Ketorolac: Wikis

  
  

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Ketorolac
Systematic (IUPAC) name
(±)-5-benzoyl-2,3-dihydro-
1H-pyrrolizine-1-carboxylic acid,
2-amino-2-(hydroxymethyl)-1,3-propanediol
Identifiers
CAS number 74103-06-3
ATC code M01AB15
PubChem 3826
DrugBank DB00465
ChemSpider 3694
Chemical data
Formula C 15H13NO3  
Mol. mass 255.27 g/mol
Pharmacokinetic data
Bioavailability 100% (All routes)
Metabolism Hepatic
Half life 3.5-9.2 hrs, young adults;
4.7-8.6 hrs, elderly (mean age 72)
Excretion Renal:91.4% (mean)
Biliary:6.1% (mean)
Therapeutic considerations
Pregnancy cat. C(AU) C(US)
Legal status Prescription only
Routes oral, I.M., I.V.

Ketorolac or ketorolac tromethamine (marketed under the trademarks Toradol and Acular in the US, where generics have also been approved, and various other brand names around the world) is a non-steroidal anti-inflammatory drug (NSAID) in the family of heterocyclic acetic acid derivatives, often used as an analgesic, antipyretic (fever reducer), and anti-inflammatory. Ketorolac acts by inhibiting the bodily synthesis of prostaglandins. Ketorolac in its oral (tablet or capsule) and intramuscular (injected) preparations is a racemic mixture of both (S)-(−)-ketorolac, the active isomer, and (R)-(+)-ketorolac. An ophthalmic (i.e., eye-drop) solution of ketorolac is available and is used to treat eye pain and to relieve the itchiness and burning of seasonal allergies.

Contents

Chemistry

Although its name would suggest some similarity with propionic acid derivatives (including ketoprofen, flurbiprofen, naproxen, ibuprofen, etc.), ketorolac is a pyrolizine carboxylic acid derivative structurally related to indomethacin.[1]

NSAIDs (Non-steroidal anti-inflammatory drug) are not recommended for use with other NSAIDs because of the potential for additive side effects.

The protein-binding effect of most non-aspirin NSAIDs is inhibited by the presence of aspirin in the blood.

Mechanism of action

The primary mechanism of action responsible for ketorolac's anti-inflammatory, antipyretic and analgesic effects is the inhibition of prostaglandin synthesis by competitive blocking of the enzyme cyclooxygenase (COX). Like most NSAIDs, ketorolac is a non-selective COX inhibitor.

Indications

Ketorolac is indicated for short-term management of moderate to severe postoperative pain. Concerns about the high incidence of reported side effects led to restriction in its dosage and maximum duration of use. In the UK, treatment should be initiated only in hospital. Maximum duration of treatment should not exceed 5 days for tablets (per package insert), or 2 days for continuous daily dosing with intravenous or intramuscular formulations[2]. The ophthalmic formulation can be used instead of steroidal anti inflammatories in cases where a raised intraocular pressure (Glaucoma) is to be avoided.

Contraindications

Ketorolac is contraindicated in patients with a previously demonstrated hypersensitivity to ketorolac, and in patients with the complete or partial syndrome of nasal polyps, angioedema, bronchospastic reactivity or other allergic manifestations to aspirin or other non-steroidal anti-inflammatory drugs (due to possibility of severe anaphylaxis). As with all NSAIDs, ketorolac should be avoided in patients with renal (kidney) dysfunction. (Prostaglandins are needed to dilate the afferent arteriole; NSAIDs effectively reverse this.) The patients at highest risk, especially in the elderly, are those with fluid imbalances or with compromised renal function (e.g., heart failure, diuretic use, cirrhosis, dehydration, and renal insufficiency).

