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Imrestor (Canada)

This page contains information on Imrestor for veterinary use.
The information provided typically includes the following:
  • Imrestor Indications
  • Warnings and cautions for Imrestor
  • Direction and dosage information for Imrestor

Imrestor

This treatment applies to the following species:
Manufacturer: Elanco

DIN 02452820

(pegbovigrastim injection)

FOR VETERINARY USE ONLY

Sterile

Active Ingredient: 15 mg pegbovigrastim per 2.7 mL single-dose syringe

For subcutaneous injection in periparturient dairy cows and periparturient replacement dairy heifers.

Description

Imrestor is a sterile injectable formulation of pegbovigrastim (an immunomodulator, bovine granulocyte stimulating factor) in single-dose syringes. Each syringe of Imrestor contains pegbovigrastim (15 mg), L-arginine hydrochloride (94 mg), L-arginine (40 mg), and citric acid monohydrate (17 mg).

INDICATION: For the reduction in the incidence of clinical mastitis in the first 30 days of lactation in dairy cows and replacement dairy heifers.

Dosage and Administration

This is a two-dose regimen. The same dose is used regardless of cow/heifer body weight. Remove surface dirt from the injection site area before injecting. Inject the entire contents of the syringe subcutaneously. Do not reuse the syringe.

Administer the first dose (syringe) 7 days prior to the cow’s or heifer’s anticipated calving date. If necessary, the first dose may be administered within a range of 4 to 10 days prior to the anticipated calving date to accommodate management schedules. Administer the second dose (syringe) within 24 hours after calving.

Animals that calve less than 7 days after the first dose should still receive the second dose within 24 hours after calving. Animals that calve more than 7 days after the first dose should also receive the second dose within 24 hours after calving.

Prior to administration, Imrestor should be visually inspected for particulate matter and discolouration. Imrestor is a clear, colourless solution and may contain a few small, translucent or white particles. Imrestor should not be used if it is discoloured or cloudy, or if other particulate matter is present. Do not shake or tap the syringe prior to use.

CAUTIONS: Imrestor is not for use in the treatment of cases of clinical mastitis. Treatment of clinical mastitis should be done in consultation with a veterinarian.

Do not use Imrestor contrary to the indications for use.

Results from the first Margin of Safety study indicated that exceeding the recommended dosage may have been associated with:

● Increased risk of splenomegaly (enlargement of the spleen)

● Increased somatic cell counts in milk

● Increased incidence of abomasal or duodenal ulcers

Warnings

WITHDRAWAL PERIODS:

No withdrawal period or milk withholding time is required when used according to the label directions.

Not for use in humans. Keep out of reach of children.

USER SAFETY WARNINGS: In case of accidental self-injection, wash the site of injection thoroughly with clean running water. Foreign proteins such as pegbovigrastim have the potential to cause anaphylactic-type reactions. If you experience swelling or redness at the site of exposure, or more severe reactions such as shortness of breath, seek medical attention immediately and take the package insert with you. Report the event to Elanco at 1-800-265-5475.

To obtain a Safety Data Sheet, contact Elanco at 1-800-265-5475.

Adverse Reactions

Hypersensitivity-type reactions have been reported rarely (more than 1 but less than 10 animals in 10,000) within five minutes to two hours, occurring most often after the first administration of Imrestor. Clinical signs may include elevated respiratory rate, dyspnea, urticaria, sweating, dependent edema, swollen mucous membranes, and/or hypersalivation. These reactions resolve within hours of onset with or without therapeutic intervention and have not been shown to reoccur with subsequent injections of Imrestor. Very rarely, clinical signs may also include death (less than 1 animal in 10,000 animals).

To report suspected adverse drug events, contact Elanco at 1-800-265-5475.

Clinical Pharmacology

Endogenous granulocyte colony stimulating factor is a protein (cytokine) which induces increased production of mature neutrophils from bone marrow stem cells and activation of the functional capabilities of mature circulating neutrophils. Pegbovigrastim is a modified form of bovine granulocyte colony stimulating factor conjugated to polyethylene glycol (PEG). This PEGylation technology enables sustained biological activity of the protein. In one study, cows treated with 20 µg/kg BW (equivalent to 1X the labeled dose) pegbovigrastim display statistically significant increased absolute neutrophil counts relative to the untreated control group beginning 5 hours post-dosing. Absolute neutrophil counts peaked 36 hours post-dosing and remained elevated up to 12 days post-dosing.

