Carefully consider the potential benefits and risks ketorolac tromethamine and other treatment options before deciding to use ketorolac. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see section 4.4).

Acute Pain in Adult Patients

Ketorolac tromethamine TBM 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 IV or IM dosing of ketorolac tromethamine, and oral ketorolac tromethamine is to be used only as continuation treatment, if necessary.

The total combined duration of use of ketorolac tromethamine injection and oral ketorolac tromethamine 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 (see section 4.5, section 4.2, and section 4.8). Patients should be switched to alternative analgesics as soon as possible, but ketorolac tromethamine therapy is not to exceed 5 days.

In adults, the combined duration of use of IV or IM dosing of ketorolac tromethamine and oral ketorolac tromethamine is not to exceed 5 days.

In adults, the use of oral ketorolac tromethamine is only indicated as continuation therapy to IV or IM dosing of ketorolac tromethamine.

Note: Oral formulation should not be given as an initial dose

Use minimum effective dose for the individual patient

Total duration of treatment in adult patients: the combined duration of use of IV or IM dosing of ketorolac tromethamine and oral ketorolac tromethamine is not to exceed 5 days.

Ketorolac tromethamine TBM may be used as a single or multiple dose on a regular or “prn” schedule for the management of moderately severe, acute pain that requires analgesia at the opioid level, usually in a postoperative setting. Hypovolemia should be corrected prior to the administration of ketorolac tromethamine (see section 4.4). Patients should be switched to alternative analgesics as soon as possible, but ketorolac tromethamine therapy is not to exceed 5 days.

When administering ketorolac tromethamine injection, the IV bolus must be given over no less than 15 seconds. The IM administration should be given slowly and deeply into the muscle. The analgesic effect begins in ~30 minutes with maximum effect in 1 to 2 hours after dosing IV or IM. Duration of analgesic effect is usually 4 to 6 hours.

Single-Dose Treatment: The following regimen should be limited to single administration use only

IM Dosing

• Patients < 65 years of age: One dose of 60 mg.

• Patients ≥ 65 years of age, renally impaired and/or less than 50 kg (110 lbs) of body weight: One dose of 30 mg.

IV Dosing

• Patients < 65 years of age: One dose of 30 mg.

• Patients ≥ 65 years of age, renally impaired and/or less than 50 kg (110 lbs) of body weight: One dose of 15 mg.

Multiple-Dose Treatment (IV or IM)

• Patients < 65 years of age: The recommended dose is 30 mg Ketorolac Tromethamine TBM every 6 hours. The maximum daily dose for these populations should not exceed 120 mg.

• For patients ≥ 65 years of age, renally impaired patients (see section 4.5), and patients less than 50 kg (110 lbs): The recommended dose is 15 mg ketorolac tromethamine injection every 6 hours. The maximum daily dose for these populations should not exceed 60 mg.

For breakthrough pain, do not increase the dose or the frequency of ketorolac tromethamine. Consideration should be given to supplementing these regimens with low doses of opioids "prn" unless otherwise contraindicated.

Ketorolac tromethamine TBM is contraindicated • in patients with previously demonstrated hypersensitivity to ketorolac tromethamine. • 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. • in patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients Ketorolac tromethamine is contraindicated as prophylactic analgesic before any major surgery. • for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see section 4.4). • in patients with advanced renal impairment or in patients at risk for renal failure due to volume depletion (see section 4.4). • in labor and delivery because, through its prostaglandin synthesis inhibitory effect, it may adversely affect fetal circulation and inhibit uterine musculature, thus increasing the risk of uterine hemorrhage. • In patients with suspected or confirmed cerebrovascular bleeding, hemorrhagic diathesis, incomplete hemostasis and those at high risk of bleeding (see section 4.4). • in nursing mothers because of the potential adverse effects of prostaglandin-inhibiting drugs on neonates. • In patients currently receiving aspirin or NSAIDs because of the cumulative risks of inducing serious NSAID-related adverse events. • for concomitant use with probenecid • for concomitant use with pentoxifylline • Ketorolac injection is contraindicated for neuraxial (epidural or intrathecal) administration due to its alcohol content.

