs at autopsy.

No signs of toxicity were observed with the 5 mg/kg dose. Other doses produced dose-related

inflammation and hemorrhaging at the injection site. Swelling of the arms or legs gradually

disappeared by the end of the dosing period.

During treatment, hematology, biochemistry and urinalysis values in all treated animals

corresponded to those of control animals. Histopathological examination revealed no drug-

related changes in individual organs.

Mutagenicity

Enoxaparin exhibited no mutagenic activity when tested in vitro by the Ames test in 5 strains of

S. typhimurium. Likewise, no mutagenic activity could be demonstrated in vitro in a mammalian

cell system, mouse lymphoma cells, with and without metabolic activation. The clastogenic

potential of enoxaparin was tested in vitro in human peripheral lymphocytes and in vivo in the

bone marrow cells of rats. No clastogenic activity could be demonstrated by either method.

Reproduction and Teratology

Fertility and Reproduction - In the Rat

Reproductive performance was evaluated in 26 male and in 26 female sexually mature

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Sprague- Dawley rats (identified as the Fo generation of animals). Starting 15 days before

mating, all animals received 0, 3, 10 or 20 mg/kg/day enoxaparin subcutaneously. Treatment

continued through mating, gestation and lactation to 4 days post-partum. One portion of the

females was sacrificed 21 days after mating and another portion following the weaning of

offspring.

Enoxaparin produced no adverse effects on the general condition of Fo animals or on

reproductive performance, gestation and parturition. Necropsy of dams revealed normal

numbers of corpora lutea, uterine contents and fetuses. The neonates (F1 generation) exhibited

no signs of toxicity and followed normal weight gain patterns. Fertility and reproductive

performance of the untreated F1 generation were normal and the fetal parameters of their

offspring (F2 generation) were normal.

In conclusion, enoxaparin, when given in doses of up to 20 mg/kg/day SC throughout a

complete gametogenic cycle, pregnancy and lactation exerted no significant adverse effects on

reproductive performance of treated Fo animals or on the growth and reproduction of their

untreated F1 offspring.

Teratology - In the Rat

Female Sprague-Dawley rats (20 animals per dose) received enoxaparin by subcutaneous

injection in doses of 3, 10 or 30 mg/kg/day from Days 6 to 15 of gestation. Control animals

received the physiological saline vehicle. All dams were killed on Day 21 of gestation.

Maternal necropsy showed no evidence of adverse effects on corpora lutea or uterine contents.

Fetuses from the 3 and 10 mg/kg dose groups showed no treatment-related abnormalities. In

the high dose group, there was a slightly higher incidence of large fetuses as compared to

historical control values and a slightly increased incidence of hydronephrosis and unilateral

hydroureter. Also in the high dose group, there was a slightly higher incidence of fetuses with

dilated brain ventricles, thought to be associated with low fetal body weight.

In another study, female Sprague-Dawley rats (24 animals per dose) received enoxaparin by

the intravenous route in doses of 0, 10, 40 and 160 mg/kg/day from Days 6 to 15 of gestation.

Fetal necropsy was performed on the 20th day of gestation. Doses of 10 and 40 mg/kg/day

exerted no adverse systemic effects on dams and did not adversely influence prenatal

development.

The 160 mg/kg/day dose was within the low lethal range for the dams and 2 animals died from

loss of blood. Fertility results from the surviving dams did not differ significantly from the controls

or lower dose groups.

There were no indications of teratogenic effects in rats with enoxaparin by either the SC or IV

routes, even with the highest doses.

Teratology - In the Rabbit

Female New Zealand rabbits (14 animals per dose) received enoxaparin by subcutaneous

injection in doses of 0, 3, 10 and 30 mg/kg/day from Days 6 to 18 of gestation. Dams were

sacrificed on Day 29 of gestation.

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Two dams (given 10 mg/kg/day) aborted all fetuses during treatment. One female each in the 10

and 30 mg/kg/day groups totally resorbed their litters.

Necropsy examination of the other animals revealed no significant differences between

enoxaparin- and vehicle-treated dams with respect to corpora lutea, uterine contents and

number of fetuses. There was one abnormal fetus from the 3 mg/kg group, but this was

considered unrelated to drug treatment.

In a second study, female New Zealand rabbits (12 animals per dose) received enoxaparin by

the intravenous route in doses of 0, 10, 40 or 160 mg/kg/day from Days 6 to 18 of gestation.

Dams were killed on Day 29 of gestation.

One rabbit in the highest dose group died from multiple systemic hemorrhages and another

animal aborted.

