Ketorolac Trometamol

Ketorolac Trometamol

30mg/ml Solution for Injection (IM/IV)

Drug Category: Non-Opioid Analgesic

Mode of Actions:

Ketorolac Trometamol is a non-narcotic analgesic. It inhibits synthesis of prostaglandins and is considered a peripherally acting analgesic since it does not have any known effects on opiate receptors. No evidence of respiratory depression has been observed after administration of Ketorolac Trometamol. It did not cause pupil constriction. It caused no more drowsiness than placebo and less drowsiness than morphine in postoperative patients. It is a non-steroidal anti-inflammatory agent that exhibits anti-inflammatory and antipyretic activity.

Pharmacokinetics:

Ketorolac Trometamol is rapidly and completely absorbed following intramuscular administration with a mean peak plasma concentration of 2.2mcg/ml occurring an average 50minute after a single 30 mg dose. The terminal plasma half-life is 5.3 hours in young adults and 7 hours in elderly subjects (mean age 72). Intravenous administration of a single 10 mg dose of ketorolac trometamol results in a terminal plasma elimination intravenous administration of a single 10 mg dose of ketorolac trometamol results in a terminal plasma elimination half-life of 5.1 hours, an average volume of distribution of 0.15L/kg and a total plasma clearance of 0.35 ml/min/kg. More than 99% of the ketorolac in plasma is protein-bound over a wide concentration range. The pharmacokinetics of ketorolac in a man following single or multiple intramuscular (IM) doses are linear. Steady-state plasma levels are achieved after dosing every 6 hours of 1 day. No changes in clearances occur with chronic dosing. The primary route of excretion of ketorolac and its metabolites (conjugates and a para-hydroxyl metabolites) is in the urine (mean 91.4%) and the remainder (mean 6.1%) is excreted in the feces (see table).

Influence of Age Liver and Kidney Function on the Clearance and Terminal Half-life of Ketorolac Trometamol
Type Of Subjects	Total clearance (L/Hr/Kg) Mean (range)	Terminal Half-life (hrs) Mean (range)
Normal subjects (n=54)	0.023 (0.010-0.045)	5.3 (3.5-9.2)
Patients with hepatic dysfunction (n=7)	0.029 (0.013-0.066)	5.4 (2.2-6.9)
Patients with renal impairment (n=10) (serum creatinine) (1.9-5mg/dl)	0.016 (0.007-0.043)	9.6 (3.2-15.7)
Renal dialysis (n=9)	0.016 (0.003-0.036)	13.6 (8-39.1)
Healthy elderly subjects (n=13) (mean age 72)	0.019 (0.013-0.034)	7 (4.7-8.67)
Estimated from 30mg single doses of Ketorolac Trometamol IM/IV

Hemodynamics of patients are not altered by parenteral administration of Ketorolac Trometamol.

Indications:

For short term management of moderate to severe acute post-operative pain following surgical procedures associated with low risk of hemorrhage.

Contraindications:

Ketorolac Trometamol should not be used:

1. In patients who have previously exhibited allergy to it.
2. In suspected or confirmed cerebrovascular bleeding or hemophilia in other bleeding problems including coagulation or platelet function disorders due to increased risk of bleeding because ketorolac inhibits platelet aggregation and may also cause gastrointestinal ulceration or hemorrhage.
3. In active, recent or history of gastrointestinal bleeding or recent gastrointestinal perforation or active or history of peptic ulceration, ulceration colitis or other ulcerative gastrointestinal disease due to increased risk of gastrointestinal ulceration, perforation and/or hemorrhage.
4. In aspirin induced nasal polyps associated with bronchospasm, or angioedema, anaphylaxis or history of other severe allergic reactions of cross-sensitivity.
5. In severe renal function impairment, due to increased risk of renal failure.
6. During pregnancy labor, delivery or lactation.
7. A history of asthma.
8. Hypovolemia or dehydration from any cause.

Adverse Effects:

The following adverse reactions were reported to be probably related to patients who receive up to 20 doses for 5 days of intramuscular administered Ketorolac Trometamol and in patients who receive up to 8 doses for 2 days, of intravenously administered ketorolac trometamol.

Incidence between 3 and 9%:

Gastrointestinal: Nausea, dyspepsia, gastrointestinal pain.

Central nervous system: Drowsiness

Incidence between 1 and 3%:

Gastrointestinal: Diarrhea

Central Nervous system: Dizziness, headache, sweating

Body as a whole: Edema

Injection site pain was reported by 2% of patient

Incidence 1% or less:

Gastrointestinal: Constipation, flatulence, gastrointestinal fullness, liver function abnormalities, melena, peptic ulcer, rectal bleeding, stomatitis, vomiting.

Body as a whole: Asthenia, myalgia

Cardiovascular: flushing, pallor

Hemic and lymphatic: purpura

Nervous system: Dry mouth, nervousness, paresthesia, abnormal thinking, depression, euphoria, excessive thirst, inability to concentrate, insonmia, stimulation, vertigo

Respiratory: Dyspnea, asthma

Urogenital: Increased urinary frequency, oliguria

Dermatologic: Pruritus, urticaria

Special senses: Abnormal taste, abnormal vision

Precautions:

As with other non-steroidal anti-inflammatory analgesic agents, ketorolac trometamol can cause gastrointestinal irritation, ulcers or bleeding with or without previous symptoms and should be given under close supervision to patients with history of gastrointestinal tract disease. Elderly and debilitated individuals are most susceptible to these complications, the incidence of which increased with dose and duration of treatment.

