Chemistry:Meloxicam

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Short description: Nonsteroidal anti-inflammatory drug (NSAID)
Meloxicam
Meloxicam2DACS.svg
Meloxicam-from-xtal-3D-bs-17.png
Clinical data
Trade namesMobic, Metacam, Anjeso, others
AHFS/Drugs.comMonograph
MedlinePlusa601242
License data
Pregnancy
category
Routes of
administration		By mouth, intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability89%[4]
Protein binding99.4%[4]
MetabolismLiver (CYP2C9 and 3A4-mediated)[4]
Elimination half-life20 hours[4]
ExcretionUrine and feces equally[4]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
Chemical and physical data
FormulaC14H13N3O4S2
Molar mass351.40 g·mol−1
3D model (JSmol)
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Meloxicam, sold under the brand name Mobic among others, is a nonsteroidal anti-inflammatory medication (NSAID) used to treat pain and inflammation in rheumatic diseases and osteoarthritis.[5][6] It is used by mouth or by injection into a vein.[6][7] It is recommended that it be used for as short a period as possible and at a low dose.[6]

Common side effects include abdominal pain, dizziness, swelling, headache, and a rash.[6] Serious side effects may include heart disease, stroke, kidney problems, and stomach ulcers.[6] Use is not recommended in the third trimester of pregnancy.[6] It blocks cyclooxygenase-2 (COX-2) more than it blocks cyclooxygenase-1 (COX-1).[6] It is in the oxicam family of chemicals and is closely related to piroxicam.[6]

Meloxicam was patented in 1977 and approved for medical use in the United States in 2000.[6][8] It was developed by Boehringer Ingelheim; however, it is also available as a generic medication.[6] In 2021, it was the 32nd most commonly prescribed medication in the United States, with more than 18 million prescriptions.[9][10] An intravenous version of meloxicam (Anjeso) was approved for medical use in the United States in February 2020.[11][7]

Adverse effects

Meloxicam use can result in gastrointestinal toxicity and bleeding, headaches, rash, and very dark or black stool (a sign of intestinal bleeding). It has fewer gastrointestinal side effects than diclofenac,[12] piroxicam,[13] naproxen,[14] and perhaps all other NSAIDs which are not COX-2 selective.[12]

In October 2020, the U.S. Food and Drug Administration (FDA) required the drug label to be updated for all nonsteroidal anti-inflammatory medications to describe the risk of kidney problems in unborn babies that result in low amniotic fluid.[15][16] They recommend avoiding NSAIDs in pregnant women at 20 weeks or later in pregnancy.[15][16]

Cardiovascular

Like other NSAIDs, its use is associated with an increased risk of cardiovascular events such as heart attack and stroke.[17] Although meloxicam inhibits formation of thromboxane A, it does not appear to do so at levels that would interfere with platelet function.[18][19] A pooled analysis of randomized, controlled studies of meloxicam therapy of up to 60 days duration found that meloxicam was associated with a statistically significantly lower number of thromboembolic complications than the NSAID diclofenac (0.2% versus 0.8% respectively) but a similar incidence of thromboembolic events to naproxen and piroxicam.[20]

People with hypertension, high cholesterol, or diabetes are at risk for cardiovascular side effects. People with family history of heart disease, heart attack, or stroke should tell their treating physician as the potential for serious cardiovascular side effects is significant.[21][22]

Gastrointestinal

NSAIDs cause an increase in the risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. Elderly patients are at greater risk for serious gastrointestinal events.[23]

Mouth

It is recommended to withhold meloxicam use for at least four to six half-lives prior to surgical or dental procedures due to increased risk for taste perversion, ulcerative stomatitis and dry mouth.

Mechanism of action

Meloxicam blocks cyclooxygenase (COX), the enzyme responsible for converting arachidonic acid into prostaglandin H2—the first step in the synthesis of prostaglandins, which are mediators of inflammation. Meloxicam has been shown, especially at low therapeutic doses, to selectively inhibit COX-2 over COX-1.[4]

Meloxicam concentrations in synovial fluid range from 40% to 50% of those in plasma. The free fraction in synovial fluid is 2.5 times higher than in plasma, due to the lower albumin content in synovial fluid as compared to plasma. The significance of this penetration is unknown,[23] but it may account for the fact that it performs exceptionally well in treatment of arthritis in animal models.[24]