On gestation Day 19, there were no adverse maternal or fetal effects for the groups given 10

and 40 mg/kg/day. In the group given 160 mg/kg/day, there were no significant differences in

the number of corpora lutea or uterine implantations compared to vehicle control values. Four

dams from this group resorbed all fetuses. The group mean resorption rate in the high dose

group was 56.8% (versus 9.8% for the control group).

There were no teratogenic effects in rabbits by either route of administration. In the high-dose

intravenous group, the frequency of vertebral malformations was slightly increased, but still

within the normal range for this species.

Perinatal and Postnatal Development - In the Rat

Enoxaparin was administered to Sprague-Dawley rats (20 animals per dose) in doses of 0, 3, 10

or 20 mg/kg/day SC from the 15th day of gestation to the 21st day of lactation. Offspring were

observed from birth to weaning.

Litter size, viability and general condition of the offspring were unaffected by treatment.

Postnatal body weights and body weight gain to weaning were marginally reduced in the low-

and mid-dose groups, but were significantly reduced in the high-dose group. Terminal

examination of offspring revealed no macroscopic changes in any of the groups.

17

SUPPORTING PRODUCT MONOGRAPHS

LOVENOX (solution for injection, 100 mg/mL) and LOVENOX HP (solution for injection,

150 mg/mL), Submission Control No. 216420, Product Monograph, sanofi-aventis

Canada Inc. (DEC. 19, 2019)

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READ THIS FOR SAFE AND EFFECTIVE USE OF YOUR MEDICINE

PATIENT MEDICATION INFORMATION

NOROMBY (nor-OM-bee)

Enoxaparin sodium solution for injection

100 mg/mL single dose syringe

Read this carefully before you start taking NOROMBY and each time you get a refill. This leaflet

is a summary and will not tell you everything about this drug. Talk to your healthcare

professional about your medical condition and treatment and ask if there is any new information

about NOROMBY.

NOROMBY is a biosimilar biologic drug (biosimilar) to the reference biologic drug LOVENOX. A

biosimilar is authorized based on its similarity to a reference biologic drug that was already

authorized for sale.

What is NOROMBY used for?

To prevent the formation of deep vein thrombosis (blood clots), which can occur as a

complication of orthopedic surgery such as hip or knee surgery or of intra-abdominal (inside

the body cavity below diaphragm which contains stomach, intestines, liver, and other

organs) surgeries;

To prevent the formation of deep vein thrombosis in medical patients who are at risk of

thromboembolic (blockage of blood vessel by a blood clot) complications due to severely

restricted mobility during acute illnesses (cardiac insufficiency [reduced ability of heart to

pump blood], respiratory failure or severe chest infections);

To treat the deep vein thrombosis with or without pulmonary embolism (blockage of blood

vessel in the lungs);

To treat the unstable angina and non-Q-wave myocardial infarction (death of a part of the

heart muscle that does not involve full thickness of the heart wall), concurrently with

acetylsalicylic acid (ASA);

To treat the acute ST-segment Elevation Myocardial Infarction (STEMI), a particular form of

heart attack. This indication includes patients to be managed medically or those with

subsequent Percutaneous Coronary Intervention (PCI), a procedure that opens up a

coronary artery (blood vessel that brings blood and oxygen to the heart muscle) and

restores blood flow;

To prevent clotting in the extra-corporeal circulation during hemodialysis.

How does NOROMBY work?

NOROMBY is an anti-thrombotic drug. This means that NOROMBY helps to prevent blood clots

from forming in patients who have either undergone surgery or are

suffering from a medical

condition that limits their mobility. It can also treat existing blood clots in deep veins or in

unstable coronary artery disease (Unstable Angina or non Q-wave Myocardial Infarction).

What are the ingredients in NOROMBY?

Medicinal ingredients: Enoxaparin sodium, a low molecular-weight heparin

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Non-medicinal ingredients: Water for injection

NOROMBY comes in the following dosage forms:

NOROMBY 100 mg/mL is available in pre-filled syringes offered with a system that shields the

needle after injection:

Single dose 20 mg/0.2 mL pre-filled syringes with protective shield

Single dose 30 mg/0.3 mL pre-filled syringes with protective shield

Single dose 40 mg/0.4 mL pre-filled syringes with protective shield

Single dose 60 mg/0.6 mL pre-filled syringes with protective shield

Single dose 80 mg/0.8 mL pre-filled syringes with protective shield

Single dose 100 mg/mL pre-filled syringes with protective shield

Do not use NOROMBY if you have:

a known allergy to NOROMBY or any of its constituents;

a known allergy to any other low molecular weight heparins and/or heparin;

thrombocytopenia (a severe decrease in the number of platelets in the blood); History (within

the past 100 days) of heparin-induced thrombocytopenia (HIT) (a blood clotting disorder

caused by heparin).