Adverse effects

Concerns over the high incidence of reported side effects with ketorolac trometamol has led to its withdrawal (apart for the ophthalmic formulation) in several countries, while in others its permitted dosage and maximum duration of treatment have been reduced. From 1990 to 1993, 97 reactions with a fatal outcome were reported worldwide[3]. A post-marketing surveillance study[4] indicated a dose-response relationship with average daily dose for both gastrointestinal bleeding and operative site bleeding, and an association between gastrointestinal bleeding and therapy for more than five days. Allergic reactions (anaphylactoid reactions, asthma, bronchospasm, Stevens Johnson syndrome, Lyell syndrome) have been reported. Fluid retention and oedema have been reported with the use of ketorolac and it should therefore be used with caution in patients with cardiac decompensation, hypertension or similar conditions. When this ophthalmic formulation is instilled into the eye it can lead to an unpleasant short term burning pain for 4–5 seconds. Other adverse effects are similar to the ones associated with other NSAIDs. See inset "Ketorolac adverse effects."

Ketorolac adverse effects
Body system Effects
General Edema. Less frequently, hypersensitivity reactions (such as anaphylaxis, bronchospasm, laryngeal edema, tongue edema, hypotension), flushing, weight gain, or fever. Very infrequently, asthenia.
Cardiovascular Hypertension. Less frequently, palpitation, pallor, or fainting (syncope).
Dermatologic Rash or pruritus. Less frequently, Lyell's syndrome, Stevens-Johnson syndrome, musculo-papular rash, exfoliative dermatitis, or urticaria.
Gastrointestinal Nausea, dyspepsia, gastrointestinal pain, constipation, diarrhea, flatulence, gastrointestinal fullness, vomiting or stomatitis. Less frequently, peptic ulceration, gastrointestinal hemorrhage, gastrointestinal perforation, melena, rectal bleeding, gastritis, eructation, anorexia, or increased appetite. Very infrequently, pancreatitis.
Hemic and lymphatic Purpura. Less frequently, postoperative wound hemorrhage, thrombocytopenia, epistaxis, or anemia. Very infrequently, leukopenia or eosinophilia.
Neurological Drowsiness, dizziness, headache, sweating, injection site pain. Less frequently convulsions, vertigo, tremors, abnormal dreams, hallucinations, or euphoria. Very infrequently, paresthesia, depression, insomnia, inability to concentrate, nervousness, excessive thirst, dry mouth, abnormal thinking, hyperkinesis, or stupor.
Respiratory Less frequently, dyspnea, asthma and pulmonary edema. Very infrequently, rhinitis or cough.
Urogenital Less frequently, acute renal failure. Very infrequently polyuria or increased urinary frequency.

Warnings and precautions

The most serious risks associated with ketorolac are, as with other NSAIDs, gastrointestinal ulcers, bleeding and perforation; renal (kidney) events ranging from interstitial nephritis to complete kidney failure; hemorrhage, and hypersensitivity reactions.

As with other NSAIDs, fluid and solute retention and edema have been reported with ketorolac. Ketorolac also elevates liver protein levels.

It should be noted that when administered intravenously through the same IV catheter as morphine, the two drugs have been known to sometimes combine to form a precipitate in the IV, which may block the line. Line flushing with a syringe of saline solution can push the blockage through.

Ketorolac is not recommended for pre-operative analgesia or co-administration with anesthesia because it inhibits platelet aggregation and thus may be associated with an increased risk of bleeding.

Ketorolac is not recommended for obstetric analgesia because it has not been adequately tested for obstetrical administration and has demonstrable fetal toxicity in laboratory animals.

Ketorolac is not recommended for long-term chronic pain patients.

However, ketorolac has been co-administered with meperidine and morphine without apparent adverse effects on patients.

Dosage, availability and cost

Oral dosage is 10 mg; United States price for 20 tablets hovers around US$28. Australian pricing for 20 tablets is around AU$44.[5] It is considerably less expensive in Mexico (where it is called ketorolaco, and marketed under various brand names, such as Glicima, from Atlantis Pharma, and Supradol, from Laboratorios Liamont), costing approximately US$10 for 20 tablets.

Injected dosages are 15, 30 and 60 mg; US price for 10 vials of 30 mg each is around US$45, making the intramuscular preparation considerably more expensive per dose. One 60-mg dose would require the administration by injection of two vials, at about $9 per dose. Australian pricing for 5 vials is around AU$58[5], or about $23 per dose. Ketorolac is not available on the Pharmaceutical Benefits Scheme.[6]

In the United States,[7] United Kingdom,[8] Canada,[9] and Australia[10] this drug cannot be sold over-the-counter and must be administered only with a prescription. It is commonly available over-the-counter in Mexico and other areas of Latin America, at the pharmacist's discretion.