The most serious risks associated with ketorolac tromethamine are: Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation: Ketorolac tromethamine is contraindicated in patients with previously documented peptic ulcers and/or gastrointestinal (GI) bleeding. Ketorolac tromethamine can cause serious gastrointestinal (GI) adverse events including bleeding, ulceration and perforation, of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with ketorolac tromethamine. 

Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Minor upper gastrointestinal problems, such as dyspepsia, are common and may also occur at any time during NSAID therapy.

The incidence and severity of gastrointestinal complications increases with increasing dose of, and duration of treatment with ketorolac tromethamine. Do not use ketorolac tromethamine for more than five days.

However, even short-term therapy is not without risk. In addition to past history of ulcer disease, other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids, or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population.

To minimize the potential risk for an adverse GI event, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of ketorolac tromethamine until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered. NSAIDs should be given with care to patients with a history of inflammatory bowel disease (ulcerative colitis, Crohn’s disease) as their condition may be exacerbated.

Hemorrhage

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 therapy that affects hemostasis, including 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. 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 peri-operative use of IV or IM dosing of ketorolac tromethamine. Therefore, peri-operative use of ketorolac tromethamine should be avoided and postoperative use be undertaken with caution when hemostasis is critical (see section 4.4).

Renal Effects

Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a NSAID may cause a dose dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.

Ketorolac tromethamine and its metabolites are eliminated primarily by the kidneys, which, in patients with reduced creatinine clearance, will result in diminished clearance of the drug (see section 5). Therefore, ketorolac tromethamine should be used with caution in patients with impaired renal function (see section 4.2) and such patients should be followed closely. With the use of ketorolac tromethamine, there have been reports of acute renal failure, interstitial nephritis and nephrotic syndrome

Impaired Renal Function

Ketorolac tromethamine is contraindicated in patients with serum creatinine concentrations indicating advanced renal impairment (see section 4.3). 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. Because patients with underlying renal insufficiency are at increased risk of developing acute renal decompensation or failure, the risks and benefits should be assessed prior to giving ketorolac tromethamine to these patients.

Anaphylactoid Reactions

As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to ketorolac tromethamine. Ketorolac tromethamine should not be given to patients with the aspirin triad.

This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see section 4.3 and section 4.4). Emergency help should be sought in cases where an anaphylactoid reaction occurs.

Cardiovascular Effects

Cardiovascular Thrombotic Events

Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal.

To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur.

There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as ketorolac, increase the risk of serious gastrointestinal (GI) events (see section 4.4).

Status Post Coronary Artery Bypass Graft (CABG) Surgery

Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see section 4.3].

Post-MI Patients

Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CVrelated death, and all cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post MI was 20 per 100 person years in NSAIDtreated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up.

Avoid the use of Ketorolac Tromethamine Injection in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If Ketorolac Tromethamine Injection is used in patient with a recent MI, monitor patients for signs of cardiac ischemia.

Hypertension

NSAIDs, including ketorolac tromethamine, can lead to onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including ketorolac tromethamine, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy.

Heart Failure and Edema

The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients.

In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death.

Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of ketorolac tromethamine may blunt the CV effects of several therapeutic agents used to treat these medical conditions [e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers (ARBs)] [see section 4.4]

Avoid the use of ketorolac tromethamine Injection in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If Ketorolac Tromethamine Injection is used in patients with severe heart failure, monitor patients for signs of worsening heart failure.

Skin Reactions

NSAIDs, including ketorolac tromethamine, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity

Pregnancy

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

PRECAUTIONS

General

Ketorolac tromethamine cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids. The pharmacological activity of ketorolac tromethamine in reducing inflammation may diminish the utility of this diagnostic sign in detecting complications of presumed noninfectious, painful conditions.

Hepatic Effects

Ketorolac tromethamine should be used with caution in patients with impaired hepatic function or a history of liver disease. Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including ketorolac tromethamine. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported.

A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with ketorolac tromethamine. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), ketorolac tromethamine should be discontinued.

Haematological Effects

Anemia is sometimes seen in patients receiving NSAIDs, including ketorolac tromethamine. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including ketorolac tromethamine, should have their hemoglobin or haematocrit checked if they exhibit any signs or symptoms of anemia. NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving ketorolac tromethamine who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.

Pre-existing Asthma

Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other nonsteroidal antiinflammatory drugs has been reported in such aspirin-sensitive patients, ketorolac tromethamine should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with pre-existing asthma.

