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A Supplement to Clinician’s Brief
A Peer-Reviewed Journal | November 2014 | Volume 1 Number 2
0steoarthritis | Alprazolam | Inflammatory Bowel Disease with Pancreatitis | Cefpodoxime
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November 2014 Plumb’s Therapeutics Brief 1
A Peer-Reviewed Journal • November 2014 • Volume 1 Number 2
EDITORS IN CHIEFDonald C. Plumb, PharmD • Lauren A. Trepanier, DVM, PhD, DACVIM, DACVCP
Published as a Supplement to Clinician’s Brief by Editor Indu Mani, DVM, ScD, FNAP [email protected] Editorial DirectorMichelle N. Munkres, [email protected] ConsultantJennifer L. Schori, [email protected] EditorCj [email protected] Assistant EditorKami [email protected] Editor at Large Antoinette Passaretti [email protected] Design/Production Mistretta Design Group [email protected] Interactive & Operations Director, OperationsNikki [email protected] Medical ContributorDawn McCluskey, [email protected] Managing Editor Lindsay [email protected] Interactive Project Manager Becca [email protected] Interactive Editorial AssistantJenny [email protected] Developers Kyle [email protected] [email protected] John O’[email protected] Kristen [email protected] Naomi Murray, [email protected] Whitney [email protected] Jillian [email protected] Chelsea [email protected]
BRIEF MEDIA 2021 S Lewis Avenue #760 Tulsa, OK 74104 T 918-749-0118 • F 918-749-1987 President Elizabeth [email protected] © 2014 Brief Media, an Educational Concepts company. All rights reserved. Reproduction in whole or in part without expressed written permission is prohibited.
WORDS OF CAUTIONAlprazolamLisa Radosta, DVM, DACVB
THERAPEUTICS SNAPSHOTCefpodoximeJennifer Schissler Pendergraft, DVM, MS, DACVD
RED LIGHT, GREEN LIGHTInflammatory Bowel Disease with Concurrent PancreatitisJulie Allen, BVMS, MS, DACVIM (Small Animal)
Rx SOLUTIONSWhich Drugs Can Be Used for Osteoarthritis in Dogs?Kelley Thieman Mankin, DVM, MS, DACVS (Small Animal)
CAPSULES IN BRIEF
ADVERTISERS INDEX
THERAPEUTICS BULLETIN
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COMING SOON! Dr. Plumb tackles key ISSUES & ANSWERS
g Front cover artwork by Kip Carter, MS, CMI
2 plumbstherapeuticsbrief.com November 2014
Side Effects & Adverse Events! Common side effects associated
with alprazolam administration include1
• Ataxia • Diarrhea • Disinhibition • Increased appetite • Paradoxical excitement • Sedation • Vomiting
! In animals, physiologic tolerance can occur and possibly lead to rebound and/or withdrawal signs when alprazolam is discontinued.2,3
• Rebound effects may include recurrence of original signs for which the medication was chosen (eg, anxiety, phobia).
• In humans, signs of withdrawal include seizures, irritability, anxiety, panic attacks, and tension.
Precautionary Measures! Use caution in patients receiving
medications that impair or induce oxidative metabolism by the cytochrome P450 3A4 enzyme,4
including • Antifungals (eg, ketoconazole,
itraconazole) 4
• Certain antibiotics (eg, doxycycline)4
• Certain anticonvulsants (eg, phenobarbital)4
! Gradual decrease of alprazolam over 2 weeks is recommended for animals that have been treated daily for >14 days.2
! Alprazolam treatment for aggression is controversial because of potential risk for disinhibition.
• Patients presented for aggression should be closely monitored for irritability and worsening of aggressive signs.1
! Certain nutraceuticals and natural substances (eg, St. John’s wort, valerian root) may decrease serum alprazolam levels by induction of CYP3A4 and increase CNS depression.
• Administer these substances with caution in patients receiving alprazolam.4
! Doses may need to be decreased in older patients or those with impaired hepatic or renal function.
Overdose Toxicity ! Clinical signs of accidental
overdose in dogs typically develop 10–30 minutes after ingestion and include1,5
• Ataxia • Depression • Diarrhea • Disorientation • Hyperactivity • Hypothermia • Increased salivation • Tachycardia • Tachypnea • Tremors • Vocalization • Vomiting • Weakness
Treatment! Induce vomiting (if <3 hours
postingestion) and provide supportive care. • In severe cases, flumazenil
(benzodiazepine receptor antagonist) can be used.1
Do Not Use ! Based on evidence of placental
passage in animals and breast milk passage in humans, alprazolam should be avoided in pregnant or lactating animals.1,3,4
! WORDS OF CAUTION | Risks | Adverse Events | ToxicitiesPEER REVIEWED
AlprazolamLisa Radosta, DVM, DACVBFlorida Veterinary Behavior ServiceJupiter, Florida
Alprazolam is generally safe to use in companion animals; however, behavioral and medical side effects and adverse events can occur.
November 2014 Plumb’s Therapeutics Brief 3
! Because of increased risk for narrow-angle glaucoma in at-risk humans, do not use alprazolam in animals with glaucoma.3,6-8
! When prescribing controlled or other substances with potential for abuse by humans, veterinarians should monitor the accuracy of their prescriptions and verify that requested refills are in agreement with dosing.
REFERENCES1. Benzodiazepines. Veterinary Psycho-
pharmacology. Crowell-Davis SL, Murray T—Ames, IA: Wiley-Blackwell, 2005, pp 34-40.
2. Pharmacological approaches to changing behavior and neurochemistry: Roles for diet, supplements, nutra-ceuticals, and medication. In Manual of Clinical Behavioral Medicine for Dogs and Cats. Overall KL—St. Louis: Mosby Elsevier, 2013, pp 477-478.
3. Alprazolam. In Stahl’s Essential Psychopharmacology: Prescriber’s Guide, 5th ed. Stahl SM—New York: Cambridge University Press, 2014, pp 1-6.
4. Drug Information Handbook for Psychiatry, 7th ed. Fuller MA, Sajatovic M—Hudson, OH: Lexi-Comp, 2009, pp 68-72.
5. Accidental ingestion of alprazolam in 415 dogs. Wismer TA. Vet Hum Toxicol 44(1):22-23, 2002.
6. Bilateral angle closure glaucoma and visual loss precipitated by antidepressant and antianxiety agents in a patient with depression. Kadoi C,
Hayasaka S, Tsukamoto E, et al. Ophthalmologica 214(5):360-361, 2000.
7. Glaucoma—The updates. Petersen-Jones SM. WSAVA Congress Proceedings, 2007; Sydney.
8. Narrow-angle glaucoma and goniodysgenesis. WVC Proceedings, 2011; Cape Town.
LISA RADOSTA, DVM, DACVB, is owner of Florida Veterinary Behavior Service in Jupiter. Dr. Radosta has authored textbook chapters, writes for Palm Beach Post, and podcasts CE for VetGirl. Her publications include research papers on thyroid disease and clinician–client communication. Dr. Radosta lectures nationally and internationally, is behavior section editor for Small Animal Advances in Medicine and Surgery, and is on the AAHA Behavior Management Guidelines task force and Fear Free advisory board. She completed her residency in behavioral medicine at University of Pennsylvania, where she received two national research awards.
Patients presented for aggression should be closely monitored for irritability and worsening of aggressive signs.1
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Cefpodoxime
THERAPEUTICSSNAPSHOTPEER REVIEWED
Cefpodoxime proxetil is an oral third-generation cephalosporin approved for treatment of skin infections in dogs.
Jennifer Schissler Pendergraft, DVM, MS, DACVDColorado State University
The bactericidal spectrum for cefpodoxime proxetil involves both gram-positive cocci and gram-negative bacilli.• Spectrum for gram-positive cocci includes methicillin-susceptible
Staphylococcus spp and group G β-hemolytic Streptococcus canis.1
• Spectrum for gram-negative bacilli includes Proteus mirabilis, Pasteurella multocida, and Escherichia coli.1
In dogs, cefpodoxime treatment is most commonly prescribed for regional or generalized Staphylococcus pseudintermedius bacterial folliculitis.• Staphylococcal pyoderma is most commonly observed in patients with
cutaneous hypersensitivity disorders.
