Ketorolac Tromethamine Injection, USP
Rx only

Ketorolac tromethamine, a nonsteroidal anti-inflammatory drug (NSAID), is indicated for the short-term (up to 5 days in adults) management of moderately severe acute pain that requires analgesia at the opioid level. It is NOT indicated for minor or chronic painful conditions. Ketorolac tromethamine is a potent NSAID analgesic, and its administration carries many risks. The resulting NSAID-related adverse events can be serious in certain patients for whom ketorolac tromethamine is indicated, especially when the drug is used inappropriately. Increasing the dose of ketorolac tromethamine beyond the label recommendations will not provide better efficacy but will result in increasing the risk of developing serious adverse events.

• Ketorolac tromethamine can cause peptic ulcers, gastrointestinal bleeding and/or perforation. Therefore, ketorolac tromethamine is CONTRAINDICATED in patients with active peptic ulcer disease, in patients with recent gastrointestinal bleeding or perforation, and in patients with a history of peptic ulcer disease or gastrointestinal bleeding.

• Ketorolac tromethamine is CONTRAINDICATED in patients with advanced renal impairment and in patients at risk for renal failure due to volume depletion (see WARNINGS).

• Ketorolac tromethamine inhibits platelet function and is, therefore, CONTRAINDICATED in patients with suspected or confirmed cerebrovascular bleeding, patients with hemorrhagic diathesis, incomplete hemostasis and those at high risk of bleeding (see WARNINGS and PRECAUTIONS).
• Ketorolac tromethamine is CONTRAINDICATED as prophylactic analgesic before any major surgery and is CONTRAINDICATED intraoperatively when hemostasis is critical because of the increased risk of bleeding.

• Hypersensitivity reactions, ranging from bronchospasm to anaphylactic shock, have occurred and appropriate counteractive measures must be available when administering the first dose of Ketorolac Tromethamine Injection (seeCONTRAINDICATIONS and WARNINGS). Ketorolac tromethamine is CONTRAINDICATED in patients with previously demonstrated hypersensitivity to ketorolac tromethamine or allergic manifestations to aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs).

• Ketorolac tromethamine is CONTRAINDICATED for intrathecal or epidural administration due to its alcohol span.

• The use of ketorolac tromethamine in labor and delivery is CONTRAINDICATED because it may adversely affect fetal circulation and inhibit uterine contractions.
• The use of ketorolac tromethamine is CONTRAINDICATED in nursing mothers because of the potential adverse effects of prostaglandin-inhibiting drugs on neonates.

• Ketorolac tromethamine is CONTRAINDICATED in patients currently receiving ASA or NSAIDs because of the cumulative risk of inducing serious NSAID-related side effects.

• Dosage should be adjusted for patients 65 years or older, for patients under 50 kg (110 lbs) of body weight (seeDOSAGE AND ADMINISTRATION) and for patients with moderately elevated serum creatinine (see WARNINGS). Doses of Ketorolac Tromethamine Injection are not to exceed 60 mg (total dose per day) in these patients. Ketorolac Tromethamine Injection is indicated as a single dose therapy in pediatric patients (see DOSAGE AND ADMINISTRATION); not to exceed 30 mg for IM administration and 15 mg for IV administration.

Ketorolac tromethamine is a member of the pyrrolo-pyrrole group of nonsteroidal anti-inflammatory drugs (NSAIDs). The chemical name for ketorolac tromethamine is (±)-5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid, compound with 2-amino-2-(hydroxymethyl)-1,3-propanediol (1:1), and the chemical structure is:

Ketorolac tromethamine is a racemic mixture of [-]S and [+]R ketorolac tromethamine. Ketorolac tromethamine may exist in three crystal forms. All forms are equally soluble in water. Ketorolac tromethamine has a pKa of 3.5 and an n-octanol/water partition coefficient of 0.26. The molecular weight of ketorolac tromethamine is 376.41. Its molecular formula is C₁₉H₂₄N₂O₆.