Laboratory Tests

Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs, should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash etc.) or if abnormal liver tests persist or worsen, ketorolac tromethamine should be discontinued.

Ketorolac is highly bound to human plasma protein (mean 99.2%). There is no evidence in animal or human studies that ketorolac tromethamine induces or inhibits hepatic enzymes capable of metabolizing itself or other drugs.

Warfarin, Digoxin, Salicylate, and Heparin

The in vitro binding of warfarin to plasma proteins is only slightly reduced by ketorolac tromethamine (99.5% control vs 99.3%) when ketorolac plasma concentrations reach 5 to 10 mcg/mL. Ketorolac does not alter digoxin protein binding. In vitro studies indicate that, at therapeutic concentrations of salicylate (300 mcg/mL), the binding of ketorolac was reduced from approximately 99.2% to 97.5%, representing a potential twofold increase in unbound ketorolac plasma levels. Therapeutic concentrations of digoxin, warfarin, ibuprofen, naproxen, piroxicam, acetaminophen, phenytoin and tolbutamide did not alter ketorolac tromethamine protein binding. In a study involving 12 adult volunteers, oral ketorolac tromethamine was coadministered with a single dose of 25 mg warfarin, causing no significant changes in pharmacokinetics or pharmacodynamics of warfarin. In another study, ketorolac tromethamine dosed IV or IM was given with two doses of 5000 U of heparin to 11 healthy volunteers, resulting in a mean template bleeding time of 6 minutes (3.2 to 11.4 min) compared to a mean of 6.0 minutes (3.4 to 7.5 min) for heparin alone and 5.1 minutes (3.5 to 8.5 min) for placebo. Although these results do not indicate a significant interaction between ketorolac tromethamine and warfarin or heparin, the administration of ketorolac tromethamine to patients taking anticoagulants should be done extremely cautiously, and patients should be closely monitored (see section 4.4)

The effects of warfarin and NSAIDs, in general, on GI bleeding are synergistic, such that the users of both drugs together have a risk of serious GI bleeding higher than the users of either drug alone.

Aspirin

When ketorolac tromethamine is administered with aspirin, its protein binding is reduced, although the clearance of free ketorolac tromethamine is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of ketorolac tromethamine and aspirin is not generally recommended because of the potential of increased adverse effects.

Diuretics

Clinical studies, as well as postmarketing observations, have shown that ketorolac tromethamine can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see section 4.4), as well as to assure diuretic efficacy.

Probenecid

Concomitant administration of oral ketorolac tromethamine and probenecid resulted in decreased clearance and volume of distribution of ketorolac and significant increases in ketorolac plasma levels (total AUC increased approximately threefold from 5.4 to 17.8 mcg/h/mL) and terminal half-life increased approximately twofold from 6.6 to 15.1 hours. Therefore, concomitant use of ketorolac tromethamine and probenecid is contraindicated.

Lithium

NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity.

Methotrexate

NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate.

ACE Inhibitors /Angiotensin II Receptor Antagonists

Concomitant use of ACE inhibitors and/or angiotensin II receptor antagonists may increase the risk of renal impairment, particularly in volume-depleted patients. Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE inhibitors and/or angiotensin II receptor antagonists. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors and/or angiotensin II receptor antagonists.

Antiepileptic Drugs

Sporadic cases of seizures have been reported during concomitant use of ketorolac tromethamine and antiepileptic drugs (phenytoin, carbamazepine).

Psychoactive Drugs

Hallucinations have been reported when ketorolac tromethamine was used in patients taking psychoactive drugs (fluoxetine, thiothixene, alprazolam).

Pentoxifylline

When ketorolac tromethamine is administered concurrently with pentoxifylline, there is an increased tendency to bleeding.

Nondepolarizing Muscle Relaxants

In postmarketing experience there have been reports of a possible interaction between ketorolac tromethamine IV/IM and nondepolarizing mus cle relaxants that resulted in apnea. The concurrent use of ketorolac tromethamine with muscle relaxants has not been formally studied.

Selective Serotonin Reuptake Inhibitors (SSRIs)

There is an increased risk of gastrointestinal bleeding when s elective s erotonin reuptake inhibitors (SSRIs) are combined with NSAIDs. Caution should be used when NSAIDs are administered concomitantly with SSRIs.