Given the gram-negative spectrum of cefpodoxime, its use as a first-tier antimicrobial for cutaneous staphylococcal infections is controversial.• Individual and population selection for antimicrobial-resistant flora may occur,
particularly extended-spectrum β-lactamase–resistant E coli.2
• In the author’s opinion, administration of cefpodoxime should be limited to cases that require less frequent dosing to ensure compliance or in patients with mixed infections that require the extended gram-negative spectrum of cefpodoxime.
Clinical Applications
The bactericidal spectrum for cefpodoxime treatment of skin infections in dogs ranges from gram-positive cocci to gram-negative bacilli.
November 2014 Plumb’s Therapeutics Brief 5
REFERENCES1. Zoetis (2013). Simplicef (package insert).
Kalamazoo, MI. 2. Guidelines for the diagnosis and
antimicrobial therapy of canine superficial bacterial folliculitis (Antimicrobial Guidelines Working Group of the International Society for Companion Animal Infectious Diseases). Hillier A, Lloyd DH, Weese JS, et al. Vet Dermatol 25(3):163-175, 2014.
3. Müller & Kirk’s Small Animal Dermatology, 7th ed. Miller WH Jr, Griffin CE, Campbell KL—St Louis: Mosby Elsevier, 2013, page 191.
4. Treatment outcome of dogs with methicillin-resistant and methicillin-susceptible Staphylococcus pseudintermedius pyoderma. Bryan J, Frank LA, Rohrbach BW, et al. Vet Dermatol 23(4):361-368, 2012.
5. The effect of ‘allergenic’ and ‘nonallergenic’ antibiotics on dog keratinocyte viability in vitro. Voie KL, Lucas BE, Schaeffer D, et al. Vet Dermatol 24(5):501-e119, 2013.
6. Drug hypersensitivity reactions targeting the skin in dogs and cats. Voie KL, Campbell KL, Lavergne SN. JVIM 26:863-874, 2012.
JENNIFER SCHISSLER PENDERGRAFT, DVM, MS, DACVD, is assistant professor of veterinary dermatology at Colorado State University with a teaching (James L. Voss Veterinary Teaching Hospital), clinical, and research appointment. Her research efforts focus on staphylococcal infections, infection control, antimicrobial resistance, canine immunology, canine atopic dermatitis, and otology. After Dr. Pendergraft earned her DVM from Colorado State University, she completed a combined MS and dermatology residency program at The Ohio State University.
Protocol & Side EffectsCefpodoxime is dosed at 5–10 mg/kg PO q24h.1
• Once-daily dosing promotes client compliance. —Can administer with food to ease patient dosing• Treatment for 1 week beyond clinical resolution, along with adjunct
topical antimicrobial therapy, is recommended for patients with staphylococcal bacterial folliculitis.2,3
The most commonly observed side effects—vomiting and diarrhea—reportedly occur in less than 5% of patients.4 • β-lactams have been implicated in canine cutaneous drug eruptions5
that may occur up to 2 weeks after treatment initiation. — The true prevalence of cutaneous adverse drug reactions in dogs
(and cats) is presently unknown for any antibiotic, as it is likely that these drug eruptions are underreported.6
Conducting bacterial culture and sensitivity testing is recommended before cefpodoxime administration to patients that • Failed to respond to empiric antimicrobial therapy• Have an extensive antimicrobial history• Had a previous multidrug-resistant infection• Cohabitate with an individual (human, animal) that has a confirmed
multidrug-resistant infection• Have a clinical diagnosis of deep pyoderma
In consideration of the worldwide presence of canine methicillin-resistant staphylococci, a recheck examination must be performed in all patients before discontinuation of cefpodoxime. • Lack of improvement or development of new cutaneous lesions
during cefpodoxime therapy should prompt examination and consideration for the presence of resistant infection or cutaneous drug eruption.
Precautionary Measures
CAPSULES IN BRIEFCURRENT RESEARCH FROM THE LITERATURE
The following capsules provide brief overviews of key therapeutics studies explored in leading scientific journals.
Pradofloxacin, a new third-generation oral fluoroquinolone, has lower in vitro minimum inhibitory concentrations against gram-positive aerobic bacteria and anaerobes. It is also active against Bartonella henselae, Pasteurella multocida, Bordetella bronchiseptica, extraintestinal Escherichia coli, and some mycobacterial species. Its dual-target mechanism of action may make it less likely than other fluoroquinolones to select for bacterial mutations.
SOURCE Pradofloxacin: A novel veterinary fluoroquinolone for treatment of bacterial infection in cats. Sykes JE, Blondeau JM. Vet J 201:207-214, 2014.
Bacterial Infection Treatment for Cats
Pamidronate, an amino bisphosphonate, was used to investigate its in vitro effects on cancer cell lines and palliation in cats with nonresectable skeletal tumors. In vitro, pamidronate decreased feline cancer cell proliferation. Pamidronate can be administered practically in a clinical setting; however, because it was used as part of multimodal treatment, clinical response and pain control could not be attributed to pamidronate alone.
SOURCE Pamidronate disodium for palliative therapy of feline bone-invasive tumors. Wypij JM, Heller DA. Vet Med Intl doi.org: 10.1155/2014/675172.
Efficacy of Pamidronate on Cancer Cells
Feline immunodeficiency virus (FIV) has been used as a model to study human immunodeficiency virus (HIV) and latent HIV reservoirs. In this study, chronically FIV-infected aviremic cats were treated with oral histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA) to induce latent viral reactiva-tion. Results suggested in vivo induction of viral transcriptional reactivation.
SOURCE Treatment of chronically FIV-infected cats with suberoylanilide hydroxamic acid. McDonnel SJ, Liepnieks ML, Murphy BG. Antiviral Res 108:74-78, 2014.
FIV as a Study of HIV
Unbound carprofen concentrations in canine interstitial fluid (ISF) were measured using in vivo ultrafiltration, and pharmacokinetic parameters of free carprofen concentrations in inflamed and normal control tissue sites were compared. Results indicated that (1) in vivo ultrafiltration techniques may be reliable for measuring unbound carprofen in ISF, (2) unbound drug disposition into tissue from unbound plasma drug concentrations is greater than predicted, and (3) minimal differences exist in drug concentrations and pharmacokinetic parameters between inflamed and uninflamed tissues.
SOURCE The effect of inflammation on the pharmacokinetics of carprofen in tissue fluid of dogs using in vivo ultrafiltration. Messenger K, Wofford J, Papich MG. AAVPT Biennial Symposium Proceedings May 2013.
Carprofen Unbound
6 plumbstherapeuticsbrief.com November 2014
November 2014 Plumb’s Therapeutics Brief 7
Mesenchymal stromal cells (MSCs) have been proposed as vehicles for delivering anticancer agents, as they are simple to isolate, are present in many different mammalian tissues, and are able to hone in on the tumor microenvironment. In this study, MSCs primed with paclitaxel (a chemotherapeutic agent) demonstrated significant antiproliferative activity when tested in vitro on a human pancreatic cell line. These results suggested that MSCs might be used to package and deliver drugs for more targeted cancer therapy.
SOURCE Paclitaxel is incorporated by mesenchymal stromal cells and released in exosomes that inhibit in vitro tumor growth: A new approach for drug delivery. Pascucci L, Coccè V, Bonomi A, et al. J Control Release 192:262-270, 2014.
Role of Mesenchymal Stromal Cells in New Drug Development
Canine hemangiosarcoma is poorly responsive to conventional chemotherapy. Progenitor cell populations from hemangiosarcoma lines grown as nonadherent sphere cell populations were found to contain subpopulations of drug-resistant cells. New treatment approaches may be utilized from this method of identifying the mechanisms that sphere cells use to elude cytotoxic drugs.
SOURCE Identification of drug-resistant subpopulations in canine hemangiosarcoma. Khammanivong A, Gorden BH, Frantz AM, et al. Vet Comp Oncol doi: 10.1111/vco.12114.