Ketorolac tromethamine is available for intravenous (IV) or intramuscular (IM) administration as: 15 mg in 1 mL (1.5%) and 30 mg in 1 mL (3%) in sterile solution; 60 mg in 2 mL (3%) of ketorolac tromethamine in sterile solution is available for IM administration only. The solutions contain 0.1% citric acid, 10% (w/v) alcohol, USP, and 6.68 mg, 4.35 mg and 8.70 mg, respectively, of sodium chloride in sterile water. The pH is adjusted with sodium hydroxide or hydrochloric acid, and the solutions are packaged with nitrogen. The sterile solutions are clear and slightly yellow in color.

Ketorolac tromethamine is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits analgesic activity in animal models. Ketorolac tromethamine inhibits synthesis of prostaglandins and may be considered a peripherally acting analgesic. The biological activity of ketorolac tromethamine is associated with the S-form. Ketorolac tromethamine possesses no sedative or anxiolytic properties.

The peak analgesic effect of ketorolac tromethamine occurs within 2 to 3 hours and was not statistically significantly different over the recommended dosage range of ketorolac tromethamine. The greatest difference between large and small doses of ketorolac tromethamine by either route was in the duration of analgesia.

Ketorolac tromethamine is a racemic mixture of [-]S- and [+]R-enantiomeric forms, with the S-form having analgesic activity.

Ketorolac tromethamine is indicated for the short-term (≤5 days) management of moderately severe acute pain that requires analgesia at the opioid level, usually in a postoperative setting. Therapy should always be initiated with Ketorolac Tromethamine Injection and ketorolac tromethamine tablets are to be used only as continuation treatment, if necessary. Combined use of Ketorolac Tromethamine Injection and ketorolac tromethamine tablets is not to exceed 5 days of use because of the potential of increasing the frequency and severity of adverse reactions associated with the recommended doses (seeWARNINGS, PRECAUTIONS, DOSAGE AND ADMINISTRATION and ADVERSE REACTIONS). Patients should be switched to alternative analgesics as soon as possible, but ketorolac tromethamine therapy is not to exceed 5 days.

The safety and effectiveness of single doses of Ketorolac Tromethamine Injection have been established in pediatric patients between the ages of 2 and 16 years. Ketorolac tromethamine, as a single injectable dose, has been shown to be effective in the management of moderately severe acute pain that requires analgesia at the opioid level, usually in the postoperative setting. There is limited data available to support the use of multiple doses of ketorolac tromethamine in pediatric patients. Safety and effectiveness have not been established in pediatric patients below the age of 2 years. Use of ketorolac tromethamine in pediatric patients is supported by evidence from adequate and well-controlled studies of ketorolac tromethamine in adults with additional pharmacokinetic, efficacy and safety data on its use in pediatric patients available in the published literature (seeCLINICAL PHARMACOLOGY, Clinical Studies, WARNINGS, and PRECAUTIONS).

Ketorolac Tromethamine Injection has been used concomitantly with morphine and meperidine and has shown an opioid-sparing effect. For breakthrough pain, it is recommended to supplement the lower end of the Ketorolac Tromethamine Injection dosage range with low doses of narcotics prn, unless otherwise contraindicated. Ketorolac Tromethamine Injection and narcotics should not be administered in the same syringe (see DOSAGE AND ADMINISTRATION - Pharmaceutical Information for Ketorolac Tromethamine Injection).

