Librela™
(bedinvetmab injection)

Canine anti-nerve growth factor monoclonal antibody for subcutaneous use in dogs only.

Single-Use Vial

Federal law restricts this product to use by or on the order of a licensed veterinarian.

LIBRELA (bedinvetmab injection) is a sterile injectable solution containing 5, 10, 15, 20, or 30 mg/mL of bedinvetmab in 20 mM histidine buffer pH 5.0 [(0.027% w/v L- histidine and 0.382% w/v histidine HCl monohydrate), 8.5% w/v trehalose dihydrate, 0.005% w/v disodium EDTA dihydrate, 0.01% w/v L-methionine, and 0.1% w/v poloxamer 188]. Bedinvetmab is a canine IgG monoclonal antibody (mAb), in which the variable regions from canine B cell sequence were joined with canine IgG constant sequences, and is expressed through recombinant DNA techniques in Chinese hamster ovary (CHO) cells. Bedinvetmab binds to nerve growth factor (NGF) to reduce NGF’s effects. Such mAbs are commonly referred to as anti-NGF mAbs.

LIBRELA is indicated for the control of pain associated with osteoarthritis in dogs.

The minimum target dose of LIBRELA is 0.23 mg/lb (0.5 mg/kg) body weight, administered subcutaneously once a month. Dogs should be dosed by weight range according to the specific dosing information below.

The product does not contain a preservative. The full content of each vial is for single-use only. Once punctured, contents of the vial should be used immediately and any remaining solution should be discarded.

Dogs weighing ≥ 11 lb (≥ 5 kg):
Dogs should be dosed by weight range according to the Dosing Table below (Table 1). Dogs are given the full content of 1 or 2 vials of the appropriate concentration based on body weight. Aseptically withdraw the total dose into a single syringe and administer immediately.

Table1. Dosing Table

Dogs < 11 lb:
Aseptically withdraw 0.045 mL/lb (0.1 mL/kg) from a 5 mg/mL vial (orange vial) into a single syringe and administer immediately. Discard the vial after the dose has been withdrawn.

Effectiveness may not be achieved until after the second dose (see EFFECTIVENESS).

LIBRELA should not be administered to dogs with known hypersensitivity to bedinvetmab.

LIBRELA should not be used in breeding dogs or in pregnant or lactating dogs. Immunoglobulin G class antibodies such as LIBRELA can pass through the placental blood barrier and be excreted in milk. Fetal abnormalities, increased rates of stillbirths and increased postpartum fetal mortality were noted in rodents and primates receiving anti-NGF monoclonal antibodies.

User Safety Warnings
Not for use in humans. Keep this and all drugs out of reach of children.
For use in dogs only.

Hypersensitivity reactions, including anaphylaxis, could potentially occur in the case of accidental self-injection.

In case of accidental self-injection, seek medical advice immediately and show the package leaflet, vial or carton to the physician.

Pregnant women, women trying to conceive, and breastfeeding women should take extreme care to avoid accidental self-injection.

The importance of Nerve Growth Factor in ensuring normal fetal nervous system development is well-established and laboratory studies conducted on nonhuman primates with human anti-NGF antibodies have shown evidence of reproductive and developmental toxicity.

Administration of monoclonal antibodies may be associated with hypersensitivity reactions and delayed hypersensitivity reactions. If anaphylaxis or other hypersensitivity reaction occurs, discontinue use and institute appropriate therapy.

The safe use of this product with other monoclonal antibodies has not been evaluated. Use with caution in dogs with known hypersensitivity to other immunoglobulin therapy.

Evaluations were not made to determine if interactions occurred between LIBRELA and veterinary vaccines.

Treatment with LIBRELA may result in the formation of anti-bedinvetmab antibodies and potentially the loss of product effectiveness (see IMMUNOGENICITY).

The safe use of anti-NGF monoclonal antibodies with concurrent nonsteroidal anti-inflammatory drugs (NSAIDs) has not been established in dogs. In human clinical trials, rapidly progressing osteoarthritis (RPOA) has been reported in a small number of patients receiving humanized anti-NGF monoclonal antibody therapy. The incidence of these events increased in human patients receiving NSAID treatment long term in combination with an anti-NGF monoclonal antibody. RPOA has not been characterized or reported in dogs.

The safety and effectiveness of LIBRELA has not been evaluated in dogs less than 12 months of age.