Fertility

The use of ketorolac tromethamine, as with any drug known to inhibit cyclooxygenase/ prostaglandin synthesis, may impair fertility and is not recommended in women attempting to conceive. In women who have difficulty conceiving or are undergoing investigation of infertility, withdrawal of ketorolac tromethamine should be considered.

Pregnancy

Reproduction studies have been performed during organogenesis using daily oral doses of ketorolac tromethamine at 3.6 mg/kg (0.37 times the human AUC) in rabbits and at 10 mg/kg (1.0 times the human AUC) in rats. Results of these studies did not reveal evidence of teratogenicity to the fetus. However, animal reproduction studies are not always predictive of human response.

Breast-feeding

Exercise caution when ketorolac is administered to a nursing woman. Available information has not shown any specific adverse events in nursing infants; however, instruct patients to contact their infants healthcare provider if they note any adverse events.

Patient may experience drowsiness, dizziness, vertigo, insomnia or depression with the use of ketorolac tromethamine. Therefore, patients should exercise caution in carrying out potentially hazardous activities that require alertness.

Adverse reaction rates increase with higher doses of ketoralac tromethamine. Practitioners should be alert for the severe complications of treatment with ketorolac tromethamine, such as G.I. ulceration, bleeding and perforation, postoperative bleeding, acute renal failure, anaphylactic and anaphylactoid reactions and liver failure (see section 4.4 and section 4.2). These NSAID-related complications can be serious in certain patients for whom ketorolac tromethamine is indicated, especially when the drug is used inappropriately.

Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data). Adverse reactions reported with tigecycline, including clinical trials and post-marketing experience

Table 1: Reported adverse experiences in patients taking ketorolac tromethamine or other NSAIDs in clinical trials and rarely observed reactions (reported from postmarketing experience in patients taking Ketorolac tromethamine or other NSAIDs)

 

System Organ Class	Very common	Common	Rare
Blood               and lymphatic     system disorders	anemia,	eosinophilia, leukopenia, thrombocytopenia	agranulocytosis, aplastic anemia, hemolytic anemia, lymphadenopathy, pancytopenia
Cardiac disorders		congestive         heartfailure,     palpitation, pallor,    tachycardia, syncope	arrhythmia,bradycardia, chest pain

Ear and labyrinth disorders	tinnitus	hearing loss
Eye disorders		abnormal        vision,blurred vision
Gastrointestinal disorders	abdominal            pain,constipation/diarrhea, dyspepsia, flatulence, GI fullness, GI ulcers (gastric/duodenal), gross             bleeding/ perforation, heartburn, nausea*,      stomatitis, vomiting,	anorexia, dry mouth,eructation, esophagitis, excessive thirst, gastritis, glossitis, haematemesis,hepatitis, increased appetite, jaundice, melena, rectal bleeding,abnormal taste	acute pancreatitis, liver failure, ulcerative stomatitis, exacerbation of inflammatory bowel disease (ulcerative colitis, crohn’s disease)
General disorders and administration site conditions	sweating, injection site pain		death
Investigations	elevated liver enzymes, increased bleeding time,
Immune        system disorders		asthma	hypersensitivityreactions such as anaphylaxis, anaphylactoid reaction, laryngeal edema, tongue edema. (see section 4.4)
Infections          and infestations		fever,        infections,sepsis, cystitis	conjunctivitis
Injury, poisoning and procedural complications			post-operative wound hemorrhage (see section 4.4)
Renal and urinarydisorders	abnormal             renalfunction,	dysuria,haematuria, increased urinary frequency, interstitial nephritis, oliguria/polyuria, proteinuria, renal failure, urinary retention
Renal and urinary disorders			hemolytic uremic syndrome
Respiratory, thoracic and mediastinal disorders		epistaxis, cough, dyspnea, pulmonary edema, rhinitis	angioedema,bronchospasm,respiratory depression, pneumonia