(see also Boxed WARNING)

• Ketorolac tromethamine is CONTRAINDICATED in patients with active peptic ulcer disease, in patients with recent gastrointestinal bleeding or perforation and in patients with a history of peptic ulcer disease or gastrointestinal bleeding.
• Ketorolac tromethamine is CONTRAINDICATED in patients with advanced renal impairment or in patients at risk for renal failure due to volume depletion (see WARNINGS for correction of volume depletion).
• Ketorolac tromethamine is CONTRAINDICATED in labor and delivery because, through its prostaglandin synthesis inhibitory effect, it may adversely affect fetal circulation and inhibit uterine contractions, thus increasing the risk of uterine hemorrhage.
• The use of ketorolac tromethamine is CONTRAINDICATED in nursing mothers because of the potential adverse effects of prostaglandin-inhibiting drugs on neonates.
• Ketorolac tromethamine is CONTRAINDICATED in patients with previously demonstrated hypersensitivity to ketorolac tromethamine, or allergic manifestations to aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs).
• Ketorolac tromethamine is CONTRAINDICATED as prophylactic analgesic before any major surgery and is CONTRAINDICATED intraoperatively when hemostasis is critical because of the increased risk of bleeding.
• Ketorolac tromethamine inhibits platelet function and is, therefore, CONTRAINDICATED in patients with suspected or confirmed cerebrovascular bleeding, hemorrhagic diathesis, incomplete hemostasis and those at high risk of bleeding (see WARNINGS and PRECAUTIONS).
• Ketorolac tromethamine is CONTRAINDICATED in patients currently receiving ASA or NSAIDs because of the cumulative risks of inducing serious NSAID-related adverse events.
• Ketorolac Tromethamine Injection is CONTRAINDICATED for neuraxial (epidural or intrathecal) administration due to its alcohol span.
• The concomitant use of ketorolac tromethamine and probenecid is CONTRAINDICATED.

(see also Boxed WARNING)

The combined use of Ketorolac Tromethamine Injection and ketorolac tromethamine tablets are not to exceed 5 days in adults. Only single doses of Ketorolac Tromethamine Injection are recommended for use in pediatric patients.

The most serious risks associated with ketorolac tromethamine are:

Ketorolac tromethamine is CONTRAINDICATED in patients with previously documented peptic ulcers and/or GI bleeding. Serious gastrointestinal toxicity, such as bleeding, ulceration and perforation, can occur at any time, with or without warning symptoms, in patients treated with ketorolac tromethamine. Studies to date with NSAIDs have not identified any subset of patients not at risk of developing peptic ulceration and bleeding. Elderly or debilitated patients seem to tolerate ulceration or bleeding less well than other individuals, and most spontaneous reports of fatal GI events are in this population. Postmarketing experience with parenterally administered ketorolac tromethamine suggests that there may be a greater risk of gastrointestinal ulcerations, bleeding and perforation in the elderly.

The incidence and severity of gastrointestinal complications increases with increasing dose of, and duration of treatment with, ketorolac tromethamine. In a non-randomized, in-hospital postmarketing surveillance study comparing parenteral ketorolac tromethamine to parenteral opioids, higher rates of clinically serious GI bleeding were seen in adult patients <65 years of age who received an average total daily dose of more than 90 mg of Ketorolac Tromethamine Injection per day (see CLINICAL PHARMACOLOGY, Postmarketing Surveillance Study).

The same study showed that elderly (≥65 years of age) and debilitated patients are more susceptible to gastrointestinal complications. A history of peptic ulcer disease was revealed as another risk factor that increases the possibility of developing serious gastrointestinal complications during ketorolac tromethamine therapy (see Tables 3A and 3B).

Because prostaglandins play an important role in hemostasis and NSAIDs affect platelet aggregation as well, use of ketorolac tromethamine in patients who have coagulation disorders should be undertaken very cautiously, and those patients should be carefully monitored. Patients on therapeutic doses of anticoagulants (e.g., heparin or dicumarol derivatives) have an increased risk of bleeding complications if given ketorolac tromethamine concurrently; therefore, physicians should administer such concomitant therapy only extremely cautiously. The concurrent use of ketorolac tromethamine and prophylactic low-dose heparin (2500 to 5000 units q12h), warfarin and dextrans have not been studied extensively, but may also be associated with an increased risk of bleeding. Until data from such studies are available, physicians should carefully weigh the benefits against the risks and use such concomitant therapy in these patients only extremely cautiously. In patients who receive anticoagulants for any reason, there is an increased risk of intramuscular hematoma formation from administered ketorolac tromethamine IM (see PRECAUTIONS - Drug Interactions). Patients receiving therapy that affects hemostasis should be monitored closely.