LIBRELA has not been studied in dogs that have a history of cruciate ligament rupture within six months before initial product use as these cases were excluded from the field studies.

Long term effects which may occur more than 9 months after the use of LIBRELA have not been evaluated.

NGF is expressed within the heart and vasculature, and the long-term effects of reduced NGF in dogs with cardiac disease are unknown.

Primates receiving high doses of anti-NGF monoclonal antibodies had anatomical changes in postganglionic cell bodies (reduced size and number of neurons). The change in cell body size returned to normal after anti-NGF monoclonal antibody administration was discontinued. NGF is involved in the normal development of sensory and sympathetic nerve fibers in developing animals. This may be important with use of LIBRELA in young growing dogs.

The safety of LIBRELA was assessed in a masked, controlled 84-day US field study evaluating the effectiveness of LIBRELA for the control of pain associated with osteoarthritis. Enrollment included 272 dogs, 135 dogs treated with LIBRELA and 137 dogs treated with a negative control (sterile saline). The enrolled dogs were at least 1 year of age (1 to 17 years old), weighed between 1.8 to 62.7 kg and were of various breeds or non-purebred. Dogs were dosed at 28-day intervals and received up to three injections. The most common adverse reactions reported during the study are summarized in Table 2 below.

Table 2. Number (%) of Dogs with Adverse Reactions Reported in the US Field Study

The safety of LIBRELA was also evaluated in a masked, controlled 84-day European field study evaluating the effectiveness of LIBRELA for the control of pain associated with osteoarthritis. Enrollment included 281 dogs, 138 dogs were treated with LIBRELA and 143 treated with a negative control (sterile saline). The enrolled dogs were at least 1 year of age (1 to 17.5 years old), weighed between 1.7 to 66 kg and were of various breeds or non-purebred. Dogs were dosed at 28-day intervals and received up to three injections. The most common adverse reactions reported during the study are summarized in Table 3 below.

Table 3. Number (%) of dogs with Adverse Reactions Reported in the European Field Study

One dog in the LIBRELA group was diagnosed with pyelonephritis on Day 15; this dog had pre-existing increased serum BUN and creatinine and a recent history of urinary tract infection that was not confirmed resolved prior to enrollment. Non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen were initiated on Day 7 for osteoarthritis-associated joint pain but NSAIDs were discontinued on Day 10 due to anorexia and gastroenteritis; azotemia worsened at Day 13 and the dog received no further LIBRELA treatment.

One dog in the LIBRELA group with a history of atopy, developed mild alopecia and mild erythema on the injection site on Days 5 and 23. Both episodes of alopecia and erythema resolved with treatment.

A total of 89 dogs were enrolled in a 6-month, single arm, open labeled, uncontrolled continuation of the EU field study and received monthly subcutaneous injections of LIBRELA. The study provided additional field safety information.

One dog experienced acute gastroenteritis and recovered following treatment for abdominal pain, fever, vomiting, and anorexia. One large breed dog enrolled for stifle osteoarthritis developed acute forelimb lameness that was diagnosed as elbow dysplasia. Two dogs presented with rear limb paresis of unknown etiology, one of whom responded to ongoing NSAID treatment and one who did not.

To report suspected adverse drug events, for technical assistance or to obtain a copy of the Safety Data Sheet (SDS), contact Zoetis Inc. at 1-888‑963-8471.

For additional information about reporting adverse drug experience for animal drugs, contact FDA at 1-888-FDA-VETS or www.fda.gov/reportanimalae.

Antibodies binding to bedinvetmab (i.e., an anti-drug antibody, ADA), were detected using a multi-tiered ADA testing approach (screening, confirmatory, and titration). Testing the confirmed ADA samples for neutralizing activity of bedinvetmab was not performed. Due to limitations of the assay methods performed to evaluate immunogenicity (confirmatory and titration), clinically relevant conclusions or correlations were not determined from the immunogenicity data reported.

In the US Field Effectiveness Study, 267 of 272 enrolled dogs with osteoarthritis were evaluated for immunogenicity after receiving up to 3 doses of LIBRELA. The presence of pre-existing ADAs was confirmed in 5 out of 267 dogs; 4 dogs in the LIBRELA group and 1 dog in the control group. Three of these LIBRELA-treated dogs continued to have ADAs confirmed after treatment with LIBRELA. Of the remaining dogs evaluated for immunogenicity, the presence of ADAs was confirmed on Day 84 in 1 dog in the LIBRELA-treated group and 1 dog in the control group.