Drug Resistance & Canine Hemangiosarcoma
Histamine type 2 (H2) receptor antagonists and proton pump inhibitors are known to induce hypergastrinemia during use. This randomized crossover study investigated how soon serum gastrin levels returned to baseline after 7 days of treatment with omeprazole and famotidine. Serum gastrin levels were analyzed during and after drug administration. Results showed serum gastrin levels decreased to baseline after a 7-day withdrawal period. Although recommended in human medicine, measuring serum gastrin levels after a 14-day withdrawal period does not appear necessary in dogs.
SOURCE Serum concentrations of gastrin after famotidine and omeprazole administration to dogs. Parente NL, Bari Olivier N, Refsal KR, Johnson CA. JVIM 28(5):1465-1470, 2014.
This study evaluated the cytotoxic effects of doxorubicin and etoposide used alone and in combination on a feline injection site sarcoma (FISS) cell line. Doxorubicin has previously been shown to delay the recurrence of FISS, but etoposide has not yet been studied in cats. Both drugs, when used as a single agent or together, significantly inhibited growth and promoted apoptosis of the FISS cell line.
SOURCE In vitro efficacy of doxorubicin and etoposide against a feline injection site sarcoma cell line. Hill J, Lawrence J, Saba C, et al. Res Vet Sci doi: 10.1016/j.rvsc.2014.07.006.
Effects of Antacids on Serum Gastrin Levels
Doxorubicin & Etoposide Effects on Feline Injection Site Sarcoma
SEE YOU INJANUARY!
MANAGEMENT TREE Immune-Mediated Hemolytic Anemia
Rx SOLUTIONSDrugs Used to Control Ventricular Arrhythmias
WORDS OF CAUTIONCyclosporine
PATHOGEN PROFILEFeline Herpesvirus
RED LIGHT, GREEN LIGHTClinical Polypharmacology Case
THERAPEUTICS SNAPSHOTCarprofen
A Glimpse of March!• Bordetella bronchiseptica
• Feline inflammatory bowel disease
• Phenobarbital risks
• Fluoroquinolone-resistant E coli
• Azathioprine drug snapshot
!
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November 2014 Plumb’s Therapeutics Brief 9
RED LIGHT, GREEN LIGHTPEER REVIEWED
Julie Allen, BVMS, MS, DACVIM (Small Animal)Aratana TherapeuticsKansas City, Kansas
PEPPER, A 7-YEAR-OLD, CASTRATED MINIATURE SCHNAUZER, presented with a history of inflammatory bowel disease (IBD) involving the stomach and duodenum for which he had been receiving prednisone at 0.5 mg/kg q48h. Overall, Pepper was doing well, with no ongoing vomiting or diarrhea, but he had been losing weight and previous laboratory work revealed fasting hyperlip-idemia. At presentation, Pepper had a 24-hour history of acute bilious vomiting and mucoid diarrhea with hematochezia. Examination revealed a slight fever and cranial abdominal pain. Laboratory abnormalities included an inflamma- tory leukogram, moderately increased ALP, mild hypercholesterolemia, and considerable hypertriglyceridemia. A Spec cPL (IDEXX) assay was elevated at a concentration consistent with pancreatitis. Abdominal ultrasonography revealed a markedly hypoechoic left pancreatic limb. Working differentials were IBD, likely primary hyperlipidemia, and probable pancreatitis.
Inflammatory Bowel Disease with Concurrent Pancreatitis
RED = do not use YELLOW = proceed with caution GREEN = safe
Prednisone
Azathioprine
Cyclosporine
Carprofen
Fentanyl
Metoclopramide
Fish oil
Chitosan
Metronidazole
Enrofloxacin
Which of the following medications would be appropriate? Based on the information provided, how would you grade the following drugs and why?
RED YELLOW GREEN
RED YELLOW GREEN
RED YELLOW GREEN
RED YELLOW GREEN
RED YELLOW GREEN
RED YELLOW GREEN
RED YELLOW GREEN
RED YELLOW GREEN
RED YELLOW GREEN
RED YELLOW GREENTurn the page and compare your results h
ALP = alkaline phosphatase, IBD = inflammatory bowel diseaseAll you need. All in one place.
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MIDDLE OF NOWHERE...
VetFolio is there.
Better your practice and career with mobile-ready VetFolio. Anywhere, anytime and on any device, you can...
• Search the world’s largest online encyclopedia of peer-reviewed, point-of-care medical information
• Navigate through thousands of articles, videos, podcasts and more, including 2,500+ NAVC Conference Proceedings
• Join our VetFolio Community: Moderated professional forums where you’ll find answers on a wide range of topics
• Access 500+ hours of Continuing Education opportunities in all areas of expertise, for you and everyone on your veterinary healthcare team
* Practices up to 15 people. More than 15 in your practice?Contact us for a special rate just for you. VetFolio.com/contact
Give VetFolioa try for FREE at
VetFolio.com/FreeTrial
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10 plumbstherapeuticsbrief.com November 2014
RED LIGHT, GREEN LIGHTPEER REVIEWED
Did you answer? The following represents the best responses based on drug metabolism, pharmacokinetics, species, diagnostic differentials, clinical and laboratory data, and other pertinent findings.
Prednisone | CORRECT RESPONSE
Prednisone, a steroid with antiinflammatory and immunomodulatory properties, is the drug of choice for IBD, but steroids have long been cited as a possible cause of pancreatitis.1 Some studies looked mainly at changes in amylase and lipase, however, so it was believed that although steroids were increasing lipase values, they were not necessarily causing pancreatitis.2 In fact, there is some debate that steroids may be helpful in certain patients with chronic pancreatitis, particularly those with concurrent IBD. Of note, a recent population-based case-control study in humans suggested that steroids are indeed associated with increased risk for acute pancreatitis.3
Azathioprine | CORRECT RESPONSE Azathioprine, a purine analog immunosuppressant, has been used successfully in the management of IBD.4 However, this drug has been implicated as a cause of pancreatitis in humans and would not, therefore, be recommended for this patient.5
Cyclosporine | CORRECT RESPONSE Cyclosporine, a calcineurin inhibitor that suppresses the immune system primarily by inhibiting T lymphocytes, has been used in patients with refractory IBD.6 Ongoing research at Texas A&M University is investigating its use in dogs with insulin-resistant diabetes mellitus and chronic pancreatitis.7 There is some evidence in the human literature that chronic pancreatitis may have an underlying immune-mediated cause, which has also been the proposed etiology in English cocker spaniels afflicted with pancreatitis.8 While evidence is insufficient to recommend routine use of cyclosporine in dogs with pancreatitis, transition from prednisone to cyclosporine might be beneficial to control the IBD in this patient, with appropriate vigilance for the many potential drug interactions as characterized by cyclosporine.
Carprofen | CORRECT RESPONSE Steroids and NSAIDs should never be administered concurrently because of the increased risk for GI bleeding, which may be increased further by existing impaired perfusion in the GI tract of patients with pancreatitis.9
JULIE ALLEN, BVMS, MS, DACVIM (Small Animal), is a medical science liaison for Aratana Therapeutics in Kansas City, Kansas. Previously, she practiced in academic and private specialty settings, in addition to industry (Pfizer Animal Health)and, more recently, as internal medicine consultant for both Antech Diagnostics and the Veterinary Information Network (VIN). Dr. Allen’s special interests include GI, hepatobiliary, and endocrine conditions in small animals. She earned her BVMS from University of Glasgow and an MS from Iowa State University, where she also completed internship and residency programs.