Patent controversy

The Syntex company, of Palo Alto, California developed the ophthalmic solution Acular, and holds the registered trademark on that name, as well as on the Toradol. The actual product using this brand name is manufactured and distributed by Allergan under license from Syntex.[11]

Apotex, a Canadian manufacturer, offers generic Ketorolac tromethamine as a 0.5% ophthalmic solution and as 10 mg tablets under the name "Apo-Ketorolac"[12 ], in Canada and some other countries. Syntex and Allergan sued Apotex for patent infringement of US Patent No. 5,110,493, over the generic ketorolac tomethamine product. In May, 2005, the United States Court of Appeals for the Federal Circuit handed Apotex a victory, ruling that a lower court upholding the Syntex patent misapplied the rules for judging whether an invention was obvious. Allergan had claimed that the patent is valid until 2009.[13 ]

Ranbaxy, an Indian manufacturer makes ketorolac in tablets and ampoules under a name "Ketanov". Another Indian manufacturer Dr. Reddy's makes ketorolac under a name "Ketorol".

External links

References

  1. ^ Martindale, The Complete Drug Reference,35th Edition, 2007
  2. ^ MHRA Drug Safety Update October 2007, Volume 1, Issue 3, pp 3-4
  3. ^ Committee on the Safety of Medicines, Medicines Control Agency: Ketorolac: new restrictions on dose and duration of treatment. Current Problems in Pharmacovigilance: June 1993; Volume 19 (pages 5-8)
  4. ^ Strom BL et al. Parenteral Ketorolac and risk of gastrointestinal and operative site bleeding: a postmarketing surveillance study JAMA 1996; 275:376-82
  5. ^ a b "Search for Toradol". ePharmacy. http://www.epharmacy.com.au/searchresults.asp?searchsection=products&terms=toradol&stype=NP&expand=0. Retrieved 2007-10-16.  
  6. ^ "Search for Ketorolac". Pharmaceutical Benefits Scheme. http://www.pbs.gov.au/html/consumer/search/results?medicine=ketorolac. Retrieved 2007-10-16.  
  7. ^ "FDA Label for Ketorolac". US Food and Drug Administration. 2004. http://redpoll.pharmacy.ualberta.ca/drugbank/drugBank/FDA_labels/019700.pdf. Retrieved 2007-10-16.  
  8. ^ "Pain: prescription-only medicines". NetDoctor.co.uk. 2007. http://www.netdoctor.co.uk/medicines/effect/pain/prescription_only_medicines.shtml. Retrieved 2007-10-16.  
  9. ^ "Prescription Drug Search". Smart Med Canada. http://www.smartmed.ca/content/search.asp?txtsearch=Ketorolac. Retrieved 2007-10-16.  
  10. ^ "Toradol (ketorolac trometamol) Product Information". Roche Australia. 2005. http://www.roche-australia.com/downloads/toradol-pi.cfm?action=get. Retrieved 2007-10-16.  
  11. ^ Allergan (2006). "ACULAR Ketorolac tromethamine 0.5% ophthalmic solution Product Information". Allergan web site. Allergan. http://www.allergan.com/site/products/consumers/home.asp?id=acular. Retrieved 2006-05-08.  
  12. ^ Apotex Products Canada (2006-05-08). "APO-KETOROLAC Product Information". Apotex Products Canada Product Catalogue. Apotex Products Canada. http://www.apotex.ca/Products/EN/Detail.asp?MaterialNumber=000000000000043869. Retrieved 2006-05-08.  
  13. ^ Albainy-Jenei, Stephen R. (May 24, 2005). "Federal Circuit Reverses Allergan's Patent Validity Decision". Patent Baristas web log. http://www.patentbaristas.com/archives/000188.php. Retrieved 2006-05-08.  
  • Handley, D.A., P. Carvoni, J.E. McCray, J.R. McCullough (1998). "Preclinical Enantioselective Pharmacology of (R)- and (S)- Ketorolac.", J Clin Pharmacol 38, 25-35.
  • 1993. Physicians' Desk Reference, Forty-seventh edition. Montvale, N.J., Medical Economics Co. Inc., 2411-2415.







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