In the EU Field Effectiveness Study, 281 of 287 enrolled dogs with osteoarthritis were evaluated for immunogenicity after receiving up to 3 doses of LIBRELA. The presence of pre-existing ADAs was confirmed in 2 out of 281 dogs; both in the control group. Of the other 141 dogs in the control group, the presence of ADA was confirmed in 1 dog after receiving treatment with placebo (on Study Visit Day 56). Of the 138 LIBRELA-treated dogs, the presence of ADA was confirmed in 2 dogs after treatment with LIBRELA (1 dog on Study Visit Day 84 and 1 dog on Study Visit Study Day 28). Eighty-nine LIBRELA-treated dogs continued on with once monthly treatment for an additional six months, and 82 of these dogs were evaluated for immunogenicity after receiving up to 6 additional doses of LIBRELA. The presence of ADA was confirmed in an additional 2 dogs.

In the 6-Month Safety Study, the presence of ADAs was confirmed in 2 out of 8 negative control dogs and no ADAs were confirmed in any of the 24 dogs administered 7 doses of LIBRELA.

The observed incidence of antibody positivity in an assay is highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to LIBRELA with the incidence of antibodies to other products may not be appropriate.

The overall evidence, based on the results of two field studies, supports the conclusion that LIBRELA is effective for the control of pain associated with osteoarthritis in dogs when given as a minimum of two doses administered one month apart.

A US field effectiveness study and a European (EU) field effectiveness study were conducted using a similar study design. Both studies included a group administered LIBRELA and a negative control group that was administered sterile saline. The primary effectiveness endpoint was treatment success (Yes/No) at Day 28 based on owner assessment of pain measured on the Canine Brief Pain Inventory (CBPI).1-2 CBPI treatment success was a secondary endpoint at Days 7, 14, 42, 56 and 84. Treatment success was defined as a reduction of ≥ 2 in Pain Interference Score (PIS) and ≥ 1 in Pain Severity Score (PSS) vs. Day 0. Dogs receiving rescue treatment (e.g., for lack of efficacy (LOE)) or withdrawn for LOE were counted as treatment failures starting on the day of rescue or withdrawal, respectively.

While the studies had similar success rates on Day 28 in the treatment groups administered LIBRELA (48% and 45.2%), the studies had differences in the success rates in the control groups. The success rate in the control group in the US study was 36.1% and the success rate of the control group in the EU study was 17.0%. Based on these results, there was a larger treatment effect size in the EU study as compared to the US study, such that the US study did not demonstrate a significant difference at Day 28. In the EU study, the primary effectiveness variable was successful and met statistical significance at Day 28 (P = 0.0018).

The CBPI data from both studies demonstrated a greater percentage of dogs achieving treatment success in the LIBRELA-treated vs. control groups at Day 42. This success rate was maintained with a third administration at Day 56 through the end of the study at Day 84. Taken together, the US and EU studies establish the effectiveness for LIBRELA (bedinvetmab injection) for the control of pain associated with osteoarthritis in dogs when given as a minimum of two doses administered one month apart.

LIBRELA (bedinvetmab injection) should be stored in a refrigerator, 2° – 8°C (36° – 46° F). Do not freeze. Store vials in their boxes to protect from prolonged exposure to light. Once punctured, contents of the vial should be used immediately and any remaining solution should be discarded.

LIBRELA is available in 5 strengths packaged in 4 mL glass vials containing an extractable volume of 1 mL of clear solution. Each strength is available in cartons containing 2 or 6 vials.

1. Brown DC, Bell M, Rhodes L. Power of treatment success definitions when the Canine Brief Pain Inventory is used to evaluate carprofen treatment for the control of pain and inflammation in dogs with osteoarthritis. Amer J Vet Rsch 2013; 74(12):1467-1473.

2. Brown DC, Bell M, Rhodes L. ERRATUM to: Power of treatment success definitions when the Canine Brief Pain Inventory is used to evaluate carprofen treatment for the control of pain and inflammation in dogs with osteoarthritis. Amer J Vet Rsch 2014; 75(4):353.

Approved by FDA under NADA # 141-562

Distributed by:
Zoetis Inc.
Kalamazoo, MI 49007
March 2023

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