What is LibrelaTM ?
Librela (aka, bedinvetmab injection; aka Barensa in Australia) is one of the newest tools in our OA management tool box. It a monoclonal antibody (mAb) that targets nerve growth factor (NGF) and is used to control pain in dogs with osteoarthritis (OA) (Enomoto). NGF has been recognized as an important mediator of pain, and levels are increased in joints of dogs with OA (Isola). The goal of using Librela is to reduce excessive NGF and thereby reduce pain.
OA remains an incurable condition and controlling pain is one of, if not the primary goal of OA management. It is exciting that we have a new tool to reach for that very effectively reduces OA pain. But it is important to understand what Librela is and how it should best be used as part of a multi-modal OA plan.
What does it mean that Librela is a monoclonal antibody (mAb)?
Monoclonal antibodies are proteins that are engineered to bind to a single target. Librela binds to NGF and does not appear to bind to any other molecules in the body. Librela is a fully canine antibody (100% canine protein), so it can only be given to dogs. While it is 100% canine protein, there is still a small chance of dogs developing an immune reaction (anti-drug antibodies, ADA)- this risk is believed to be low (around 1-2% of dogs) (Krautmann). If ADA’s develop, they may reduce the efficacy of the product. Studies did not show the development of any immune complexes. Post approval there have been reports of hypersensitivity reactions (allergic type reactions) that typically including vomiting, diarrhea and lethargy. If a hypersensitivity reaction is seen following Librela injection, it should not be given again.
Monoclonal antibodies are typically long lasting after injection. Librela lasts about 1 month after subcutaneous injection. There is minimal processing of mAbs by the liver and kidneys and these types of drugs are generally considered safe to use in dogs with liver or kidney disease, although Librela was not studied in dogs with acute or severe liver or kidney disease.
How is Librela given?
Librela is given as a subcutaneous injection once a month. This can be an advantage for many dog owners that struggle with giving oral medications. Injections should be performed at the veterinary clinic. This provides the added advantage of the veterinary team being able to closely monitor weight, exercise recommendations, and assess how the dog is doing overall on a frequent basis.
Is Libela an anti-inflammatory?
Librela is not labeled as an anti-inflammatory medication, but according to the product label (LibrelaPI.com), NGF increases neurogenic inflammation as well as the release of pro-inflammatory mediators from immune cells. Librela is not indicated for use in acute inflammation (such as after surgery), but it may contribute to reducing chronic low- grade and neurogenic inflammation associated with OA through reducing NGF levels, though there are no studies in dogs confirming this.
When is Librela indicated?
According to recent pain management guidelines, Librela can be considered a first-line option for managing OA pain in dogs (Gruen, Monteiro). However, it is crucial that before using Librela veterinarians (1) establish that the pain being treated is due to osteoarthritis and not a condition that should be treated another way (such as a CCL injury for which surgery remains the recommendation), and (2) determine that Librela is the appropriate treatment for the individual dog in front of them. While guidelines are a good place to turn for expert opinion, it remains up to the individual veterinarian to determine what the best therapy for each patient with OA pain is. Veterinarians should weigh the risks and benefits of every potential treatment (because no medication is without potential side effects), consider the available evidence, utilize clinical reasoning, and have open and honest conversations with pet owners about the recommended treatment plan.
Librela was approved for use in dogs with OA pain. There are many dogs for which Librela may be a great option, and since its release, there have been many dogs for which Librela has provided exceptional pain control and improvement in their quality of life. But, Librela nor NSAIDs are meant to be prescribed without first establishing a diagnosis. It is important that a complete physical and orthopedic exam is performed and a diagnosis of OA induced pain is established prior to starting Librela.
Librela is not indicated to treat CCL disease; surgical stabilization of the stifle remains the first line recommendation for this condition. Librela has not been studied in dogs with CCL disease or following surgery and use post-operatively is not indicated.
Librela is not labeled for treating cancer pain or any other types of chronic pain and there are currently no studies of Librela in painful conditions other than OA. However, NGF is involved in other types of pain, and this is an area where future research may potentially support the use of anti-NGF mAbs in conditions other than OA (Denk).
Librela is not recommended for acute pain.
Establishing a diagnosis prior to using Librela allows you to discuss appropriate expectations and prognosis.
How quickly does Librela start working?
There are studies in which dogs receiving Librela showed significant improvement in mobility and reduced pain as early as 7 days after the first injection, but in some dogs it can take up to 6 weeks (2 weeks after the second injection) to see improvement (Corral, Michels). Not all dogs treated with Librela will show significant improvement, and if improvement has not been seen at the time of the 3rd injection, you should ensure that the correct diagnosis has been made prior to continuing therapy.