bacterial endocarditis (bacterial infection inside of the heart);

active bleeding;

a major clotting disorder;

gastric or duodenal ulcer (defect of the internal walls of the stomach or small intestine);

cerebrovascular accident (except if there are systemic emboli);

severe uncontrolled hypertension (high blood pressure);

eye problems due to diabetes (diabetic retinopathy) or hemorrhage (bleeding);

a tendency to bleeding regardless of the reason;

injury or surgery on the brain, spinal cord, eyes and ears;

kidney problems;

liver problems;

spinal/epidural anesthesia is contraindicated where repeated treatment doses of NOROMBY

(1 mg/kg every 12 hours or 1.5 mg/kg once daily) are required, due to an increased risk of

bleeding;

other conditions or diseases involving an increased risk of bleeding;

To help avoid side effects and ensure proper use, talk to your healthcare professional

before you take NOROMBY. Talk about any health conditions or problems you may have,

including if you:

prosthetic (artificial) heart valve,

stroke (cerebrovascular accident),

a known allergy to NOROMBY or any of its constituents, or to other low molecular weight

heparins and/or heparin,

thrombocytopenia (a severe decrease in the number of platelets in the blood), a history of

heparin-induced thrombocytopenia (HIT) (a blood clotting disorder caused by heparin).

bacterial endocarditis (bacterial infection inside of the heart),

a major clotting disorder,

gastric or duodenal ulcer (defect of the internal walls of the stomach or small intestine),

NOROMBY

Page 63 of 78

hypertension (high blood pressure),

a tendency to bleeding regardless of the reason,

injury or surgery (spinal surgery with spinal/epidural anesthesia) involving the central

nervous system, eyes or ears,

spinal defect (or deformity),

kidney problems,

liver problems,

eye problems due to diabetes or hemorrhage (bleeding).

Other warnings you should know about:

You should also inform your doctor at once if you are pregnant or if you are breast-feeding, so

he can evaluate the possible risks to you and the infant.

Certain medications may intensify the anticoagulant effect (increase the anti-clotting effect) of

NOROMBY. Therefore, it is important for you to advise your doctor of all drugs that you are

presently taking.

It is necessary that you follow the instructions of your doctor or nurse carefully. Only give

yourself the injections prescribed and do so the entire time period specified by your doctor.

Do not take any drugs other than those prescribed by your doctor while you are taking

NOROMBY.

If you need to consult with another doctor or see your dentist, be absolutely sure to tell them

that you are being treated with NOROMBY.

Tell your healthcare professional about all the medicines you take, including any drugs,

vitamins, minerals, natural supplements or alternative medicines.

The following may interact with NOROMBY:

Acetylsalicylic acid (ASA), salicylates, and non- steroidal anti-inflammatories (e.g.

diclofenac, ibuprofen, ketorolac);

Prednisolone

Dextran, vitamin K antagonists, clopidogrel, ticlopidine and dipyridamole.

How to take NOROMBY:

NOROMBY is a prescription drug and must be used as directed. Usually it is administered as a

subcutaneous injection, which means the injection is made just under the surface of the skin.

For some conditions, NOROMBY may be administered as an intravenous (IV) injection.

NOROMBY must NOT be administered by the intramuscular route.

Usual dose:

Hip or Knee Replacement Surgery: While you are in the hospital, your doctor or a nurse will

give your first injection within 24 hours after your operation, so as to prevent blood clots from

forming. After that, your doctor or a nurse will give you 2 subcutaneous injections every day

(one injection every 12 hours) while you are in hospital.

NOROMBY

Page 64 of 78

In case of hip replacement surgery, after completing the treatment with 2 subcutaneous

injections per day, your

doctor may ask you to take 1 subcutaneous injection every day for the

following days at home or in hospital for an additional 3 weeks.

Abdominal or Colorectal Surgery: While you are in the hospital, your doctor or a nurse will

give your first injection 2 hours prior to surgery. After that, your doctor or a nurse will give you 1

subcutaneous injection once a day while you are in hospital, your doctor may ask you to

continue to take 1 subcutaneous injection every day for up to 4 weeks.

Medical Patients: While you are in the hospital, your doctor or a nurse will give you 1

subcutaneous injection once a day. The usual duration of administration is 6 to 11 days.