November 2014 Plumb’s Therapeutics Brief 11
Fentanyl | CORRECT RESPONSE
Pain control is very important in the management of pancreatitis. Although traditionally there was concern that opioids induced “spasm” of the sphincter of Oddi, no study or evidence has indicated that fentanyl is contraindicated in patients with pancreatitis.10
Metoclopramide | CORRECT RESPONSE Metoclopramide, a dopamine antagonist, is both an antiemetic and a prokinetic drug. However, dopamine may actually be helpful in both ameliorating pancreatic inflammation and improving pancreatic perfusion; therefore, the use of metoclopramide may be detrimental.11 In addition, more effective antiemetics are available, including ondansetron, dolasetron, and maropitant. Maropitant may also have beneficial antiinflammatory and analgesic effects because of its actions on substance P.12
Fish oil | CORRECT RESPONSE Although it may seem counterintuitive in hyperlipidemic patients, fish oil products (particularly those high in omega-3 fatty acids) may reduce serum triglyceride concentrations by decreasing the synthesis of very low-density lipoproteins (VLDLs).13 Studies in humans with ulcerative colitis, Crohn’s disease, and pancreatitis have also suggested that because of their antiinflammatory properties, fish oils may be beneficial, although the results have been controversial. No studies in veterinary medicine have assessed the efficacy of fish oil in patients with IBD or pancreatitis.13-15
Chitosan | CORRECT RESPONSE Chitosan, a form of fiber derived from shellfish, essentially acts as a fat sponge in the intestinal tract and can therefore be effective in the management of hyperlipidemia. There are no controlled studies evaluating its efficacy, but in general it is considered fairly safe. At high doses, deficiencies of fat-soluble vitamins and minerals may occur.16
What Did You Say?Become a part of our ongoing dialogue by sharing your thoughts with colleagues. Email your answers and comments for this issue’s Red Light, Green Light to [email protected]
REFERENCES 1. Acute canine pancreatitis. Hall JA, Macy
DW, Husted PW. Compend Contin Educ Pract Vet 10(4):403-416, 1998.
2. Effects of dexamethasone on pancreatic tissue and on serum amylase and lipase activities in dogs. Parent J. JAVMA 180(7):743-746, 1982.
3. Association of oral glucocorticoid use with an increased risk of acute pancreatitis: A population-based nested case-control study. Sadr-Azodi O, Mattsson F, Bexlius TS, et al. JAMA Intern Med 173(6):444-449, 2013.
4. Management of canine inflammatory bowel disease. Marks SL. Compend Contin Educ Pract Vet 20(3):317-332, 1998.
5. The risk of azathioprine-induced pancreatitis depends on genetic variants in the HLA gene region. Dubois PCA. Gut 60(Suppl 1), 2011.
6. Pharmacokinetics and clinical efficacy of cyclosporine treatment of dogs with steroid-refractory inflammatory bowel disease. Allenspach K, Rüfenacht S, Sauter S, et al. JVIM 20(2):239-244, 2006.
7. Texas A&M University Veterinary & Biomedical Sciences Gastrointestinal Laboratory: Clinical trial on cyclosporine in pancreatitis. Kretzschmar T. http://vetmed.tamu.edu/gilab/research/cyclosporine-in-pancreatitis; accessed Sept 2014.
8. Characterization of chronic pancreatitis in English cocker spaniels. Watson PJ, Roulois A, Scase T, et al. JVIM 25(4):797-804, 2011.
9. Splanchnic and pancreatic tissue perfusion in experimental acute pancreatitis. Kinnala PJ, Kuttila KT, Grönroos JM, et al. Scand J Gastroenterol 37(7):845-849, 2002.
10. Narcotic analgesic effects on the sphincter of Oddi: A review of the data and therapeutic implications in treating pancreatitis. Thompson DR. Am J Gastroenterol 96(4):1266-1272, 2001.
11. Low-dose dopamine reduces inflammatory factors of acute pancreatitis in rats. Zhang S, Peng XG,
IBD = inflammatory bowel disease, VLDL = very low-density lipoprotein
MORE h
12 plumbstherapeuticsbrief.com November 2014
RED LIGHT, GREEN LIGHTPEER REVIEWED
Liu CC, et al. Hepatobiliary Pancreat Dis Intl 6(6):646-649, 2007. 12. Treatment with neurokinin-1 receptor antagonist reduces
severity of inflammatory bowel disease induced by Cryptosporidium parvum. Sonea IM, Palmer MV, Akili D, Harp JA. Clin Diagn Lab Immunol 9(2):333-340, 2002.
13. Omega-3 fatty acids for the treatment of elevated triglycerides. Maki KC, Dicklin MR, Lawless A, Reeves MS. Clin Lipidology 4(4):425-437, 2009.
14. An oral supplement enriched with fish oil, soluble fiber, and antioxidants for corticosteroid sparing in ulcerative colitis: A randomized, controlled trial. Seidner DL, Lashner BA, Brzezinski A, et al. Clin Gastroenterol Hepatol 3(4):358-369, 2005.
15. Effects of omega-3 fatty acids on acute necrotizing pancreatitis in rats. Alhan E, Türkyilmaz S, Erçin C, et al. Eur Surg Res 38(3):314-321, 2006.
Metronidazole | CORRECT RESPONSE Metronidazole, a nitroimidazole antibiotic believed to have immunomodulatory properties, has often been used as adjunct therapy for IBD, although one study revealed no difference in response to prednisone alone versus prednisone and metronidazole.17 Recent studies have suggested that long-term or high-dose use may lead to DNA damage, so courses should be limited.18 In addition, several case reports in the human literature have suggested that metronidazole may increase the risk for acute pancreatitis.19
Enrofloxacin | CORRECT RESPONSE Although enrofloxacin penetrates the pancreas well, the debate remains whether this drug is beneficial in patients with pancreatitis. Antibiotic coverage for enteric bacteria may be warranted if the patient is febrile, has toxic changes, and/or has evidence of GI mucosal barrier compromise. Infectious complications are rare in dogs as compared with humans. One experimental study in dogs suggested possible improvement in patient survival with antibiotic therapy, but only when given via the cranial mesenteric artery.20 Human literature wavers as to whether antibiotic therapy benefits these patients. No clinical studies have investigated the effect of antibiotics in dogs with pancreatitis.
IBD = inflammatory bowel disease
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TM
(carprofen)
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14 plumbstherapeuticsbrief.com November 2014
NSAIDs As mainstay treatment for osteoarthritis (OA), NSAIDs inhibit one or more steps in arachidonic acid metabolism, including inhibition of prostaglandins by cyclooxygenase (COX).
COX Isoforms → COX-1 and COX-2 are known isoforms; COX-3 was recently recognized.1 • COX-1 catalyzes formation of constitutive prostaglandins.2
• COX-2 appears to catalyze formation of induced prostaglandins expressed in damaged or inflamed tissue.2
— Also involved in pain response to injury• Recently COX-3, a brain-specific COX-1 variant, was identified in dogs.3 — Preferentially inhibited by acetaminophen
Inhibition of COX-2 → Thought to supply desired benefits of NSAID administration by • Inhibiting induced prostaglandins • Avoiding unwanted NSAID side effects of inhibiting constitutive prostaglandins
Recent studies → COX-2 may have some activity in constitutive prostaglandins, and COX-1 may have some activity in induced prostaglandins.4,5 • COX-1 and COX-2 inhibition, therefore, is not clear-cut.4,5
— In addition, little difference in improvement of clinical signs has been detected in studies comparing different NSAIDs with different COX-2 selectivity as administered to large groups of dogs.6
• One NSAID may work better than another for an individual dog, with different classes of NSAIDs having different side effect profiles.6
CarprofenCarprofen, one of the first COX-2 preferential NSAIDs approved for dogs, has been shown to be effective treatment for canine OA.7-9
Formulation → Oral, injectable
Dose → 4.4 mg/kg q24h or divided 2.2 mg/kg q12h6,10
Key Points• Dose-dependent side effects include — Anorexia, vomiting, diarrhea — In dehydrated or older dogs, renal decompensation11
RxSOLUTIONSPEER REVIEWED
Which Drugs Can Be Used for Osteoarthritis in Dogs? Kelley Thieman Mankin, DVM, MS, DACVS (Small Animal)Texas A&M University
One NSAID may work better than another for an individual dog, with different classes of NSAIDs having different side effect profiles.6
ALT = alanine aminotransferase, COX = cyclooxygenase
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November 2014 Plumb’s Therapeutics Brief 15
• Idiosyncratic hepatotoxicity associated with markedly increased serum ALT occurs less commonly but can lead to acute hepatic failure.12
— Reported more commonly in the Labrador retriever as compared with other breeds12
Meloxicam Clinical trials have shown meloxicam to be effective treatment for OA in dogs.13-15 Like carprofen, meloxicam preferentially inhibits COX-2.