In postmarketing experience, postoperative hematomas and other signs of wound bleeding have been reported in association with the perioperative use of Ketorolac Tromethamine Injection. Therefore, perioperative use of ketorolac tromethamine should be avoided and postoperative use be undertaken with caution when hemostasis is critical (see WARNINGS and PRECAUTIONS).

Physicians should consider the increased risk of bleeding before deciding to administer ketorolac tromethamine in patients following tonsillectomy. Ketorolac Tromethamine Injection is not recommended for use in pediatric patients below the age of 2 years. In a retrospective analysis of patients having undergone tonsillectomy with or without adenoidectomy, the risk of bleeding was 10.1% in patients administered Ketorolac Tromethamine Injection compared to 2.2% in those receving opioids. The postoperative hemorrhage rate in patients 12 years and younger was 6.5% and 3.3% with and without ketorolac tromethamine, respectively. In a prospective study of ketorolac tromethamine in pediatric patients (ages 3 to 9 years) undergoing tonsillectomy with or without adenoidectomy, the overall incidence of bleeding was similar between the patients receiving ketorolac tromethamine and morphine (16.3% versus 17%, respectively). However, during the first 24 hours after surgery, a higher incidence of bleeding was observed in the Ketorolac Tromethamine Injection group (14.3%) versus the morphine group (4.2%).

Anaphylactoid reactions may occur in patients without a known previous exposure or hypersensitivity to aspirin, ketorolac tromethamine or other NSAIDs, or in individuals with a history of angioedema, bronchospastic reactivity (e.g., asthma) and nasal polyps. Anaphylactoid reactions, like anaphylaxis, may have a fatal outcome.

Ketorolac tromethamine should be used with caution in patients with impaired renal function or a history of kidney disease because it is a potent inhibitor of prostaglandin synthesis. Renal toxicity with ketorolac tromethamine has been seen in patients with conditions leading to a reduction in blood volume and/or renal blood flow where renal prostaglandins have a supportive role in the maintenance of renal perfusion. In these patients administration of ketorolac tromethamine may cause a dose-dependent reduction in renal prostaglandin formation and may precipitate acute renal failure. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, heart failure, liver dysfunction, those taking diuretics and the elderly. Discontinuation of ketorolac tromethamine therapy is usually followed by recovery to the pretreatment state.

Fluid retention, edema, retention of NaCl, oliguria, elevations of serum urea nitrogen and creatinine have been reported in clinical trials with ketorolac tromethamine. Therefore, ketorolac tromethamine should be used only very cautiously in patients with cardiac decompensation, hypertension or similar conditions.

In late pregnancy, as with other NSAIDs, ketorolac tromethamine should be avoided because it may cause premature closure of the ductus arteriosus.

Ketorolac tromethamine is a potent NSAID and may cause serious side effects such as gastrointestinal bleeding or kidney failure, which may result in hospitalization and even fatal outcome.

Physicians, when prescribing ketorolac tromethamine, should inform their patients or their guardians of the potential risks of ketorolac tromethamine treatment (see Boxed WARNING, WARNINGS, PRECAUTIONS and ADVERSE REACTIONS sections). Advise patients not to give ketorolac tromethamine tablets to other family members and to discard any unused drug.

Remember that the total duration of ketorolac tromethamine therapy is not to exceed five (5) days in adults or a single dose in pediatric patients ages 2 to 16 years.

Ketorolac is highly bound to human plasma protein (mean 99.2%).