Treatment of Deep Vein Thrombosis, with or without Embolism: while you are in the

hospital, your doctor or a nurse will give you 1 subcutaneous injection once or twice daily for

about 10 days.

Treatment of Unstable Angina or Non-Q-Wave Myocardial Infarction: while you are in the

hospital, your doctor or a nurse will give you 2 subcutaneous injections every day (one injection

every 12 hours) along with oral ASA (100 to 325 mg once daily) for a minimum of 2 days.

Treatment of acute ST-segment Elevation Myocardial Infarction (STEMI): while you are in

the hospital, your doctor or a nurse will give you a single intravenous (IV) injection followed by 2

subcutaneous injections every day (one injection every 12 hours) along with oral ASA (75 to 325

mg once daily) for a minimum of 8 days, unless contraindicated.

It is possible that after you go home, you may need to continue your injections of NOROMBY for

a few days.

Prevention of thrombus formation in the extra- corporeal circulation during

hemodialysis: while you are in the hospital, your doctor or a nurse will inject NOROMBY into

the arterial line of the circuit at the beginning of the dialysis session. The effect of this dose is

usually sufficient for a 4-hour session.

Instructions for self-injection of NOROMBY

Your doctor may want you to continue your NOROMBY injections at home for a few days. If so,

the doctor or a nurse will show you how to administer your NOROMBY injections before

you are released from hospital. It is essential that you follow these instructions exactly. If

you have questions, be sure you ask your doctor or nurse to provide the explanations

you require.

Proper subcutaneous (under the skin) injection of NOROMBY is essential to prevent pain and

bruising at the injection site.

When at home, there is nothing for you to prepare. The syringe is pre-filled with the exact

amount of drug required. Do not press on the plunger prior to injection.

NOROMBY solution should be inspected visually for clarity, particulate matter, precipitation,

discolouration, and leakage prior to administration. Do not use if solution shows haziness,

particulate matter, discolouration or leakage.

NOROMBY

Page 65 of 78

The recommended site for injection is into the fat of the lower abdomen. This should be at least

5 centimeters away from your belly button and out towards your sides.

Prior to injection, wash your hands and cleanse (do not rub) the selected site for injection with

an alcohol swab. Select a different site of the lower abdomen for each injection.

Remove the needle cover by pulling it straight off the syringe. If adjusting the dose is required,

the dose adjustment must be done prior to injecting NOROMBY.

NOROMBY

Page 66 of 78

NOTE: To avoid the loss of drug when using the 30 and 40 mg pre-filled syringes, do not expel

the air bubble from the syringe before the injection.

Sit or lie down in a comfortable position and gather a fold of skin with your thumb and forefinger.

Then holding the syringe at a right angle to the skin folded between your thumb and forefinger,

insert the needle as far as it will go. Hold the skin fold throughout the injection process. Once

the needle has been inserted, the syringe should not be moved. Push the plunger to inject

NOROMBY. Be sure the syringe is empty and the plunger is pushed all the way down before

removing the syringe.

Remove the needle at a right angle, by pulling it straight out. A protective sleeve will

automatically cover the needle.

NOTE: the safety system allowing release of the protective sleeve can only be activated when

the syringe has been emptied by pressing the plunger all the way down.

You can now let go of the skin fold and apply light pressure to the skin at the injection site for

several seconds with an alcohol swab. This action will help lessen any oozing of NOROMBY or

bleeding. Do not rub the injection site.

NOROMBY

Page 67 of 78

You should then safely dispose of the syringe and needle with its protective sleeve, so they

remain out of reach of children.

Overdose:

Accidental overdosage may result in hemorrhaging, which cannot be treated at home.

Therefore, if you suspect that you have used too much NOROMBY, call your doctor immediately

even if you do not yet observe any unusual symptoms. Your doctor can then make

arrangements to bring you to hospital for observation and/or treatment.

If you think you have taken too much NOROMBY, contact your healthcare professional, hospital

emergency department or regional poison control centre immediately, even if there are no

symptoms.

Missed Dose:

If you miss a dose of this medication by a few hours, take it as soon as you remember.

However, if you are close to the time of the next dose, skip the missed dose and proceed with

the regular dosing schedule. Do not double doses. If you are unsure about how to proceed

contact your doctor or your pharmacist.

What are possible side effects from using NOROMBY?

These are not all the possible side effects you may feel when taking NOROMBY. If you

experience any side effects not listed here, contact your healthcare professional.

Administration of NOROMBY may result in bleeding which can have serious or life-threatening

consequences. Hemorrhagic strokes (bleeding inside of the brain) and serious intra-abdominal

bleeding (bleeding into the body cavity below diaphragm which contains stomach, intestines,

liver, and other organs) have been reported. NOROMBY is generally well tolerated when used

according to directions of use.