Pharmacokinetics

Absorption

The bioavailability of meloxicam is decreased when administered orally compared to an equivalent IV bolus dose. Different oral formulations of meloxicam are not bioequivalent.[6] Use of oral meloxicam following a high-fat breakfast increases the mean peak drug levels by about 22%; however, the manufacturer does not make any specific meal recommendations. In addition, the use of antacids does not show pharmacokinetic interactions.[2] With chronic dosing, the time to maximum plasma concentration following oral administration is approximately 5–6 hours.[25]

Distribution

The mean volume of distribution of meloxicam is approximately 10 L. It is highly protein-bound, mainly to albumin.[19][25]

Metabolism

Meloxicam is extensively metabolized in the liver by the enzymes CYP2C9 and CYP3A4 (minor) into four inactive metabolites. Peroxidase activity is thought to be responsible for the other two remaining metabolites.[2][26]

Excretion

Meloxicam is predominantly excreted in the form of metabolites and occurs to equal extents in the urine and feces.[2] Traces of unchanged parent drug are found in urine and feces.[2] The mean elimination half-life ranges from 15 to 20 hours.[2]

Specific populations

Geriatrics

Use of meloxicam is not recommended in people with peptic ulcer disease or increased gastrointestinal bleed risk, including those over 75 years of age or those taking medications associated with bleeding risk.[27] Adverse events have been found to be dose-dependent and associated with length of treatment.[27][2]

Veterinary use

Meloxicam is used in veterinary medicine to treat dogs,[28][29] but also sees off-label use in other animals such as cattle and exotics.[30][31]

The most common side effects include gastrointestinal irritation (vomiting, diarrhea, and ulceration).[28]

In healthy dogs given meloxicam, no perioperative adverse effects on the cardiovascular system have been reported at recommended dosages.[32] Perioperative administration of meloxicam to cats did not affect postoperative respiratory rate nor heart rate.[33]

A peer-reviewed journal article cites NSAIDs, including meloxicam, as causing gastrointestinal upset and, at high doses, acute kidney injury and CNS signs such as seizures and comas in cats. It adds that cats have a low tolerance for NSAIDs.[34][35]

No decline in renal excretory function was observed when meloxicam was administered to cats with chronic kidney disease. Cats that received meloxicam had greater proteinuria at 6 months than cats that received placebo. It was concluded that meloxicam should be used with caution in cats with chronic kidney disease.[36]

Meloxicam has been investigated as an alternative to diclofenac by the Royal Society for the Protection of Birds (RSPB) to prevent deaths of vultures.[37]

Pharmacokinetics

In dogs, the absorption of meloxicam from the stomach is not affected by the presence of food,[38] with the peak concentration (Cmax) of meloxicam occurring in the blood 7–8 hours after administration.[38] The half-life of meloxicam is approximately 24 hours in dogs.[38]

In the koala (Phascolarctos cinereus), very little meloxicam is absorbed into the blood after oral administration (that is, it has poor bioavailability).[39]

Legal status

United States

In 2003, meloxicam was approved in the U.S. for use in dogs for the management of pain and inflammation associated with osteoarthritis, as an oral (liquid) formulation of meloxicam.[40] In January 2005, the product insert added a warning in bold-face type: "Do not use in cats."[41] An injectable formulation for use in dogs was approved by the U.S. Food and Drug Administration (FDA) in November 2003.[42]

In October 2004, a formulation for use in cats was approved for use prior to surgery only.[43] This is an injectable meloxicam, indicated for as a single, one-time dose only, with specific and repeated warnings not to administer a second dose.[44]

In 2005, the FDA sent a Notice of Violation to the manufacturer for its promotional materials which included promotion of the drug for off-label use.[45]

In February 2020, meloxicam injection was approved for use in the United States. The FDA granted the approval of Anjeso to Baudax Bio.[7][46]

European Union

In Europe the product is licensed for other anti-inflammatory benefits including relief from both acute and chronic pain in dogs. Meloxicam is also licensed for use in horses, to relieve the pain associated with musculoskeletal disorders.[47]

Meloxicam was authorised for use in cattle throughout the European Union in January 1998, via a centralised marketing authorisation.[48] The first generic meloxicam product was approved in 2006.[48]

Other countries

(As of June 2008), meloxicam is registered for long-term use in cats in Australia, New Zealand, and Canada.[49] In the United Kingdom, meloxicam is licensed for use in cats, guinea pigs, horses, and livestock including pigs and cattle. [50]