Effectiveness

A randomized, controlled, blinded clinical trial was performed at four dairy farms in the USA (n=641) and one dairy farm in France (n=160). A total of 801 animals were enrolled in the trial (approximately 160 animals per site, 80 treated with Imrestor and 80 treated with saline control). A total of 243 heifers (30.3%) and 558 cows (69.7%) were enrolled. Animals included both Jersey (n=160) and Holstein or Holstein-cross (n=641) breeds.

Animals received a first dose of Imrestor or saline control at approximately 7 days before parturition (i.e., the day the herdsman identified the animal exhibiting clinical signs of impending parturition). The second dose was administered within 24 hours of calving.

The primary outcome parameter was incidence of clinical mastitis. An animal was considered a treatment failure if she had clinical mastitis at any time during the first 30 days of lactation. Clinical mastitis was defined as an overall mastitis score of ≥ 3 / 5 in any quarter, based on quarter appearance, milk appearance, and California Mastitis Test results (as shown below in the Clinical Score Assessment Chart).

Clinical Score Assessment Chart

Appearance of Quarter

Appearance of Milk

CMT Results

Clinical Score

Normal

Normal

No Test Required

1

Normal

Suspect Milk

(a few transient flakes, or a few transient small clots or slight discolouration)

Negative, trace or 1

2

Normal

Abnormal Milk

(flakes, clots or discolouration)

≥ 2

3

Abnormal

(slight inflammation or slight swelling and/or warm to touch)

Normal

Abnormal

(moderate inflammation or moderate swelling, red colour and/or hot to touch)

Abnormal Milk

[obvious flakes, obvious clots or discolouration (bloody or serous consistency)]

4

Abnormal

(severe inflammation or severe swelling, with defined red colour and/or hot to touch)

Abnormal Milk or Agalactic

[numerous flakes, clots or severe discolouration (severe blood or serous consistency)]

5

(rectal temperature to determine systemic involvement)

Animals with dystocia, lameness, or non-mastitis infectious disease (i.e. footrot) which required antimicrobial or anti-inflammatory therapy that may have masked or altered the severity of mastitis were excluded from the analysis.

Imrestor-treated animals had an overall Day 0-30 mastitis incidence that was 31.9% lower than saline-treated animals. This difference was statistically significant (p = 0.02). The overall absolute reduction in mastitis incidence was 7.9% (Imrestor incidence = 16.8%, saline incidence = 24.6%) Imrestor-treated animals at all sites had a lower incidence of mastitis than saline controls. See table below for further details. Imrestor was effective in both cows and heifers; the overall clinical mastitis rates between Imrestor and saline-treated groups were statistically significantly different after adjusting for the effects of parity.

Location

GROUP

Mastitis Cases (n=)

Animals included (n=)

Mastitis Incidence (%)*

Absolute Risk Reduction (ARR) (= control - treatment incidence)*

Relative Risk Reduction (RRR) (= ARR / control incidence)*

Washington

Saline

11

38

28.9%

15.4%

53.3%

Imrestor

5

37

13.5%

Wisconsin

Saline

24

72

33.3%

8.0%

24.0%

Imrestor

19

75

25.3%

Colorado

Saline

14

73

19.2%

7.1%

36.8%

Imrestor

8

66

12.1%

California

Saline

20

76

26.3%

8.1%

30.9%

Imrestor

14

77

18.2%

France

Saline

13

74

17.6%

5.2%

29.8%

Imrestor

9

73

12.3%

COMBINED

Saline

82

333

24.6%

7.9%

31.9%

Imrestor

55

328

16.8%

*All rounding was performed after all calculations were complete.

TARGET ANIMAL SAFETY:

Margin of Safety: In the first study, forty primiparous and multiparous Jersey cows were assigned to one of four treatments: saline control, 1X, 2X, or 3X the intended dose of Imrestor administered at Days -7 and -3 prior to anticipated calving date and within 24 hours after calving. This dosing regimen resulted in the treatment being equivalent to 1.5X, 3X and 4.5X the recommended dose. Cows and heifers were monitored daily until 4 days postpartum. Calves were monitored daily for 14 days after birth. Measurements on cows included bodyweights, feed consumption, milk production, somatic cell counts, physical examinations, and clinical pathology. A complete postmortem examination was conducted on each adult animal. Measurements in calves included physical examinations, bodyweights, and hematology. There were no test article related findings associated with abnormal clinical observations, feed consumption, milk production, physical examinations, or urinalysis in adult animals. A mature neutrophilia was seen in all treated animals, regardless of dose group. This was considered a test article related change and consistent with the mechanism of action of Imrestor. No test article related hematology changes were observed in the calves. Observations of mastitis, metritis, and abomasal ulcers were documented, with more animals in the treated groups affected compared to the controls. Two animals (one each from 1X and 3X groups) had perforated abomasal ulcers found at necropsy.