During your hospital stay or when using NOROMBY at home, it is important that you notify your

doctor immediately if you notice any of the following symptoms which may be a sign of an

underlying complication:

Bleeding or oozing from the surgical wound;

Any other bleeding episodes, for example, at the site of the injection, nosebleeds, blood in

the urine or if you cough or throw up blood, or have bloody stools;

Bleeding gums while brushing teeth;

Spontaneous bruising (a bruise not caused by a blow or any apparent reason);

NOROMBY

Page 68 of 78

Purplish or reddish discolouration or pain around the injection site;

Skin discolouration as caused by ruptured blood vessels;

Pain or swelling in any part of your leg, foot or hip;

Dizziness; Headache;

Rapid or unusual heart beat;

Chest pain or shortness of breath;

Vomiting;

Confusion;

Abdominal pain.

Talk to you doctor or pharmacist if you experience other side effects such as:

Changes in the results of blood tests done to check how your liver is working during

treatment with NOROMBY.

Signs of liver problems such as loss of appetite, dark urine, light-colored stools,

yellowing of the skin or eyes (jaundice).

If you have an allergic reaction. The signs may include: skin rash, angioedema

(swelling of lips, face, throat and tongue, breathing difficulties) and

anaphylactic/anaphylactoid reactions including shock.

Long term use of NOROMBY (greater than 3 months) may increase your risk of bone

thinning (osteoporosis).

Some patients may experience hair loss. The hair usually grows back once the

treatment is discontinued.

If you have had a spinal puncture or a spinal anesthetic and notice tingling, numbness

and muscular weakness, particularly in the lower part of your body, or if you have

problems controlling your bowels and/or bladder.

If you have a troublesome symptom or side effect that is not listed here or becomes bad enough

to interfere with your daily activities, talk to your healthcare professional.

Reporting Side Effects

You can report any suspected side effects associated with the use of health products to

Health Canada by:

Visiting the Web page on Adverse Reaction Reporting (http://www.hc-sc.gc.ca/dhp-

mps/medeff/report-declaration/index-eng.php) for information on how to report online,

by mail or by fax; or

Calling toll-free at 1-866-234-2345.

NOTE: Contact your health professional if you need information about how to manage your

side effects. The Canada Vigilance Program does not provide medical advice.

Storage:

Store at room temperature between 15

C and 25

C. Protect from heat and freezing.

Keep out of reach and sight of children.

If you want more information about NOROMBY:

NOROMBY

Page 69 of 78

Talk to your healthcare professional

Find the full product monograph that is prepared for healthcare professionals and

includes this Patient Medication Information by visiting the Health Canada website

(http://hc-sc.gc.ca/index-eng.php); or by calling the sponsor at 1-855-819-0505.

This leaflet was prepared by Juno Pharmaceuticals Corp.

Last Revised December 16, 2020

NOROMBY

Page 70 of 78

READ THIS FOR SAFE AND EFFECTIVE USE OF YOUR MEDICINE

PATIENT MEDICATION INFORMATION

NOROMBY HP (nor-OM-bee aych pee))

Enoxaparin sodium solution for injection

150 mg/mL single dose syringe

Read this carefully before you start taking NOROMBY HP and each time you get a refill. This

leaflet is a summary and will not tell you everything about this drug. Talk to your healthcare

professional about your medical condition and treatment and ask if there is any new information

about NOROMBY HP.

NOROMBY HP is a biosimilar biologic drug (biosimilar) to the reference biologic drug

LOVENOX HP. A biosimilar is authorized based on its similarity to a reference biologic drug that

was already authorized for sale.

What is NOROMBY HP used for?

To prevent the formation of deep vein thrombosis (blood clots), which can occur as a

complication of orthopedic surgery such as hip or knee surgery or of intra-abdominal (inside

the body cavity below diaphragm which contains stomach, intestines, liver, and other

organs) surgeries;

To prevent the formation of deep vein thrombosis in medical patients who are at risk of

thromboembolic (blockage of blood vessel by a blood clot) complications due to severely

restricted mobility during acute illnesses (cardiac insufficiency [reduced ability of heart to

pump blood], respiratory failure or severe chest infections);

To treat the deep vein thrombosis with or without pulmonary embolism (blockage of blood

vessel in the lungs);

To treat the unstable angina and non-Q-wave myocardial infarction (death of a part of the

heart muscle that does not involve full thickness of the heart wall), concurrently with

acetylsalicylic acid (ASA);

To treat the acute ST-segment Elevation Myocardial Infarction (STEMI), a particular form of

heart attack. This indication includes patients to be managed medically or those with

subsequent Percutaneous Coronary Intervention (PCI), a procedure that opens up a

coronary artery (blood vessel that brings blood and oxygen to the heart muscle) and

restores blood flow;

To prevent clotting in the extra-corporeal circulation during hemodialysis.