Formulation → Oral (tablet or liquid), injectable
Dose → 0.1 mg/kg q24h6,10
Key Points• Like carprofen, most commonly reported side effects are — Anorexia, vomiting, diarrhea14
• The following severe adverse events can occur with meloxicam administration — Hepatotoxicity10,16
— GI ulceration, including perforating ulcers10,17
DeracoxibDeracoxib, a COX-2 selective NSAID as compared with being COX-2 preferential, is labeled for treatment of canine OA.
Formulation → Oral (chewable tablet)
Dose → 1–2 mg/kg q24h6,10
Key Points• Approved for treatment of pain and inflammation associated with OA in dogs — Effective in controlling pain associated with induced synovitis18,19
— Clinical trials have shown that deracoxib is effective at improving signs associated with OA.20,21
• When administered at doses higher than labeled, dogs reportedly developed kidney abnormalities.22
• Caution/Warning — While no kidney problems have been reported in dogs receiving the
recommended dose, deracoxib should be used with caution in dogs with renal disease.
The NSAIDs presented here have all been approved for use in dogs with osteoarthritis and/or associated clinical signs.
16 plumbstherapeuticsbrief.com November 2014
RxSOLUTIONSPEER REVIEWED
— Has been associated with GI ulceration and perforation, particularly with administration of higher than recommended doses or in combination with another NSAID or glucocorticoid23,24
FirocoxibFirocoxib, approved for treatment of canine OA, is a COX-2 selective NSAID shown to be effective in treating pain and inflammation associated with induced synovitis.8
Formulation → Oral (chewable tablet)
Dose → 5 mg/kg q24h6,10
Key Points• In a study comparing firocoxib with carprofen, fewer dogs experienced health
problems with firocoxib than with carpofen.8 • The most frequent side effects are vomiting and decreased appetite. — Margin of safety is narrow in puppies. • Label Warning — Using doses higher than recommended in puppies younger than 7 months
of age has been associated with serious complications, including hepatic abnormalities and decreased weight gain.
Chondroitin Sulfate–Glucosamine Hydrochloride–Manganese Ascorbate Chondroitin sulfate–glucosamine hydrochloride–manganese ascorbate is proposed to reduce clinical signs of OA and slow or prevent progression of the degenerative process.
Formulation → Oral (chewable tablet)
Dose → Varies based on dog’s weight; refer to product label for recommended initial and maintenance dose schedules for joint disease in dogs
Key Points• Glucosamine hydrochloride and chondroitin sulfate have been shown to
accumulate in plasma after multiple doses and to have substantial carryover effect.25
• This drug combination can produce beneficial effects in vitro, protect against synovitis,26 slow the degenerative process,27 and modulate metabolism of articular cartilage.28
• When administered to dogs in vivo, results have not been as promising. — One clinical study in dogs showed no improvement in objective gait analysis or
subjective analysis by owner or orthopedic surgeon during the study period.13 • Ground reaction forces measured before and after were not significantly
improved.
NSAIDs(continued)
Chondroprotectants
ASU = avocado/soybean unsaponifiables, COX = cyclooxygenase, HA = hyaluronic acid, IL = interleukin, MMP = matrix metalloproteinase, TGF = transforming growth factor
November 2014 Plumb’s Therapeutics Brief 17
Glucosamine Hydrochloride–Chondroitin Sulfate–Avocado/Soybean Unsaponifiables The combination of glucosamine hydrochloride–chondroitin sulfate–avocado/soybean unsaponifiables (ASU) is similar to chondroitin sulfate–glucosamine hydrochloride–manganese ascorbate and likewise is purported to reduce clinical signs of OA and slow or prevent progression of the degenerative process.
Formulation → Oral (chewable tablet)
Dose → Varies based on dog’s weight; refer to product label for recommended initial and maintenance dose schedules for joint disease in dogs
Key Points• Numerous research studies have shown that ASU can decrease inflammation at
the cellular level, decrease cartilage degradation, and promote cartilage repair.29-31
— Can partially reverse the effects of IL-1 on chondrocytes and decrease matrix metalloproteinase (MMP) production, decreasing inflammation and cartilage degradation29,30
— Can increase expression of TGF-β, suggesting stimulation of cartilage repair31,32
• An experimental study evaluating ASU administered to dogs with transected cranial cruciate ligaments found reduced development of cartilage and subchondral bone lesions.33
— Study authors suspected that ASU worked by inhibiting nitric oxide synthase and MMP-13.33
Hyaluronan Hyaluronan, also known as hyaluronic acid (HA), is a polysaccharide found in many tissues. HA is concentrated in synovial fluid, where its major function is to bind water and lubricate joints.
Formulation → Injection (intraarticular)
Dose → Using high molecular weight hyaluronan compound, 10 mg weekly34-36; in Plumb’s Veterinary Drug Handbook, 3–5 mg/kg weekly also recommended for adjunct treatment of synovitis • Follow aseptic technique
Key Points• Most commonly administered directly into the joint. — By this route, HA has been shown to improve gait function in OA mouse models.37 • In human studies, intraarticular HA improved viscoelasticity, provided
antiinflammatory activity, provided analgesia, and decreased degradation of articular cartilage.38,39
• Studies showed no clinical improvement or prevention of OA when administered to dogs with transected cranial cruciate ligaments.34-36,40
Avocado/soybean unsaponifiables can decrease inflammation and cartilage degradation and promote cartilage repair.29-31
18 plumbstherapeuticsbrief.com November 2014
Polysulfated Glycosaminoglycan Polysulfated glycosaminoglycan (PSGAG) is labeled as a disease-modifying OA supplement purported to slow OA development and diminish associated clinical signs.
Formulation → Injection (IM)• For treatment of noninfectious, traumatic, or degenerative arthritis41
Dose → 4.4–5 mg/kg IM twice weekly for 4 weeks (recommended)42,43
Key Points• In one study, 75% of dogs had significantly improved lameness scores after
treatment with PSGAG.42
• Potential use in inhibiting cartilage matrix degradation42
— Full mechanism of action is unknown but has been shown to decrease COMP (cartilage oligomeric matrix protein), a substrate for catabolic MMP enzymes.42
• May increase synthesis of collagen (in vitro)44 • Young puppies treated with PSGAGs showed less hip subluxation than did
untreated puppies.45
• Warning — Similar in structure to heparin and should not be used in dogs with coagulation
abnormalities41
Tramadol Tramadol is a central-acting synthetic opiate-like (mu-receptor) agonist. Its mechanism of action involves numerous metabolites.
Formulation → Oral (tablet)
Dose → 4–10 mg/kg q8h46
Key Points• Now a class IV schedule drug• In part, analgesia may be achieved because tramadol and its metabolites are
opiate-like mu-receptor agonists. — Because of how dogs metabolize tramadol, they are not expected to experience
substantial opioid effects.46 — Mechanism of action in dogs likely results from metabolites acting as serotonin
and norepinephrine reuptake inhibitors.46 • Shown to be effective in alleviating clinical signs of OA in dogs47 • Sedation most common side effect; dogs may develop decreased bioavailability
over time (ie, tramadol may undergo decreased absorption with multiple doses).46 • Evidence that tramadol alone has a detrimental effect on gastric barrier function
is lacking.48
• Caution — Dose adjustments may be required in dogs with impaired renal or hepatic
function.
RxSOLUTIONSPEER REVIEWED
Analgesics
Chondroprotectants (continued)
November 2014 Plumb’s Therapeutics Brief 19
Gabapentin & Pregabalin Both gabapentin and pregabalin were developed as antiepileptic drugs but have been used for treatment of chronic pain.46
Formulation → Oral (liquid or capsule)
Dose recommended (empiric) for gabapentin → 10–20 mg/kg q8h46
Dose recommended for pregabalin → 4 mg/kg q12h46
Key Points• Both are alkylated analogs of gamma-aminobutyric acid (GABA). — Believed to work by blocking voltage-gated calcium channels, reducing
neurotransmitter release, and attenuating postsynaptic excitability — Suspected neuropathic pain has been successfully treated with gabapentin.49
• Although both drugs are reportedly effective treatment for chronic pain in humans, no studies have evaluated gabapentin or pregabalin for management of canine OA.