See also

  • Bupivacaine/meloxicam

References

  1. ↑ Use During Pregnancy and Breastfeeding
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 "Mobic- meloxicam tablet". https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=676e73fb-51d2-449a-8749-1a7bcc257b11. 
  3. ↑ "Anjeso- meloxicam injection". https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6f517ef8-9478-494e-adfd-4944b9900df4. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 "Meloxicam". Drugs 51 (3): 424–30; discussion 431–32. March 1996. doi:10.2165/00003495-199651030-00007. PMID 8882380. 
  5. ↑ British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 1112–1113. ISBN 9780857113382. 
  6. ↑ 6.00 6.01 6.02 6.03 6.04 6.05 6.06 6.07 6.08 6.09 6.10 "Meloxicam Monograph for Professionals". AHFS. https://www.drugs.com/monograph/meloxicam.html. 
  7. ↑ 7.0 7.1 7.2 "Baudax Bio Announces FDA Approval of Anjeso for the Management of Moderate to Severe Pain". Baudax Bio, Inc. (Press release). 20 February 2020. Archived from the original on 21 February 2020. Retrieved 20 February 2020.
  8. ↑ Analogue-based Drug Discovery. John Wiley & Sons. 2006. p. 519. ISBN 9783527607495. https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA519. Retrieved 30 June 2020. 
  9. ↑ "The Top 300 of 2021". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  10. ↑ "Meloxicam - Drug Usage Statistics". https://clincalc.com/DrugStats/Drugs/Meloxicam. 
  11. ↑ "Anjeso- meloxicam injection". 22 February 2022. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6f517ef8-9478-494e-adfd-4944b9900df4. 
  12. ↑ 12.0 12.1 "Gastrointestinal tolerability of meloxicam compared to diclofenac in osteoarthritis patients. International MELISSA Study Group. Meloxicam Large-scale International Study Safety Assessment". British Journal of Rheumatology 37 (9): 937–45. September 1998. doi:10.1093/rheumatology/37.9.937. PMID 9783757. 
  13. ↑ "Improvement in gastrointestinal tolerability of the selective cyclooxygenase (COX)-2 inhibitor, meloxicam, compared with piroxicam: results of the Safety and Efficacy Large-scale Evaluation of COX-inhibiting Therapies (SELECT) trial in osteoarthritis". British Journal of Rheumatology 37 (9): 946–51. September 1998. doi:10.1093/rheumatology/37.9.946. PMID 9783758. 
  14. ↑ "A six-month double-blind trial to compare the efficacy and safety of meloxicam 7.5 mg daily and naproxen 750 mg daily in patients with rheumatoid arthritis". British Journal of Rheumatology 35 (Suppl 1): 22–8. April 1996. doi:10.1093/rheumatology/35.suppl_1.22. PMID 8630632. 
  15. ↑ 15.0 15.1 "FDA Warns that Using a Type of Pain and Fever Medication in Second Half of Pregnancy Could Lead to Complications". U.S. Food and Drug Administration (FDA) (Press release). 15 October 2020. Retrieved 15 October 2020. This article incorporates text from this source, which is in the public domain.
  16. ↑ 16.0 16.1 "NSAIDs may cause rare kidney problems in unborn babies". 21 July 2017. https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-avoiding-use-nsaids-pregnancy-20-weeks-or-later-because-they-can-result-low-amniotic.  This article incorporates text from this source, which is in the public domain.
  17. ↑ "Development of a special electrode for continuous subcutaneous pH measurement in the infant scalp". American Journal of Obstetrics and Gynecology 124 (2): 193–195. January 1976. doi:10.1016/S0002-9378(16)33297-5. PMID 2012. 
  18. ↑ "A review of the efficacy, safety, and cost-effectiveness of COX-2 inhibitors for Africa and the Middle East region". Pain Practice 13 (4): 316–331. April 2013. doi:10.1111/j.1533-2500.2012.00591.x. PMID 22931375. 