How does NOROMBY HP work?

NOROMBY HP is an anti-thrombotic drug. This means that NOROMBY HP helps to prevent

blood clots from forming in patients who have either undergone surgery or are

suffering from a

medical condition that limits their mobility. It can also treat existing blood clots in deep veins or

in unstable coronary artery disease (Unstable Angina or non Q-wave Myocardial Infarction).

What are the ingredients in NOROMBY HP?

NOROMBY

Page 71 of 78

Medicinal ingredients: Enoxaparin sodium, a low molecular-weight heparin

Non-medicinal ingredients: Water for injection

NOROMBY HP comes in the following dosage forms:

NOROMBY HP 150 mg/mL is available in pre-filled syringes offered with a system that shields

the needle after injection:

Single dose 120 mg/0.8 mL pre-filled syringes with protective shield

Single dose 150 mg/mL pre-filled syringes with protective shield

Do not use NOROMBY HP if you have:

a known allergy to NOROMBY HP or any of its constituents;

a known allergy to any other low molecular weight heparins and/or heparin;

thrombocytopenia (a severe decrease in the number of platelets in the blood); History (within

the past 100 days) of heparin-induced thrombocytopenia (HIT) (a blood clotting disorder

caused by heparin).

bacterial endocarditis (bacterial infection inside of the heart);

active bleeding;

a major clotting disorder;

gastric or duodenal ulcer (defect of the internal walls of the stomach or small intestine);

cerebrovascular accident (except if there are systemic emboli);

severe uncontrolled hypertension (high blood pressure);

eye problems due to diabetes (diabetic retinopathy) or hemorrhage (bleeding);

a tendency to bleeding regardless of the reason;

injury or surgery on the brain, spinal cord, eyes and ears;

kidney problems;

liver problems;

spinal/epidural anesthesia is contraindicated where repeated treatment doses of NOROMBY

HP (1 mg/kg every 12 hours or 1.5 mg/kg once daily) are required, due to an increased risk

of bleeding;

other conditions or diseases involving an increased risk of bleeding;

To help avoid side effects and ensure proper use, talk to your healthcare professional

before you take NOROMBY HP. Talk about any health conditions or problems you may

have, including if you:

prosthetic (artificial) heart valve,

stroke (cerebrovascular accident),

a known allergy to NOROMBY HP or any of its constituents, or to other low molecular

weight heparins and/or heparin,

thrombocytopenia (a severe decrease in the number of platelets in the blood), a history of

heparin-induced thrombocytopenia (HIT) (a blood clotting disorder caused by heparin).

bacterial endocarditis (bacterial infection inside of the heart),

a major clotting disorder,

gastric or duodenal ulcer (defect of the internal walls of the stomach or small intestine),

hypertension (high blood pressure),

a tendency to bleeding regardless of the reason,

NOROMBY

Page 72 of 78

injury or surgery (spinal surgery with spinal/epidural anesthesia) involving the central

nervous system, eyes or ears,

spinal defect (or deformity),

kidney problems,

liver problems,

eye problems due to diabetes or hemorrhage (bleeding).

Other warnings you should know about:

You should also inform your doctor at once if you are pregnant or if you are breast-feeding, so

he can evaluate the possible risks to you and the infant.

Certain medications may intensify the anticoagulant effect (increase the anti-clotting effect) of

NOROMBY HP. Therefore, it is important for you to advise your doctor of all drugs that you are

presently taking.

It is necessary that you follow the instructions of your doctor or nurse carefully. Only give

yourself the injections prescribed and do so the entire time period specified by your doctor.

Do not take any drugs other than those prescribed by your doctor while you are taking

NOROMBY HP.

If you need to consult with another doctor or see your dentist, be absolutely sure to tell them

that you are being treated with NOROMBY HP.

Tell your healthcare professional about all the medicines you take, including any drugs,

vitamins, minerals, natural supplements or alternative medicines.

The following may interact with NOROMBY HP:

Acetylsalicylic acid (ASA), salicylates, and non- steroidal anti-inflammatories (e.g.

diclofenac, ibuprofen, ketorolac);

Prednisolone

Dextran, vitamin K antagonists, clopidogrel, ticlopidine and dipyridamole.