Reproductive system and breast disorders		infertility
Metabolism and nutrition disorders	edema	weight change	hyperglycemia, hyperkalemia, hyponatremia
Musculoskeletal and connective tissue disorders			myalgia, flank pain with or without haematuria and/or azotemia
Nervous        system disorders	dizziness, headache	abnormal dreams, abnormal thinking, anxiety, asthenia, confusion, depression,euphoria,extrapyramidal symptoms, hallucinations, hyperkinesis, inability to concentrate, insomnia, nervousness, paresthesia, somnolence, stupor, tremors, vertigo, malaise	aseptic meningitis, convulsions,coma, psychosis
Vascular disorders	Hypertension		hypotension,myocardial infarction, vasculitis
Skin and subcutaneoustissue disorders	pruritus, Purpura, Rashes	alopecia, photosensitivity, urticarial, ecchymosis	flushing, exfoliative dermatitis, erythema multiforme, Lyell's syndrome, bullous reactions including Stevens-Johnsonsyndrome and toxic epidermal necrolysis

*Incidence greater than 10%

Postmarketing Surveillance Study

A large postmarketing observational, nonrandomized study, involving approximately 10,000 patients receiving ketorolac tromethamine, demonstrated that the risk of clinically serious gastrointestinal (GI) bleeding was dose-dependent (see Tables 2A and 2B). This was particularly true in elderly patients who received an average dailydose greater than 60 mg/day of ketorolac tromethamine (see Table 2A).

Table 2 Incidence of Clinically Serious G.I. Bleeding as Related to Age, Total Daily Dose, and History of G.I. Perforation, Ulcer, Bleeding (PUB) after up to 5 Days of Treatmentwith Ketorolac Tromethamine Injection
A. Adult Patients without History of PUB
Age of Patients	Total Daily Dose of Ketorolac Tromethamine Injection
	≤ 60 mg	> 60 to 90 mg	> 90 to 120 mg	> 120 mg
<65 years of age	0.4%	0.4%	0.9%	4.6%
≥ 65 years of age	1.2%	2.8%	2.2%	7.7%
B. Adult Patients with History of PUB
Age of Patients	Total Daily Dose of Ketorolac Tromethamine Injection
	≤ 60 mg	> 60 to 90 mg	> 90 to 120 mg	> 120 mg
<65 years of age	2.1%	4.6%	7.8%	15.4%
≥ 65 years of age	4.7%	3.7%	2.8%	25.0%

 

Pediatric

Ketorolac tromethamine is not indicated for use in pediatric patients. The safety and effectiveness of ketorolactromethamine in pediatric patients below the age of 17 have not been established.

Other special population(s)

Geriatric Use

(≥65 Years of Age)

Because ketorolac tromethamine may be cleared more slowly by the elderly (see section 5) who are also more sensitive to the dose-related adverse effects of NSAIDs (see section 4.4), extreme caution and reduced dosages(see section 4.2) and careful clinical monitoring must be used when treating the elderly with ketorolac tromethamine.

Reporting of suspected adverse reactions

To reports any side effect(s):

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allowscontinued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked toreport any suspected adverse reactions to the competent authority in Saudi Arabia as per details below:

-               The National Pharmacovigilance and Drug Safety Centre (NPC)

o Fax: +966-11-205-7662

o Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.

o   Toll free phone: 8002490000

o   E-mail: npc.drug@sfda.gov.sa

o   Website: www.sfda.gov.sa/npc

To report the Adverse event in other GCC States - Please contact the relevant competent authority.

Symptoms and Signs

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. Anaphylactoidreactions have been reported with therapeutic ingestion of NSAIDs and may occur following an overdose.

Treatment

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/orosmotic 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). Forced diuresis, alkalization of urine, hemodialysis orhemoperfusion may not be useful due to high protein binding.

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.

Pharmacotherapeutic Group: Anti-inflammatory agents, non-steroids, ATC Code: S01BC05

 

Ketorolac tromethamine is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits analgesic activity in animal models. The mechanism of action of ketorolac, like that of other NSAIDs, is not completelyunderstood but may be related to prostaglandin synthetase inhibition.

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 is not statistically significantly different over the recommended dosage range of ketorolac tromethamine. The greatest difference between large and small doses of ketorolac tromethamine is in the duration of analgesia.

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

Comparison of IV, IM and Oral Pharmacokinetics: The pharmacokinetics of ketorolac tromethamine, following IV, IM and oral doses of ketorolac tromethamine are compared in Table 3. In adults, the extent ofbioavailability following administration of the ORAL and IM forms of ketorolac tromethamine was equal to that following an IV bolus.