— Studies have shown no significant benefit to administration of gabapentin as an adjunct to other analgesics in dogs undergoing forelimb amputation or intervertebral disk surgery.50,51
• Caution — Gabapentin liquid contains xylitol; however, the concentration of xylitol in the
liquid is low enough that routine dosing of gabapentin is unlikely to result in toxicity.46
AmantadineAmantadine, first used as an antiviral medication against influenza in humans, is now primarily prescribed for pain relief in both human and veterinary medicine because of its ability to inhibit the N-methyl-d-aspartate (NMDA) receptor.
Formulation → Oral (liquid or tablet)
Dose (recommended) → 3–5 mg/kg q24h46
Key Points• Should not be used as sole therapy for OA but should be combined with
and may enhance the effects of NSAIDs, opioids, or gabapentin or pregabalin46 • Inhibits the NMDA receptor by encouraging channel closure and inhibiting
NMDA responses • In one study of dogs with OA pain refractory to NSAID treatment, addition of
amantadine to NSAID therapy resulted in improved function, presumably because of pain relief.52
— In the same study, no adverse effects or significant changes in laboratory results were detected.
Therapeutic success has been achieved with certain analgesics as treatment for chronic pain and inflammation prevalent in dogs with osteoarthritis.
COMP = cartilage oligomeric matrix protein, GABA = gamma-aminobutyric acid, MMP = matrix metalloproteinase, NMDA = N-methyl-d-aspartate, PSGAG = polysulfated glycosaminoglycan
20 plumbstherapeuticsbrief.com November 2014
Dried Milk Protein • Collected from hyperimmunized cows; purported to contain factors that block
cytokines and inhibit neutrophil participation in an inflammatory response • One clinical trial reported improvement in clinical signs of OA.53
Green-Lipped Mussel Extract • Green-lipped mussel extract (GLME; Perna canaliculus) has improved clinical
signs of canine OA.54
— Long-term administration may be required. • How GLME exerts beneficial effects is unknown but suspected to be secondary to
high concentrations of omega-3 fatty acids,55 which act as inhibitors of arachidonic acid metabolism by COX and lipoxygenase (LOX) pathways.55,56
• Has been shown to have antiinflammatory effects57
Omega-3 Fatty Acids• Supplementation may lead to decreased inflammation.6 • Higher blood levels were detected in dogs fed diets supplemented with omega-3
fatty acids; owners reported improved mobility in arthritic pets.58
• Supplementation may allow reduced NSAID dose.59
S-Adenosyl l-Methionine• S-adenosyl l-methionine (SAMe), a nutraceutical most commonly used to treat
canine liver disease, has no reported side effects in dogs.60
• SAMe has antioxidant properties that may benefit osteoarthritic joints61 but in one study was not an effective standalone treatment for reducing clinical signs of OA in dogs.62
COX = cyclooxygenase, GLME = green-lipped mussel extract, LOX = lipoxygenase, SAMe = S-adenosyl l-methionine
RxSOLUTIONSPEER REVIEWED
Other Oral Supplements
KELLEY THIEMAN MANKIN, DVM, MS, DACVS (Small Animal), is clinical assistant professor at Texas A&M University, with a specialty in small animal soft tissue surgery. Dr. Thieman Mankin completed a surgical residency at University of Florida College of Veterinary Medicine and received her DVM from University of Missouri. She recently presented a session on surgical checklists at the NAVC Conference.
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November 2014 Plumb’s Therapeutics Brief 21
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19. The effects of epidural deracoxib on the ground reaction forces in an acute stifle synovitis model. Karnik PS, Johnston S, Ward D, et al. Vet Surg 35(1):34-42, 2006.
20. Field comparison of canine NSAIDs firocoxib and deracoxib. Ryan WG, Carithers D, Moldave K, Bell M. Intern J Appl Res Vet Med 8(2):114-123, 2010.
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22. Safety and tolerability of 3-week and 6-month dosing of Deramaxx (deracoxib) chewable tablets in dogs. Roberts ES, Van Lare KA, Marable BR, Salminen WF. J Vet Pharmacol Ther 32(4):329-337, 2009.
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26. Scintigraphic evaluation of dogs with acute synovitis after treatment with glucosamine hydrochloride and chondroitin sulfate. Canapp SO Jr, McLaughlin RM Jr, Hoskinson JJ, et al. Am J Vet Res 60(12):1552-1557, 1999.
27. In vivo chondroprotection and metabolic synergy of glucosamine and chondroitin sulfate. Lipiello L, Woodward J, Karpman R, Hammad TA. Clin Orthop Relat Res 381:229-240, 2000.
28. Effects of an orally administered mixture of chondroitin sulfate, glucosamine hydrochloride and manganese ascorbate on synovial fluid chondroitin 3B3 and 7D4 epitope in a canine cruciate ligament transection model of osteoarthritis. Johnson KA, Hulse DA, Hart RC, et al. Osteoarthritis Cartilage 9(1):14-21, 2001.
29. Effects of three avocado/soybean unsaponifiable mixtures on metalloproteinases, cytokines and
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30. Avocado/soybean unsaponifiables increase aggrecan synthesis and reduce catabolic and proinflammatory mediator production by human osteoarthritic chondrocytes. Henrotin YE, Sanchez C, Deberg MA, et al. J Rheumatol 30(8):1825-1834, 2003.
31. Treatment with unsaponifiable extracts of avocado and soybean increases TGF-β1 and TGF-β2 levels in canine joint fluid. Altinel L, Saritas ZK, Kose KC, et al. Tohoku J Exp Med 211(2):181-186, 2007.
32. Avocado/soya unsaponifiables enhance the expression of transforming growth factor β1 and β2 in cultured articular chondrocytes. Boumediene K, Felisaz N, Bogdanowicz P, et al. Arthritis Rheum 42(1):148-156, 1999.
33. Protective effects of total fraction of avocado/soybean unsaponifiables on the structural changes in experimental dog osteoarthritis: Inhibition of nitric oxide synthase and matrix metallo-proteinase-13. Boileau C, Martel-Pelletier J, Caron J, et al. Arthritis Res Ther 11(2):R41, 2009.
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35. Effect of intraarticular hyaluronan injection in experimental canine osteoarthritis. Smith GN Jr, Myers SL, Brandt KD, Mickler EA. Arthritis Rheum 41(6):976-985, 1998.
36. Effect of intraarticular hyaluronan injection on synovial fluid hyaluronan in the early stage of canine post-traumatic osteoarthritis. Smith GN Jr, Mickler EA, Myers SL, Brandt KD. J Rheumatol 28(6):1341-1346, 2001.
37. Improvements in gait with hyaluronan treatment in a model of osteoarthritis. Harrison A, Kobla V, Sandy J, et al. J Bone Joint Surg Br 94-B(Supp XVIII):30, 2012.
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39. Hyaluronans in the treatment of osteoarthritis of the knee: Evidence for
22 plumbstherapeuticsbrief.com November 2014
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44. Effects of three antiarthritic drugs on fibronectin and keratin sulfate synthesis by cultured canine articular cartilage chondrocytes. Steinmeyer J, Burton-Wurster N, Lust G. Am J Vet Res 53(11):2077-2083, 1992.
45. Effects of intramuscular administration of glycosaminoglycan polysulfates on signs of incipient hip dysplasia in growing pups. Lust G, Williams AJ, Burton-Wurster N, et al. Am J Vet Res 53(10):1836-1843, 1992.
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53. Use of client-specific outcome measures to assess treatment effects in geriatric, arthritic dogs: Controlled clinical evaluation of a nutraceutical. Gingerich DA, Strobel JD. Vet Ther 4(1):56-66, 2003.
54. Clinical efficacy and tolerance of an extract of green-lipped mussel (Perna canaliculus) in dogs presumptively diagnosed with degenerative joint disease. Pollard B, Guilford WG, Ankenbauer-Perkins KL, Hedderley D. NZ Vet J 54(3):114-118, 2006.
55. Systematic review of a marine nutraceutical supplement in clinical
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56. Anti-inflammatory activity of a lipid fraction (lyprinol) from the NZ green-lipped mussel. Whitehouse MW, Macrides TA, Kalafatis N, et al. Inflammopharmacology 5(3):237-246, 1997.