A second study evaluated the margin of safety of pegbovigrastim in multiparous Holstein dairy cows. Forty-five multiparous Holstein dairy cows were assigned to one of five treatments: saline control, 1X, 2X, 2.5X, or 3X the recommended dose of one syringe of pegbovigrastim administered subcutaneously on Day -7 relative to the anticipated calving date and within 24 hours after calving. Cows were monitored daily until 14 days postpartum. Measurements included bodyweights, feed consumption, milk production, somatic cell counts, physical examinations, and clinical pathology, including reticulocyte counts and fecal occult blood. A postmortem examination that focused on the gastrointestinal tract, uterus, and mammary tissue was conducted on each cow. Calves were not evaluated in this study. There were no test article related findings associated with abnormal clinical observations, feed consumption, milk production, or physical examinations. A mature neutrophilia was observed in all treated animals which was consistent with the Imrestor mechanism of action and was similar to what was observed in the first margin of safety study. Treated animals had a greater number of mild gastrointestinal erosions and small areas of reddened or thinned mucosa along various portions of the gastrointestinal tract as compared to the control animals. No abomasal ulcers were seen on necropsy.

It was concluded from these studies that abomasal ulcerations/erosions could be test article related. However, given the lack of clinical signs associated with such gastrointestinal pathology in conjunction with the mild nature of the erosions in the second study, it was concluded that these findings were not clinically relevant.

Injection Site Safety: Injection site safety was evaluated following the injection of Imrestor into healthy periparturient dairy cows. Results of the injection site toleration study showed that subcutaneous injections of pegbovigrastim administered 14 days prior to slaughter in 6 cows had no gross lesions and would require no carcass trim at slaughter. Additionally, subcutaneous injections of pegbovigrastim administered approximately 12 hours prior to slaughter in 6 cows caused minimal acute local tissue reactions generally characterized by focal hemorrhage and edema and would be removed along with the hide at the time of slaughter and would not result in any carcass trim.

Field Safety: A total of 801 healthy periparturient commercial dairy heifers and cows were enrolled and treated with Imrestor or saline by subcutaneous injection in the neck when they were identified as being approximately 7 days before their anticipated calving date (Day -7), and again within 24 hours after calving (Day 0). There were no significant differences between treatment groups with respect to the following:

● Milk composition, somatic cell counts or daily milk production

● Subsequent reproductive performance, including first-service conception rates

● Fresh cow health outcomes, such as endometritis, displaced abomasum, or ketosis

● Duration of gestation, the percent of live births, or calf birth weight

● Health of calves from treated dams

STORAGE INFORMATION: Store under refrigeration (2° to 8°C). DO NOT FREEZE. Avoid prolonged exposure to sunlight. Excursions of up to 24 hours at room temperature (15° to 30°C) are allowed after receipt.

ENVIRONMENTAL SAFETY: Dispose of used syringes in a leak-resistant, puncture-resistant container in accordance with applicable federal, provincial and local regulations.

How Supplied

10 single-dose syringe packages with each syringe containing 15 mg of pegbovigrastim.

Manufactured by Elanco, Division Eli Lilly Canada, Inc., 150 Research Lane, Suite 120, Guelph, ON, N1G 4T2

For technical assistance or to report suspected adverse drug events, contact Elanco at 1-800-265-5475.

Elanco, Imrestor and the diagonal bar are trademarks owned or licensed by Eli Lilly and Company, its subsidiaries or affiliates.

AH0955

Revised 10-Mar-16

NAC No.: 1184068.0

ELANCO, Division Eli Lilly Canada Inc. & ELANCO CANADA LIMITED (successor to Novartis Animal Health Canada Inc.)
RESEARCH PARK CENTRE, 150 RESEARCH LANE, SUITE 120, GUELPH, ON, N1G 4T2
Telephone:   519-821-0277
Order Desk:   800-773-7603
Fax:   519-821-7831
Elanco Canada Limited Customer Service Telephone:   800-387-6325
Elanco Canada Limited Customer Service Fax:   800-827-5782
Website:   www.Elanco.ca
Every effort has been made to ensure the accuracy of the Imrestor information published above. However, it remains the responsibility of the readers to familiarize themselves with the product information contained on the Canadian product label or package insert.

Copyright © 2016 North American Compendiums. Updated: 2016-08-21

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