An 18-month study in mice with oral doses of ketorolac tromethamine at 2 mg/kg/day (0.9 times the human systemic exposure at the recommended IM or IV dose of 30 mg qid, based on area-under-the-plasma-concentration curve [AUC]), and a 24-month study in rats at 5 mg/kg/day (0.5 times the human AUC) showed no evidence of tumorigenicity.

Ketorolac tromethamine was not mutagenic in the Ames test, unscheduled DNA synthesis and repair, and in forward mutation assays. Ketorolac tromethamine did not cause chromosome breakage in the in vivo mouse micronucleus assay. At 1590 mcg/mL and at higher concentrations, ketorolac tromethamine increased the incidence of chromosomal aberrations in Chinese hamster ovarian cells.

Impairment of fertility did not occur in male or female rats at oral doses of 9 mg/kg (0.9 times the human AUC) and 16 mg/kg (1.6 times the human AUC) of ketorolac tromethamine, respectively.

The use of ketorolac tromethamine is contraindicated in labor and delivery because, through its prostaglandin synthesis inhibitory effect, it may adversely affect fetal circulation and inhibit uterine contractions, thus increasing the risk of uterine hemorrhage (see CONTRAINDICATIONS).

After a single administration of 10 mg of ketorolac tromethamine tablets to humans, the maximum milk concentration observed was 7.3 ng/mL, and the maximum milk-to-plasma ratio was 0.037. After 1 day of dosing (qid), the maximum milk concentration was 7.9 ng/mL, and the maximum milk-to-plasma ratio was 0.025. Because of the possible adverse effects of prostaglandin-inhibiting drugs on neonates, use in nursing mothers is CONTRAINDICATED.

The safety and effectiveness of single doses of Ketorolac Tromethamine Injection have been established in pediatric patients between the ages of 2 and 16 years. Ketorolac Tromethamine Injection has been shown to be effective in the management of moderately severe acute pain that requires analgesia at the opioid level, usually in a postoperative setting. Safety and efficacy in pediatric patients below the age of 2 have not been established. Therefore, Ketorolac Tromethamine Injection is not recommended in pediatric patients below the age of 2. The risk of bleeding was greater in those patients administered Ketorolac Tromethamine Injection following tonsillectomy. Physicians should consider the increased risk of bleeding before deciding to administer Ketorolac Tromethamine Injection in patients following tonsillectomy (see WARNINGS, Hemorrhage and Pediatrics and Tonsillectomy).

The risks identified in the adult population with Ketorolac Tromethamine Injection use also apply to pediatric patients. Therefore, consult the CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, and ADVERSE REACTIONS sections when prescribing Ketorolac Tromethamine Injection to pediatric patients.

Because ketorolac tromethamine may be cleared more slowly by the elderly (see CLINICAL PHARMACOLOGY) who are also more sensitive to the adverse effects of NSAIDs (see WARNINGS, Renal Effects), extra caution and reduced dosages (see DOSAGE AND ADMINISTRATION) must be used when treating the elderly with Ketorolac Tromethamine Injection. The lower end of the Ketorolac Tromethamine Injection dosage range is recommended for patients over 65 years of age, and total daily dose is not to exceed 60 mg. The incidence and severity of gastrointestinal complications increases with increasing dose of, and duration of treatment with, ketorolac tromethamine.

Adverse reaction rates increase with higher doses of ketorolac tromethamine. Practitioners should be alert for the severe complications of treatment with ketorolac tromethamine, such as GI ulceration, bleeding and perforation, postoperative bleeding, acute renal failure, anaphylactic and anaphylactoid reactions and liver failure (see Boxed WARNING, WARNINGS, PRECAUTIONS and DOSAGE AND ADMINISTRATION). These NSAID-related complications can be serious in certain patients for whom ketorolac tromethamine is indicated, especially when the drug is used inappropriately.