57. Anti-inflammatory activity in fractionated extracts of the green-lipped mussel. Couch RA, Ormrod DJ, Miller TE, Watkins WB. NZ Med J 95(720):803-806, 1982.
58. Multicenter veterinary practice assessment of the effects of omega-3 fatty acids on osteoarthritis in dogs. Roush JK, Dodd CE, Fritsch DA, et al. JAVMA 236(1):59-66, 2010.
59. A multicenter study of the effect of dietary supplementation with fish oil omega-3 fatty acids on carprofen dosage in dogs with osteoarthritis. Fritsch DA, Allen TA, Dodd CE, et al. JAVMA 236(5):535-539, 2010.
60. Evaluation of the influence of S-adenosylmethionine on systemic and hepatic effects of prednisolone in dogs. Center SA, Warner KL, McCabe J, et al. Am J Vet Res 66(2):330-341, 2005.
61. SAMe restores the changes in the proliferation and in the synthesis of fibronectin and proteoglycans induced by tumour necrosis factor alpha on cultured rabbit synovial cells. Gutierrez S, Palacios I, Sánchez-Pernaute O, et al. Br J Rheumatol 36(1):27-31, 1997.
62. Evaluation of S-adenosyl l-methionine in a double-blinded, randomized, placebo-controlled, clinical trial for treatment of presumptive osteoarthritis in the dog. Imhoff DJ, Gordon-Evans WJ, Evans RB, et al. Vet Surg 40(2):228-232, 2011.
RxSOLUTIONSPEER REVIEWED
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5 mg/mL Solution for InjectionNon-steroidal anti-inflammatory drug for use in dogs and cats onlyCaution: Federal law restricts this drug to use by or on the order of a licensed veterinarian.
Warning: Repeated use of meloxicam in cats has been associated with acute renal failure and death. Do not administer additional injectable or oral meloxicam to cats. See Contraindications, Warnings, and Precautions for detailed information.
Description: Meloxicam is a non-steroidal anti-inflammatory drug (NSAID) of the oxicam class. Each mL of this sterile product for injection contains meloxicam 5.0 mg, alcohol 15%, glycofurol 10%, poloxamer 188 5%, sodium chloride 0.6%, glycine 0.5% and meglumine 0.3%, in water for injection, pH adjusted with sodium hydroxide and hydrochloric acid.Indications: Dogs: Metacam (meloxicam) Solution for Injection is indicated in dogs for the control of pain and inflammation associated with osteoarthritis. Cats: For the control of postoperative pain and inflammation associated with orthopedic surgery, ovariohysterectomy and castration when administered prior to surgery.Contraindications: Dogs and cats with known hypersensitivity to meloxicam should not receive Metacam Solution for Injection. Additional doses of meloxicam or other NSAIDs in cats are contraindicated, as no safe dosage for repeated NSAID administration has been established (See Animal Safety). Do not use meloxicam in cats with pre-existing renal dysfunction. Warnings: Not for use in humans. Keep this and all medications out of reach of children. Consult a physician in case of accidental ingestion by humans. For IV or SQ injectable use in dogs. All dogs and cats should undergo a thorough history and physical examination before administering any NSAID. Appropriate laboratory testing to establish hematological and serum biochemical baseline data is recommended prior to, and periodically during use of any NSAID in dogs and cats. For subcutaneous (SQ) injectable use in cats. Do not use IV in cats. When treating cats: do not administer a second dose of meloxicam. Do not follow the single, one-time dose of meloxicam with any other NSAID. Do not administer Metacam Oral Suspension following the single, one-time injectable dose of meloxicam. Do not repeat the single, one-time dose of meloxicam in cats or dogs. Owners should be advised to observe their dogs and cats for signs of potential drug toxicity.Precautions: The safe use of Metacam Solution for Injection in cats younger than 4 months of age or dogs younger than 6 months of age, cats or dogs used for breeding, or in pregnant or lactating females has not been evaluated. Use a syringe of appropriate size to ensure precise dosing. As a class, cyclo-oxygenase inhibitory NSAIDs may be associated with gastrointestinal, renal and hepatic toxicity. Sensitivity to drug-associated adverse events varies with the individual patient. Dogs and cats that have experienced adverse reactions from one NSAID may experience adverse reactions from another NSAID. Patients at greatest risk for renal toxicity are those that are dehydrated, on concomitant diuretic therapy, or those with existing renal, cardiovascular, and/or hepatic dysfunction. Concurrent administration of potentially nephrotoxic drugs should be carefully approached and monitored. NSAIDs may inhibit the prostaglandins that maintain normal homeostatic function. Such anti-prostaglandin effects may result in clinically significant disease in patients with underlying or preexisting disease that has not been previously diagnosed. Anesthetic drugs may affect renal perfusion; approach concomitant use of anesthetics and NSAIDs cautiously. Appropriate monitoring procedures should be employed during all surgical procedures. The use of perioperative parenteral fluids is recommended to decrease potential renal complications when using NSAIDs in cats. If additional pain medication is needed after the single one-time dose of meloxicam, a non-NSAID class of analgesic may be necessary. In one study1, one cat in each NSAID treatment group had increased intraoperative hemorrhage. Since NSAIDs possess the potential to induce gastrointestinal ulcerations and/or perforation, concomitant use of meloxicam with other anti-inflammatory drugs, such as NSAIDs or corticosteroids, should be avoided. The use of another NSAID is not recommended. Consider appropriate washout times when switching from corticosteroid use or from one NSAID to another in dogs and cats. As a single use product in cats, meloxicam should not be followed by additional NSAIDs or corticosteroids. The use of concomitantly protein-bound drugs with Metacam Solution for Injection has not been studied in dogs and cats. Commonly used protein-bound drugs include cardiac, anticonvulsant and behavioral medications. The influence of concomitant drugs that may inhibit metabolism of Metacam Solution for Injection has not been evaluated. Drug compatibility should be monitored in patients requiring adjunctive therapy. The effect of cyclo-oxygenase inhibition and the potential for thromboembolic occurrence or a hypercoagulable state has not been studied.