When is Librela contra-indicated?
NGF is required for normal growth and development of the nervous system, so Librela is contraindicated in dogs that are pregnant, nursing or breeding (including male dogs).
It should not be used in dogs under 12 months of age (and perhaps not in giant breed dogs less than 18 months).
If a dog has a reaction to Librela, it should not be given again.
Librela cannot be used in any other species; anti-drug antibodies would be expected to develop if Librela is given to other species.
What side effects are seen with Librela?
In one of the clinical trials for Librela approval, slightly more dogs that were treated with Librela developed UTIs and skin infections compared to placebo, but the researchers did not believe that these signs were due to Librela (Michels). In the European clinical trial, more dogs in the Librela group had elevation in BUN compared to placebo. However, this elevation in BUN was not associated with elevated creatinine– elevation of creatinine and/or diagnosis of renal disease was equal between treatment (Librela) and placebo (Corral).
Librela was released in Europe about 2.5 years before it became available in the US. According to the manufacturer, the most common side effect that has been attributed to Librela in Europe since its release is increased thirst (polydypsia, PD) which leads to increased urination (polyuria, PU) and in some cases urinary incontinence. The manufacture does not believe that this PU/PD is associated with organ dysfunction but it does seem to be related to the use of Librela. Some dogs that develop PU/PD are continued on Librela and there are reports of the symptoms resolving or improving over time. The mechanism of how Librela causes increased thirst is not known at this time.
There are also reports of injection site reactions (swelling, warmth), vomiting, diarrhea, anorexia, lethargy, lack of efficacy, seizures, ataxia (see below for more about neurologic symptoms), death, allergic reactions, immune mediated disease (hemolytic anemia and thrombocytopenia). (Canadian Package Insert) It is not known at this time if these adverse reactions are caused by Librela. It is very important that any potential side effects be reported (see last question) so that we can understand the true incidence of these events and if there is truly a causality. This will then help guide case selection and conversations with dog owners when discussing the potential use of Librela.
Has RPOA been seen in dogs treated with Librela?
RPOA (Rapidly Progressive Osteoarthritis) is a condition that was reported in humans that were enrolled in clinical trials for anti-NGF mAbs. RPOA is a known condition in humans unrelated to anti-NGF mAbs, but in clinical trials studying anti-NGF mAbs, people receiving the mAbs had a higher incidence of developing RPOA compared to those getting placebo. The risk increased if people were also taking NSAIDs. The disease of RPOA in humans is a very rapid (weeks to months) destruction of the joint with associated severe pain. Radiographs show collapse of the joint space and bone lysis, but don’t show proliferation. An equivalent disease to RPOA has not been reported previously in dogs. As of May 2024 there have been a few cases of suspected RPOA reported in dogs receiving Librela, but the condition has not not been confirmed (Werts).
Can Librela be used with NSAIDs or other medications used to treat OA?
There are no studies of concurrent, long-term use of NSAIDs and Librela. Concurrent use is not considered contra-indicated, but perhaps there should be some caution until we know more. While the manufacture does not give explicit recommendations of how to use Librela with NSAIDs, many veterinarians are using NSAIDs for a few weeks as dogs get started on Librela. A wash-out period between NSAIDs and Librela is not believed to be needed. In dogs with severe OA pain, it may be necessary to use multiple analgesics, including Librela, NSAIDs, and other analgesics such as amantadine and acetaminophen.
There are no studies of Librela with other analgesics and there are no known drug interactions or contraindications.
Librela can be given at the same time as Adequan, but it should be given at a different location on the body.
Is Librela a stand-alone therapy?
No, Librela does not replace the need for multi-modal management of OA. It is essential that the fundamental strategies of weight management, appropriate exercise and environmental modifications be included in an OA plan, with or without Librela. One of the most proven methods of reducing the progression and severity of OA is through maintenance of a lean body condition (“on the skinny side of normal”) and this should be accomplished through caloric restriction (see all of the CARE resources on weight management techniques for dogs with OA). Dogs with OA should also exercise regularly, primarily by going for leash walks and doing low-impact exercises. (Learn more about exercise and activity here) It is particularly important that dogs gradually increase their activity after starting Librela in order to reduce the chance of new or worsening injuries. Adapting your home and even car for dogs with OA is also important. Check out all of the tips on environmental modifications and visit the CARE shop for our recommendations for traveling with your dog in the car.
There will certainly be times when Librela is not sufficient alone as a pain reliever. There are no studies yet on the combined use of Librela with other pain relievers, so it is up to the individual veterinarian to determine the best recommendation for the dog, knowing that pain must be addressed even if there are some unknowns or potential risks.