Renal Effects: As with other non-steroidal anti-inflammatory drugs that inhibits prostaglandin biosynthesis, elevations of serum urea nitrogen and creatinine have been reported with ketorolac trometamol. Since ketorolac trometamol and its metabolites are excreted primarily by the kidney, patients with significance impairment or renal functions should not receive ketorolac trometamol unless the expected benefits out weight the risks. If used in patients with impaired renal function, ketorolac trometamol dosage should be reduced and renal status should be closely monitored. In patients with serum creatinine values ranging from 1.9-5mg/dl, the rate of ketorolac clearance was reduced to approximately half of normal. The total daily dose of ketorolac should be reduced by half in such patients. With more severe degrees of renal impairment, ketorolac is not recommended for patients with serum creatinine serum levels above 5 mg/dl. Patients who are volume-depleted because of blood loss or severe dehydration may be dependent on renal prostaglandin production to maintain renal perfusion and therefore, glomerular filtration rate. In such situation, the use of drugs which inhibit prostaglandin synthesis might be expected to further decrease renal blood flow. Caution is advised if ketorolac trometamol is used in such circumstances. Close monitoring of urine output, serum urea and serum creatinine is recommended until the patient is normo-volemic. As with other drugs that inhibit prostaglandin biosynthesis, the following renal abnormalities may be associated with the use of ketorolac trometamol: Glomerular nephritis, interstitial nephritis, renal papillary necrosis, nephrotic syndrome and acute renal failure. Other renal disease is possible.

Fluid retention and edema: Fluid retention and edema have been reported with use of ketorolac trometamol; therefore ketorolac trometamol should be used with caution in patients with cardiac decompensation, hypertension or similar conditions.

Hematological Effects: Ketorolac trometamol inhibits platelet aggregation and may prolong bleeding time. Patients on full anticoagulation therapy (e.g. Heparin or dicumarol derivatives) may be at increased risk of bleeding, if given ketorolac trometamol concurrently. Thus, the benefits should be weighed against the risk. Low-dose heparin (5000 units SC 2 times a day) appears to be associated with less risk. Patients who have coagulation disorders or are receiving drug therapy that interferes with homeostasis should be carefully observed if ketorolac trometamol is administered. Unlike the prolonged effects from aspirin, the inhibition of platelet function by ketorolac disappears within 24-48 hours after the drug is discontinued. Ketorolac does not affect platelet count, prothrombin time (PT) or partial thromboplastin similar to control groups i.e. 5/11750 (0.4%) with ketorolac trometamol compared to 1/570 (0.2%) with opiates. Postoperative wound hemorrhage has been reported rarely in association with the immediate perioperative use of ketorolac trometamol. Therefore caution should be used where strict homeostasis is critical. Specifically in cosmetic plastic surgery, hematomas and other other signs of wound hemorrhage have been reported with the use of ketorolac trometamol. Physicians should be alert to the pharmacologic similarity of ketorolac to other non-steroidal anti-inflammatory drugs that inhibits cyclooxygenase.

Hepatic effects: Borderline elevation of one or more liver tests may occur. These abnormalities may progress, may remain unchanged or may be transient with continued therapy. Meaningful elevations (>3 times normal) of serum glutamic oxaloacetic transaminase (SGOT or AST) occurred in <1% of patients. If clinical signs and symptoms consistent with liver disease develop or if systemic manifestation occur (e.g. eosinophilia, rash, etc.) ketorolac trometamol should be discontinued. Patients with impaired hepatic functions from cirrhosis do not have any clinical important changes in ketorolac clearance.

Ketorolac trometamol is not an anesthetic agent and possesses no sedative or anxiolytic properties: therefore it is not recommended as an preoperative medication when these effects are required. Ketorolac is not recommended in obstetric analgesia.

Carcinogenicity, mutagenicity, and impairment of fertility: In animal ketorolac was not associated with tumourigenicity or mutagenicity and did not demonstrate teratogenic potential.

Use in pregnancy and lactation: Ketorolac trometamol is not recommended during pregnancy, labor or delivery. Ketorolac trometamol is not recommended for treatment of nursing mothers. Secretion of ketorolac in human milk after ingestion of ketorolac trometamol is limited. The milk to plasma ration of ketorolac concentrations ranged between 0.015 and 0.037.

Use in children: Safety and efficacy in children have not been established. Therefore, it is not recommended for use in children under 16 years.

Use in the Elderly: Because ketorolac is cleared somewhat more slowly by the elderly who are also more sensitive to the renal effects of NSAIDs (see Renal effects), extra caution and the lowest effective dose should be given when treating the elderly with ketorolac trometamol.