NADA 141-219, Approved by FDA
Metacam®(meloxicam)
Adverse Reactions:Dogs: A field study involving 224 dogs was conducted wherein 109 were administered meloxicam and 115 were administered a placebo. Based on the results of this study, GI abnormalities, such as vomiting (31 dogs), soft stools/diarrhea (15 dogs), bloody stool (1 dog), and inappetance (3 dogs) were the most common adverse reactions associated with the administration of meloxicam. Dogs may have experienced more than one episode of the adverse reaction during the study. In foreign suspected adverse drug reaction (SADR) reporting, adverse reactions related to meloxicam administration included: auto-immune hemolytic anemia (1 dog), thrombocytopenia (1 dog), polyarthritis (1 dog), nursing puppy lethargy (1 dog), and pyoderma (1 dog). Adverse reactions reported post-approval were: Gastrointestinal (vomiting, diarrhea, melena, gastrointestinal ulceration), urinary (azotemia, elevated creatinine, renal failure), neurological/behavioral (lethargy, depression), hepatic (elevated liver enzymes), and dermatologic (pruritus).Cats: A field study involving 138 cats was conducted. Of the 72 cats receiving Metacam Solution for Injection, six cats (8.3%) experienced post-treatment elevated serum blood urea nitrogen (BUN) levels. The pre-treatment values were in the normal range. Of the 66 cats in the butorphanol treatment group, no cats experienced post-treatment elevated serum BUN levels. Nine cats (12.5%) receiving Metacam Solution for Injection had post-treatment anemia. Four cats (6.1%) in the butorphanol treatment group had post-treatment anemia. Twenty-four hours after the injection with Metacam Solution for Injection, one cat experienced pain upon palpation of the injection site. In studies used for the foreign approval of Metacam Solution for Injection in cats, lethargy, vomiting, inappetance, and transient pain immediately after injection were noted. Diarrhea and fecal occult blood have also been reported. Adverse reactions reported post-approval were: Urinary (azotemia, elevated creatinine, elevated phosphorus, renal failure), gastrointestinal (anorexia, vomiting, diarrhea), neurological/behavioral (lethargy, depression), and hematologic (anemia). Acute renal failure and death have been associated with the use of meloxicam in cats.Information for Dog and Cat Owners: Owners should be advised of the potential for adverse reactions and be informed of the clinical signs associated with NSAID intolerance. Adverse reactions may include vomiting, diarrhea, lethargy, decreased appetite and behavioral changes. Dog and cat owners should be advised when their pet has received a meloxicam injection. They should contact their veterinarian immediately if possible adverse reactions are observed, and DOG OWNERS should be advised to discontinue Metacam therapy. Effectiveness:Dogs: The effectiveness of Metacam Solution for Injection was demonstrated in a field study involving a total of 224 dogs representing various breeds, all diagnosed with osteoarthritis. This placebo-controlled, masked study was conducted for 14 days. Dogs received a subcutaneous injection of 0.2 mg/kg Metacam Solution for Injection on day 1. The dogs were maintained on 0.1 mg/kg oral meloxicam from days 2 through 14. Dogs showed clinical improvement with statistical significance in lameness, weight-bearing, pain on palpation, mobility, ability to rise, limping, and overall improvement after 14 days of meloxicam treatment for all variables.Cats: The effectiveness of Metacam Solution for Injection was demonstrated in a masked field study involving a total of 138 cats representing various breeds. This study used butorphanol as an active control. Cats received either a single subcutaneous injection of 0.3 mg/kg Metacam Solution for Injection or 0.4 mg/kg butorphanol prior to onychectomy, either alone or in conjunction with surgical neutering. Pain assessment variables evaluated by veterinarians included additional pain intervention therapy, gait/lameness score, analgesia score, sedation score, general impression score, recovery score, and visual analog scale score. Additionally, a cumulative pain score, which was the summation of the analgesia, sedation, heart rate and respiratory rate scores was evaluated. A palpometer was used to quantify the pain threshold. A substantial number of cats required additional intervention in the 0–24 hour postsurgical period, with the majority of these interventions taking place within the first hour. Therefore, the percentage of cats in each group that received one or more interventions was designated as the primary assessment variable. The median number of interventions was one per cat in the meloxicam group and two per cat in the butorphanol group and this difference was statistically significant (p=0.0021). The statistical evaluation supports the conclusion that the meloxicam test article is non-inferior to the butorphanol active control. The number of interventions administered to the meloxicam group was less than the butorphanol group at 1, 3, 5, 8, 12, and 24 hours post-surgery. Cats receiving Metacam Solution for Injection showed improvement in the pain assessment variables.Reference: 1. Slingsby LS, Waterman-Pearson AE. Comparison between meloxicam and carprofen for postoperative analgesia after feline ovariohysterectomy. J Small Anim Pract. 2002;43(7):286–289.Manufactured for:Boehringer Ingelheim Vetmedica, Inc.St. Joseph, MO 64506 U.S.A.US Patent 6,184,220Metacam is a registered trademark of Boehringer Ingelheim Vetmedica GmbH, licensed to Boehringer Ingelheim Vetmedica, Inc.601307L-05-1006 M601502-00Code 601311 02/2014
ISSUE How can I avoid medication errors in my practice?
ANSWER By implementing key strategies
ISSUES & ANSWERSFROM THE DESK OF DONALD C. PLUMB, PharmD
VIP ADVERTISERS INDEX COMING SOON!
24 plumbstherapeuticsbrief.com November 2014
THERAPEUTICS BULLETIN DRUGS, BIOLOGICS, NUTRACEUTICALS, DIETS
D NEW | ALFAXALONE
The IV anesthetic Alfaxan1,2 (alfaxalone; Jurox, alfaxan.com), a neurosteroid that potentiates GABA in the CNS to cause general anesthesia, has been approved by the FDA as an injectable anesthetic agent for use in dogs and cats. Anesthesia can be induced with Alfaxan, followed by maintenance with an inhalant or CRI infusion. Alfaxan is a schedule IV controlled substance available in 10-mL single-use vials (10 mg/mL).3
Sources 1. FDA Center for Veterinary Medicine, NADA #141-342, approval
September 1, 2014. 2. Freedom of Information Summary, Alfaxan, NADA #141-342,
September 6, 2012. 3. alfaxan.com
D LABEL CHANGE | ONDANSETRON
The labeled risks for Zofran (ondansetron; GlaxoSmithKline) have been modified to include serotonin syndrome.1 Ondansetron is a 5-HT3 receptor antagonist used to treat patients with nausea and vomiting. Patients concurrently receiving other drugs that potentiate serotonin (eg, SSRIs, MAO inhibitors, tramadol, fentanyl, mirtazapine) may be at risk for serotonin syndrome.
Source 1. FDA.org, Zofran, Label and Approval History, letter dated
September 18, 2014.
D LABEL CHANGE | TRAMADOL & HYDROCODONE
Pain medications containing tramadol1 & hydrocodone2 have been reclassified based on potential for abuse and addiction. The DEA has reclassified tramadol as a schedule IV controlled substance; hydrocodone is now labeled in the schedule II category. Prescribers should review DEA regulations for handling and prescribing both drugs (deadiversion.usdoj.gov/pubs/manuals/sec/message.htm).
Sources1. Drug Enforcement Administration, Federal Register vol 79, no.
127, 37623-37630, July 2, 2014. 2. Drug Enforcement Administration, Federal Register vol 79, no.
163, 49661-49682, August 22, 2014.
D NEW RELEASE | OXYTETRACYCLINE
Terramycin1,2 ophthalmic ointment (oxytetracycline hydrochloride with polymyxin B sulfate; Zoetis, zoetis.com) has been reintroduced after being taken off the market for manufacturing disruptions. This broad-spectrum ophthalmic antibiotic ointment for use in dogs and cats with superficial ocular infections is distributed in 3.5-g tubes and available from multiple distributors as well as the manufacturer.
Sources1. Press release, Zoetis, Terramycin Returns to US Veterinary
Practices, October 1, 2014.2. zoetisus.com/products/cats/terramycin-ophthalmic-ointment.
aspx
KEYD DrugT Therapeutic Diet
For more Therapeutics News information and discussion, visit plumbstherapeuticsbrief.com/bulletin
GABA = gamma-aminobutyric acid, MAO = monoamine oxidase, SSRI = selective serotonin reuptake inhibitor
N NutraceuticalB Biologic
And you can inject with confidence, because every vial of METACAM is backed by Boehringer Ingelheim Vetmedica, Inc. —a company you know and trust.
METACAM was the first NSAID injection approved for both cats and dogs in the US1 and has been trusted around the globe for more than a dozen years.2 A single preoperative injection controls postoperative pain in cats.1 Plus, an in-office injection of METACAM provides timely relief of pain and inflammation associated with osteoarthritis in dogs.
Try injectable METACAM for both dogs and cats. Even they can agree it’s the go-to treatment for pain and inflammation!
Now both cats and dogscan get BACK IN
ACTION.
METACAM is a registered trademark of Boehringer Ingelheim Vetmedica GmbH, licensed to Boehringer Ingelheim Vetmedica, Inc. © 2014 Boehringer Ingelheim Vetmedica, Inc. MET0214006 14406
IMPORTANT SAFETY INFORMATION: Repeated use of meloxicam in cats has been associated with acute renal failure and death. Do not administer additional injectable or oral meloxicam to cats. Do not follow meloxicam injection in cats with any other NSAID. As a class, cyclo-oxygenase inhibitory NSAIDs may be associated with gastrointestinal, kidney, or liver side effects. The most common side effects of METACAM reported in field studies were vomiting and soft stool/diarrhea. Pets should be evaluated for pre-existing conditions and currently prescribed medications prior to and during treatment with METACAM. Concurrent use with another NSAID, corticosteroid, or nephrotoxic medication should be avoided. The safe use of METACAM in dogs younger than 6 months of age, cats younger than 4 months of age, dogs and cats used for breeding, or in pregnant or lactating female cats and dogs has not been evaluated. Please refer to the package insert for complete product information or visit www.metacam.com.
References: 1. METACAM® (meloxicam) Solution for Injection [Freedom of Information Summary]. St. Louis, MO: Boehringer Ingelheim Vetmedica, Inc.; 2003. 2. Data on file, Boehringer Ingelheim Vetmedica, Inc.
See product information summary on page 23.