Does Librela cause neurologic symptoms?
There have been reports of dogs developing new or worsening ataxia (uncoordinated gait) and/or paresis (weakness) after starting Librela. Librela was not studied in dogs with neurological disease that would interfere with assessment of the dog’s mobility. So it is not known how Librela could impact dogs with neurologic diseases such as polyneuropathy (ie GOLPP), degenerative myelopathy or intervertebral disc disease. The drug itself is too large to cross an intact blood brain barrier (BBB), so it is not likely that Librela would lower NGF levels in the central nervous system of a dog with a healthy, intact BBB. What is not known is how Librela may impact dogs with peripheral nerve disease (NGF does play a role in supporting degenerating peripheral nerves) or diseases of the CNS which may or may not have a compromised BBB. This is an area where we need to learn more and use of Librela in dogs with concurrent neurologic disease should follow a risk/benefit discussion with the individual dog owner. In dogs that do not have a prior diagnosis of neurologic disease it is still worth advising the dog owner that there have been reports of new neurologic symptoms in dogs treated with Librela. According to the manufacture, these reports are considered rare (1-10/10,000 dogs treated). However, the reported frequency of adverse events associated with any product (not just Librela) likely underestimates the true frequency of occurrence due to under-reporting by veterinarians and pet owners (see the last question below).
Are there any recommendations for monitoring after giving Librela?
It is always a good idea to do blood work before starting a new drug. If you identify a new medical condition it is recommended to have the patient stabilized before starting Librela and blood work should be monitored as you would routinely for the specific disease. Blood work monitoring is not currently recommended as routine monitoring for Librela use.
Dogs should be rechecked by a veterinarian after starting Librela to ensure that the product is effective and side effects aren’t seen. If dogs are returning for tech appointments for their injections, it is a good idea that the vet tech has a checklist of questions such as this to ask before administering Librela in order to identify potential red flags.
Are there any restrictions or activity recommendations after starting Librela?
Yes! Some dogs may feel better than they have in years (which is great!) and want to run/jump/play in ways that their body is not ready for. There have been dogs that experience new or worsening injuries after starting Librela (not so great). It is strongly recommended that dogs follow an exercise program that gradually increases their fitness and endurance after starting Librela. The manufacture has developed guidelines for gradual increase in activity after starting Librela. Alternatively (and more ideally) dogs could have a personalized exercise program developed for them by a rehabilitation professional.
What if I have a patient that develops a side effect that might be due to Librela?
While Librela has been available since 2021 in many countries, and many millions of doses have been sold, it is still a relatively new drug and there are still things we need to learn about it. The best way to track anything abnormal is to report it to the manufacture (Zoetis). You can contact your Zoetis representative or in the US, call 1-888-963-8471 or email [email protected]. The FDA monitors these reports and it is the best way for veterinarians and the public to document any concerns with a product. Alternatively you can report directly to the FDA by calling 1-888-FDA-VETS. It is very important that you report any potential side effects from any medication to the manufacture- this is true even for drugs that have been out for a long time.
References:
Enomoto M, Mantyh PW, Murrell J, et al. Anti-nerve growth factor monoclonal antibodies for the control of pain in dogs and cats. Vet Record, 2018. https://pubmed.ncbi.nlm.nih.gov/30368458/
Isola M, Ferrari V, Miolo A, et al. Nerve growth factor concentrations in the synovial fluid from healthy dogs and dogs with secondary osteoarthritis. VCOT, 2011 https://pubmed.ncbi.nlm.nih.gov/21674121/
Krautmann M, Walters R, Cole P, et al. Laboratory safety evaluation of bedinvetmab, a canine anti-NGF mAb, in dogs. Vet J, 2021. https://pubmed.ncbi.nlm.nih.gov/34391918/
Corral MJ, Moyaert H, Fernandes T, et. al. A prospective, randomized, blinded, placebo-controlled multisite clinical study of bedinvetmab, a canine monoclonal antibody targeting nerve growth factor, in dogs with osteoarthritis. Vet Anesthesia Analgesia, 2021. https://doi.org/10.1016/j.vaa.2021.08.001
Michels GM, Honsberger NA, Walters, RR, et.al. A prospective, randomized, double-blind, placebo-controlled multisite, parallel-group field study in dogs with osteoarthritis conducted in the United States of America evaluating bedinvetmab, a canine anti-nerve growth factor monoclonal antibody. Vet Anesthesia and Analgesia, 2023. https://doi.org/10.1016/j.vaa.2023.06.003.
Denk F, Bennett DL, McMahon SB. Nerve growth factor and pain mechanisms. Annu Rev Neurosci, 2017.
Librela Freedom of Information Summary