Drug abuse and Physical dependence: Ketorolac is not a narcotic agonist or antagonist. No subjective symptoms or objective signs of drug withdrawal upon abrupt discontinuation of IV or IM dosing. Patients receiving Ketorolac Trometamol for 6 months or longer have not developed tolerance to the drug and there is no pharmacological basis to expect addition. Ketorolac Trometamol did not exhibit activity in classical animal which are reasonable predictors of opiate analgesic action (hot plate and tail withdrawal test). In vitro, ketorolac does not bind to opiate receptors. These demonstrate that ketorolac trometamol does not have opiate-like activity.

Warnings:

Risk of GI ulceration, bleeding and perforation with NSAID

Serious GI toxicity such bleeding, ulceration and perforation can occur at any time, with or without symptoms, in patients treated with NSAID therapy. Although minor upper GI problems (e.g. dyspepsia) are common, usually developing early in therapy, prescribers should remain alert for ulceration and bleeding in patients treated with NSAID even in the absence of previous GI tract symptoms.

Studies to date have not identified any subset of patients not at risk of developing peptic ulceration and bleeding. Patients with prior history of serious adverse events and other risk factors associated with peptic ulcer disease (e.g. alcoholism, smoking, and corticosteroid therapy) are at increased risk. Elderly or debilitated patients seem to tolerate ulceration or bleeding less then other individuals and account for most spontaneous for fatal GI events.

Drug Interactions:

Given 10 mg orally for 6 days prior to coadministration of single dose of warfarin 25mg, no significant changes in pharmacokinetics of the warfarin enantiomers were detected. Ketorolac is highly bound to plasma proteins (mean 99.2%) and binding is independent of concentration. The in-vitro binding of warfarin to plasma proteins is only slightly reduced by ketorolac. Ketorolac does not alter digoxin, protein binding. In vitro at therapeutic concentration of salicylate (300mcg/ml). The binding of ketorolac was reduced from approximately 99.2%-97.5%. Therapeutic concentrations of digoxin, warfarin, acetaminophen, phenytoin and tolbutamine did not alter ketorolac protein-binding. Because ketorolac is highly potent drug and present in low concentrations in plasma, it would be expected to displace other protein bound drugs significantly. There is no evidence that ketorolac induces or inhibits the hepatic enzymes capable of metabolizing itself or other drugs. Hence ketorolac would not be expected to alter the pharmacokinetics of other drugs due to enzyme induction of inhibition mechanisms. Concomitant administration of ketorolac trometamol and probenecid results in the decreased clearance of ketorolac and a significant increase in ketorolac plasma levels and terminal half-life of ketorolac. Ketorolac trometamol reduces the diuretic response to furosemide in normo-volemic healthy subjects by approximately 20%. Inhibition of renal lithium clearance leading to an increase in plasma lithium concentrations and potential lithium toxicity has been reported with some prostaglandin synthesis inhibiting drugs. Concomitant administration of ketorolac trometamol and methotrexate should be done with caution, since some prostaglandin synthesis inhibiting drugs have been reported to reduce the clearance of methotrexate, and thus possibly enhance the toxicity of methotrexate. Ketorolac trometamol has been administered concurrently with morphine in postoperative pain without evidence of adverse interactions. There are no clinical data available dealing with the safety or efficacy of concomitant use with other non-steroidal anti-inflammatory drugs. It is not recommended that ketorolac trometamol be routinely used with other non-steroidal anti-inflammatory drugs because of potential for additive side effects.

Cautions for Usage:

Incompatibilities: This product should not be mixed in a small volume (e.g. in a syringe) with Morphine Sulfate, Pethidine hydrochloride, Promethazine hydrochloride or Hydroxyzine hydrochloride as precipitation of ketorolac trometamol will occur. It is compatible with normal saline, 5% dextrose, Ringer's solution, Ringer's Lactate Solution or Plasmalyte solution.

Recommended Dosage, Dosage Schedule and Route of Administration:

Dosage and Administration: Dosage should be adjusted according to the severity of the pain and the patient response. The recommended usual initial dose of ketorolac trometamol is 30mg followed by 10-30 mg every 4-6 hours as needed to control pain. A lower initial dose is recommended for patients under 50kg for patients over 65 years and for patients with reduced renal function. In the initial postoperative period, ketorolac trometamol may be given as often as every 2 hours if needed. A total daily dose >120mg/day is not recommended. Intravenous injections should be administered over at least 15 seconds.

Opiates analgesic (e.g. Morphine, Pethidine) may be concomitantly used if further pain relief, anxiolytic effects and/or sedative effects of opiates are desired. Supplemental opiates may be most appropriate in the early postoperative period when pain is most severe. The administration of continuous multiple daily intramuscular doses of ketorolac trometamol should not exceed 2 days because adverse events may increase with prolonged usage.

Symptoms and treatment for overdosage and antidotes:

Overdosage: The absence of experience with acute overdosage precludes characterization of sequalae and assessment of antidotal efficacy at this time. In gastroscopic uses, daily doses of 360mg given over an 8 hour interval for each of 5 consecutive days (3 times the highest recommended dose) caused abdominal pain and peptic ulcers which healed after discontinuation of dosing.

Storage Conditions:

Store at temperatures not exceeding 30^oC. Protect from light.