How to take NOROMBY HP:

NOROMBY HP is a prescription drug and must be used as directed. Usually it is administered

as a subcutaneous injection, which means the injection is made just under the surface of the

skin. For some conditions, NOROMBY HP may be administered as an intravenous (IV)

injection. NOROMBY HP must NOT be administered by the intramuscular route.

Usual dose:

Hip or Knee Replacement Surgery: While you are in the hospital, your doctor or a nurse will

give your first injection within 24 hours after your operation, so as to prevent blood clots from

forming. After that, your doctor or a nurse will give you 2 subcutaneous injections every day

(one injection every 12 hours) while you are in hospital.

In case of hip replacement surgery, after completing the treatment with 2 subcutaneous

injections per day, your

doctor may ask you to take 1 subcutaneous injection every day for the

following days at home or in hospital for an additional 3 weeks.

NOROMBY

Page 73 of 78

Abdominal or Colorectal Surgery: While you are in the hospital, your doctor or a nurse will

give your first injection 2 hours prior to surgery. After that, your doctor or a nurse will give you 1

subcutaneous injection once a day while you are in hospital, your doctor may ask you to

continue to take 1 subcutaneous injection every day for up to 4 weeks.

Medical Patients: While you are in the hospital, your doctor or a nurse will give you 1

subcutaneous injection once a day. The usual duration of administration is 6 to 11 days.

Treatment of Deep Vein Thrombosis, with or without Embolism: while you are in the

hospital, your doctor or a nurse will give you 1 subcutaneous injection once or twice daily for

about 10 days.

Treatment of Unstable Angina or Non-Q-Wave Myocardial Infarction: while you are in the

hospital, your doctor or a nurse will give you 2 subcutaneous injections every day (one injection

every 12 hours) along with oral ASA (100 to 325 mg once daily) for a minimum of 2 days.

Treatment of acute ST-segment Elevation Myocardial Infarction (STEMI): while you are in

the hospital, your doctor or a nurse will give you a single intravenous (IV) injection followed by 2

subcutaneous injections every day (one injection every 12 hours) along with oral ASA (75 to 325

mg once daily) for a minimum of 8 days, unless contraindicated.

It is possible that after you go home, you may need to continue your injections of NOROMBY

HP for a few days.

Prevention of thrombus formation in the extra- corporeal circulation during

hemodialysis: while you are in the hospital, your doctor or a nurse will inject NOROMBY HP

into the arterial line of the circuit at the beginning of the dialysis session. The effect of this dose

is usually sufficient for a 4-hour session.

Instructions for self-injection of NOROMBY HP

Your doctor may want you to continue your NOROMBY HP injections at home for a few days. If

so, the doctor or a nurse will show you how to administer your NOROMBY HP injections

before you are released from hospital. It is essential that you follow these instructions

exactly. If you have questions, be sure you ask your doctor or nurse to provide the

explanations you require.

Proper subcutaneous (under the skin) injection of NOROMBY HP is essential to prevent pain

and bruising at the injection site.

When at home, there is nothing for you to prepare. The syringe is pre-filled with the exact

amount of drug required. Do not press on the plunger prior to injection.

NOROMBY HP solution should be inspected visually for clarity, particulate matter, precipitation,

discolouration, and leakage prior to administration. Do not use if solution shows haziness,

particulate matter, discolouration or leakage.

NOROMBY

Page 74 of 78

The recommended site for injection is into the fat of the lower abdomen. This should be at least

5 centimeters away from your belly button and out towards your sides.

Prior to injection, wash your hands and cleanse (do not rub) the selected site for injection with

an alcohol swab. Select a different site of the lower abdomen for each injection.

Remove the needle cover by pulling it straight off the syringe. If adjusting the dose is required,

the dose adjustment must be done prior to injecting NOROMBY HP.

NOROMBY

Page 75 of 78

NOTE: To avoid the loss of drug when using the 30 and 40 mg pre-filled syringes, do not expel

the air bubble from the syringe before the injection.

Sit or lie down in a comfortable position and gather a fold of skin with your thumb and forefinger.

Then holding the syringe at a right angle to the skin folded between your thumb and forefinger,

insert the needle as far as it will go. Hold the skin fold throughout the injection process. Once

the needle has been inserted, the syringe should not be moved. Push the plunger to inject

NOROMBY HP. Be sure the syringe is empty and the plunger is pushed all the way down

before removing the syringe.

Remove the needle at a right angle, by pulling it straight out. A protective sleeve will

automatically cover the needle.