  19. ↑ 19.0 19.1 "Meloxicam: a reappraisal of pharmacokinetics, efficacy and safety". Expert Opinion on Pharmacotherapy 6 (12): 2117–2140. October 2005. doi:10.1517/14656566.6.12.2117. PMID 16197363. "Meloxicam is extensively bound to plasma proteins (99.4%), primarily to albumin. Meloxicam has an apparent volume of distribution (Vd) 10 – 15 L in humans (0.1 – 0.2 L/kg) after oral administration and a mean volume of distribution at steady-state of 0.2 L/kg after intravenous administration."
    "None of the meloxicam treatment groups demonstrated inhibition of platelet aggregation to either arachidonic acid (AC) or adenosine diphosphate (ADP). However, there were no significant changes in the platelet count, prothrombin and activated partial thromboplastin time in any of the meloxicam and indomethacin groups. Other crossover studies also confirmed that meloxicam 15 mg/day caused a major reduction of maximum thromboxane production, but no reduction in collagen- or AC-induced platelet aggregation.".     
  20. ↑ "Risk of serious upper gastrointestinal and cardiovascular thromboembolic complications with meloxicam". The American Journal of Medicine 117 (2): 100–106. July 2004. doi:10.1016/j.amjmed.2004.03.012. PMID 15234645. 
  21. ↑ "Meloxicam". MedlinePlus. https://www.nlm.nih.gov/medlineplus/druginfo/meds/a601242.html. 
  22. ↑ "Meloxicam". Drugs.com. https://www.drugs.com/meloxicam.html. 
  23. ↑ 23.0 23.1 "Meloxicam official FDA information, side effects, and uses". Drugs.com. March 2010. https://www.drugs.com/pro/meloxicam.html. 
  24. ↑ "Anti-inflammatory, analgesic, antipyretic and related properties of meloxicam, a new non-steroidal anti-inflammatory agent with favourable gastrointestinal tolerance". Inflammation Research 44 (10): 423–33. October 1995. doi:10.1007/BF01757699. PMID 8564518. 
  25. ↑ 25.0 25.1 "Meloxicam in the management of post-operative pain: Narrative review". Journal of Anaesthesiology Clinical Pharmacology 34 (4): 450–457. 2018. doi:10.4103/joacp.JOACP_133_18. PMID 30774225. 
  26. ↑ "Meloxicam (Professional Patient Advice)". Drugs.com. https://www.drugs.com/ppa/meloxicam.html. 
  27. ↑ 27.0 27.1 "American Geriatrics Society 2019 Updated AGS Beers Criteria® for Potentially Inappropriate Medication Use in Older Adults". Journal of the American Geriatrics Society 67 (4): 674–694. April 2019. doi:10.1111/jgs.15767. PMID 30693946. 
  28. ↑ 28.0 28.1 "Metacam- meloxicam suspension". https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ed2227e6-8c69-4057-a8b2-94f74cb11264. 
  29. ↑ "Metacam- meloxicam injection, solution". https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ca78caf5-2b47-46c1-abec-0f925b39f455. 
  30. ↑ Off-label use discussed in: Arnold Plotnick MS, DVM, ACVIM, ABVP, Pain Management using Metacam , and Stein, Robert, Perioperative Pain Management Part IV, Looking Beyond Butorphanol, Sep 2006, Veterinary Anesthesia & Analgesia Support Group.
  31. ↑ For off-label use example in rabbits, see Krempels, Dana, Hind Limb Paresis and Paralysis in Rabbits , University of Miami Biology Department.
  32. ↑ "Effects of meloxicam on renal function in dogs with hypotension during anaesthesia". Veterinary Anaesthesia and Analgesia 33 (1): 62–9. January 2006. doi:10.1111/j.1467-2995.2005.00208.x. PMID 16412133. 
  33. ↑ "Effect of non-steroidal anti-inflammatory drugs on postoperative respiratory and heart rate in cats subjected to ovariohysterectomy". Journal of Feline Medicine and Surgery 20 (10): 980–984. October 2018. doi:10.1177/1098612X17742290. PMID 29165006. 
  34. ↑ "Toxicology Brief: The 10 most common toxicoses in cats". Dvm360. 1 June 2006. http://veterinarymedicine.dvm360.com/toxicology-brief-10-most-common-toxicoses-cats?id=&sk=&date=&pageID=3. Retrieved 16 September 2018. 
  35. ↑ "The 10 most common toxicoses in cats". Veterinary Medicine: 340–342. June 2006. https://www.aspcapro.org/sites/default/files/zl-vetm0606_339-342.pdf. Retrieved 9 August 2019. 
  36. ↑ "Effects of low-dose meloxicam in cats with chronic kidney disease". Journal of Feline Medicine and Surgery 23 (2): 138–148. February 2021. doi:10.1177/1098612X20935750. PMID 32594827. 