Body as a Whole: hypersensitivity reactions such as anaphylaxis, anaphylactoid reaction, laryngeal edema, tongue edema (see Boxed WARNING, WARNINGS), angioedema, myalgia

Cardiovascular: hypotension, flushing

Dermatologic: Lyell’s syndrome, Stevens-Johnson syndrome, exfoliative dermatitis, maculopapular rash, urticaria

Gastrointestinal: peptic ulceration, GI hemorrhage, GI perforation (see Boxed WARNING, WARNINGS), melena, acute pancreatitis, hematemesis, esophagitis

Hemic and Lymphatic: postoperative wound hemorrhage (rarely requiring blood transfusion—see Boxed WARNING, WARNINGS and PRECAUTIONS), thrombocytopenia, leukopenia

Hepatic: hepatitis, liver failure, cholestatic jaundice

Nervous System: convulsions, psychosis, aseptic meningitis

Respiratory: asthma, bronchospasm

Urogenital: acute renal failure (see Boxed WARNING, WARNINGS), flank pain with or without hematuria and/or azotemia, interstitial nephritis, hyponatremia, hyperkalemia, hemolytic uremic syndrome

Symptoms following acute NSAIDs overdoses are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression and coma may occur, but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose.

Patients should be managed by symptomatic and supportive care following a NSAIDs overdose. There are no specific antidotes. Emesis and/or activated charcoal (60 g to 100 g in adults, 1 g/kg to 2 g/kg in children) and/or osmotic cathartic may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large oral overdose (5 to 10 times the usual dose).

In controlled overdosage, daily doses of 360 mg of Ketorolac Tromethamine Injection given for five (5) days (three times the highest recommended dose), caused abdominal pain and peptic ulcers which healed after discontinuation of dosing. Metabolic acidosis has been reported following intentional overdosage.

Single overdoses of ketorolac tromethamine have been variously associated with abdominal pain, nausea, vomiting, hyperventilation, peptic ulcers and/or erosive gastritis and renal dysfunction which have resolved after discontinuation of dosing. Dialysis does not significantly clear ketorolac tromethamine from the blood stream.

IN ADULTS, THE COMBINED DURATION OF USE OF KETOROLAC TROMETHAMINE INJECTION AND KETOROLAC TROMETHAMINE TABLETS IS NOT TO EXCEED FIVE (5) DAYS. IN ADULTS, THE USE OF KETOROLAC TROMETHAMINE TABLETS IS ONLY INDICATED AS CONTINUATION THERAPY TO KETOROLAC TROMETHAMINE INJECTION.

The pediatric population should receive only a single dose of Ketorolac Tromethamine Injection, as follows:

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Ketorolac Tromethamine Injection should not be mixed in a small volume (e.g., in a syringe) with morphine sulfate, meperidine hydrochloride, promethazine hydrochloride or hydroxyzine hydrochloride; this will result in precipitation of ketorolac from solution.

Shortening the recommended dosing intervals may result in increased frequency and severity of adverse reactions.

Ketorolac Tromethamine Injection, USP is available as follows:

For IV or IM Single Dose use:

NDC 10019-029-02, 2 mL vials containing 1 mL of 15 mg/mL Ketorolac Tromethamine, USP, available in boxes of 25.

NDC 10019-030-03, 2 mL vials containing 1 mL of 30 mg/mL Ketorolac Tromethamine, USP, available in boxes of 25.

For IM Single Dose use only:

NDC 10019-030-04, 60 mg/2 mL, 2 mL vials containing 2 mL of 30 mg/mL Ketorolac Tromethamine, USP, (60 mg), available in boxes of 25.

Store at 20°-25°C (68°-77°F), excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature].

PROTECT FROM LIGHT

Retain in carton until time of use.

Manufactured by

Baxter Healthcare Corporation

Deerfield, IL 60015 USA

For Product Inquiry 1 800 ANA DRUG (1-800-262-3784)

MLT-01480/1.0