NOTE: the safety system allowing release of the protective sleeve can only be activated when

the syringe has been emptied by pressing the plunger all the way down.

You can now let go of the skin fold and apply light pressure to the skin at the injection site for

several seconds with an alcohol swab. This action will help lessen any oozing of NOROMBY HP

or bleeding. Do not rub the injection site.

You should then safely dispose of the syringe and needle with its protective sleeve, so they

remain out of reach of children.

NOROMBY

Page 76 of 78

Overdose:

Accidental overdosage may result in hemorrhaging, which cannot be treated at home.

Therefore, if you suspect that you have used too much NOROMBY HP, call your doctor

immediately even if you do not yet observe any unusual symptoms. Your doctor can then make

arrangements to bring you to hospital for observation and/or treatment.

If you think you have taken too much NOROMBY HP, contact your healthcare professional,

hospital emergency department or regional poison control centre immediately, even if there are

no symptoms.

Missed Dose:

If you miss a dose of this medication by a few hours, take it as soon as you remember.

However, if you are close to the time of the next dose, skip the missed dose and proceed with

the regular dosing schedule. Do not double doses. If you are unsure about how to proceed

contact your doctor or your pharmacist.

What are possible side effects from using NOROMBY HP?

These are not all the possible side effects you may feel when taking NOROMBY HP. If you

experience any side effects not listed here, contact your healthcare professional.

Administration of NOROMBY HP may result in bleeding which can have serious or life-

threatening consequences. Hemorrhagic strokes (bleeding inside of the brain) and serious intra-

abdominal bleeding (bleeding into the body cavity below diaphragm which contains stomach,

intestines, liver, and other organs) have been reported. NOROMBY HP is generally well

tolerated when used according to directions of use.

During your hospital stay or when using NOROMBY HP at home, it is important that you notify

your doctor immediately if you notice any of the following symptoms which may be a sign of an

underlying complication:

Bleeding or oozing from the surgical wound;

Any other bleeding episodes, for example, at the site of the injection, nosebleeds, blood in

the urine or if you cough or throw up blood, or have bloody stools;

Bleeding gums while brushing teeth;

Spontaneous bruising (a bruise not caused by a blow or any apparent reason);

Purplish or reddish discolouration or pain around the injection site;

Skin discolouration as caused by ruptured blood vessels;

Pain or swelling in any part of your leg, foot or hip;

Dizziness; Headache;

NOROMBY

Page 77 of 78

Rapid or unusual heart beat;

Chest pain or shortness of breath;

Vomiting;

Confusion;

Abdominal pain.

Talk to you doctor or pharmacist if you experience other side effects such as:

Changes in the results of blood tests done to check how your liver is working during

treatment with NOROMBY HP.

Signs of liver problems such as loss of appetite, dark urine, light-colored stools,

yellowing of the skin or eyes (jaundice).

If you have an allergic reaction. The signs may include: skin rash, angioedema

(swelling of lips, face, throat and tongue, breathing difficulties) and

anaphylactic/anaphylactoid reactions including shock.

Long term use of NOROMBY HP (greater than 3 months) may increase your risk of

bone thinning (osteoporosis).

Some patients may experience hair loss. The hair usually grows back once the

treatment is discontinued.

If you have had a spinal puncture or a spinal anesthetic and notice tingling, numbness

and muscular weakness, particularly in the lower part of your body, or if you have

problems controlling your bowels and/or bladder.

If you have a troublesome symptom or side effect that is not listed here or becomes bad enough

to interfere with your daily activities, talk to your healthcare professional.

Reporting Side Effects

You can report any suspected side effects associated with the use of health products to

Health Canada by:

Visiting the Web page on Adverse Reaction Reporting (http://www.hc-sc.gc.ca/dhp-

mps/medeff/report-declaration/index-eng.php) for information on how to report online,

by mail or by fax; or

Calling toll-free at 1-866-234-2345.

NOTE: Contact your health professional if you need information about how to manage your

side effects. The Canada Vigilance Program does not provide medical advice.

Storage:

Store at room temperature between 15

C and 25

C. Protect from heat and freezing.

Keep out of reach and sight of children.

If you want more information about NOROMBY HP:

Talk to your healthcare professional

Find the full product monograph that is prepared for healthcare professionals and

includes this Patient Medication Information by visiting the Health Canada website

NOROMBY

Page 78 of 78

(http://hc-sc.gc.ca/index-eng.php); or by calling the sponsor at 1-855-819-0505.

This leaflet was prepared by Juno Pharmaceuticals Corp.

Last Revised February 12, 2021

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