  37. ↑ "Removing the threat of diclofenac to critically endangered Asian vultures". PLOS Biology 4 (3): e66. March 2006. doi:10.1371/journal.pbio.0040066. PMID 16435886. 
  38. ↑ 38.0 38.1 38.2 "Toxicology of frequently encountered nonsteroidal anti-inflammatory drugs in dogs and cats". The Veterinary Clinics of North America. Small Animal Practice 42 (2): 289–306, vi-vii. March 2012. doi:10.1016/j.cvsm.2012.01.003. PMID 22381180. 
  39. ↑ "Pharmacokinetics of meloxicam in koalas (Phascolarctos cinereus) after intravenous, subcutaneous and oral administration". Journal of Veterinary Pharmacology and Therapeutics 36 (5): 486–93. October 2013. doi:10.1111/jvp.12038. PMID 23406022. 
  40. ↑ "NADA 141-213: New Animal Drug Application Approval (for Metacam (meloxicam) 0.5 mg/mL and 1.5 mg/mL Oral Suspension)". Food and Drug Administration (FDA). 15 April 2003. https://www.fda.gov/downloads/AnimalVeterinary/Products/ApprovedAnimalDrugProducts/FOIADrugSummaries/ucm118006.pdf. 
  41. ↑ "Client Information Sheet For Metacam (meloxicam) 1.5 mg/mL Oral Suspension". Food and Drug Administration (FDA). January 2005. https://www.fda.gov/downloads/AnimalVeterinary/Products/ApprovedAnimalDrugProducts/DrugLabels/UCM050394.pdf. "Metacam is a prescription non-steroidal anti-inflammatory drug (NSAID) that is used to control pain and inflammation (soreness) due to osteoarthritis in dogs. Osteoarthritis (OA) is a painful condition caused by “wear and tear” of cartilage and other parts of the joints that may result in the following changes or signs in your dog: Limping or lameness, decreased activity or exercise (reluctance to stand, climb stairs, jump or run, or difficulty in performing these activities), stiffness or decreased movement of joints. Metacam is given to dogs by mouth. Do not use Metacam Oral Suspension in cats. Acute kidney injury and death have been associated with the use of meloxicam in cats." 
  42. ↑ "NADA 141-219: Metacam (meloxicam) 5 mg/mL Solution for Injection". U.S. Food and Drug Administration (FDA). 12 November 2003. https://www.fda.gov/downloads/AnimalVeterinary/Products/ApprovedAnimalDrugProducts/FOIADrugSummaries/ucm118026.pdf. 
  43. ↑ "Metacam 5 mg/mL Solution for Injection, Supplemental Approval". U.S. Food and Drug Administration (FDA). 28 October 2004. https://www.fda.gov/downloads/AnimalVeterinary/Products/ApprovedAnimalDrugProducts/FOIADrugSummaries/ucm118027.pdf. 
  44. ↑ See the manufacturer's FAQ on its website, and its clinical dosing instructions for cats.
  45. ↑ "Notice of Violation". U.S. Food and Drug Administration (FDA). 19 April 2005. https://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/ComplianceEnforcement/ucm042460.pdf. 
  46. ↑ "Anjeso (meloxicam) injection, for intravenous use". U.S. Food and Drug Administration (FDA). February 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/210583s000lbl.pdf. 
  47. ↑ "Meloxicam". Small animal clinical pharmacology (2nd ed.). Edinburgh: Saunders/Elsevier. 2008. pp. 301–302. ISBN 9780702028588. https://archive.org/details/smallanimalclini00mrcv. 
  48. ↑ 48.0 48.1 "Generic and biosimilar medicinal products in the European Union". Chemistry Today 25 (2): 4–6. March 2007. https://www.hoganlovells.com/~/media/hogan-lovells/pdf/publication/chemistrytodayapr07_pdf.pdf. Retrieved 28 January 2020. 
  49. ↑ "Recent NSAID developments". Clinical medicine of the dog and cat (3rd ed.). CRC Press. 2016. ISBN 9781482226065. https://books.google.com/books?id=fjqLDQAAQBAJ&dq=meloxicam+cat+australia&pg=PT2004. Retrieved 28 January 2020. 
  50. ↑ "Product Information Database". DEFRA. https://www.vmd.defra.gov.uk/ProductInformationDatabase/current?page=79&order=ActiveSubstances&descending=True. 



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