Table 3 Table of Approximate Average Pharmacokinetic Parameters (Mean ± SD) Following Oral, Intramuscular and Intravenous Doses of KetorolacTromethamine
Pharmacokinetic Parameters	Oral*	Intramuscular†			Intravenous Bolus‡
	10 mg	15 mg	30 mg	60 mg	15 mg	30 mg
Bioavailability (extent)	100%
Tmax1 (min)	44±34	33±21§	44±29	33±21§	1.1±0.7§	2.9±1.8
Cmax2 (mcg/mL) [single-dose]	0.87±0.22	1.14±0.32§	2.42±0.68	4.55±1.27§	2.47±0.51§	4.65±0.96
Cmax(mcg/mL) [steady state qid]	1.05±0.26§	1.56±0.44§	3.11±0.87§	N/A	3.09±1.17§	6.85±2.61
3 Cmin mcg/mL) [steady state qid]	0.29±0.07§	0.47±0.13§	0.93±0.26§	N/A	0.61±0.21§	1.04±0.35
Cavg4 (mcg/mL) [steady state qid]	0.59±0.20§	0.94±0.29§	1.88±0.59§	N/A	1.09±0.30§	2.17±0.59
Vß5 (L/kg)	0.175±0.039				0.210±0.044

% Dose metabolized = <50 ; % Dose excreted in feces = 6 ; % Dose excreted in urine = 91 ;% Plasma protein binding = 99

1Time-to-peak plasma concentration; ²Peak plasma concentration; ³Trough plasma concentration; ⁴Average plasma concentration; ⁵Volume of distribution

*Derived from PO pharmacokinetic studies in 77 normal fasted volunteers

†Derived from IM pharmacokinetic studies in 54 normal volunteers

‡Derived from IV pharmacokinetic studies in 24 normal volunteers

**Mean value was simulated from observed plasma concentration data and standard deviation was simulated from percent coefficient of variation for observed Cmax and Tmax data

††Not applicable because 60 mg is only recommended as a single dose

Linear Kinetics

In adults, following administration of single ORAL, IM or IV doses of ketorolac tromethamine in therecommended dosage ranges, the clearance of the racemate does not change. This implies that the pharmacokinetics of ketorolac tromethamine in adults, following single or multiple IM, IV or recommended oral doses of ketorolac tromethamine, are linear. At the higher recommended doses, there is a proportional increase in the concentrations of free and bound racemate.

Distribution

The mean apparent volume (Vβ) of ketorolac tromethamine following complete distribution was approximately 13 liters. This parameter was determined from single-dose data. The ketorolac tromethamine racemate has been shown to be highly protein bound (99%). Nevertheless, plasma concentrations as high as 10 mcg/mL will only occupy approximately 5% of the albumin binding sites.

Thus, the unbound fraction for each enantiomer will be constant over the therapeutic range. A decrease in serum albumin, however, will result in increased free drug concentrations.

Ketorolac tromethamine is excreted in human milk (see section 4.4).

Metabolism

Ketorolac tromethamine is largely metabolized in the liver. The metabolic products are hydroxylated andconjugated forms of the parent drug. The products of metabolism, and some unchanged drug, are excreted in the urine.

Excretion

The principal route of elimination of ketorolac and its metabolites is renal. About 92% of a given dose is found in the urine, approximately 40% as metabolites and 60% as unchanged ketorolac.

Approximately 6% of a dose is excreted in the feces. A single-dose study with 10 mg ketorolac tromethamine (n=9) demonstrated that the S-enantiomer is cleared approximately two times faster than the R-enantiomer and that the clearance was independent of the route of administration. This means that the ratio of S/R plasmaconcentrations decreases with time after each dose. There is little or no inversion of the R- to S- form in humans. The clearance of the racemate in normal subjects, elderly individuals and in hepatically and renally impaired patients is outlined in Table 4 (see section 5).

The half-life of the ketorolac tromethamine S-enantiomer was approximately 2.5 hours (SD ± 0.4) compared with 5 hours (SD ± 1.7) for the R-enantiomer. In other studies, the half-life for the racemate has been reported to lie within the range of 5 to 6 hours.

Accumulation

Ketorolac tromethamine administered as an IV bolus, every 6 hours for 5 days to healthy subjects (n = 13), showed no significant difference in C on Day 1 and Day 5. Trough levels averaged 0.29 mcg/mL (SD ± 0.13) onDay 1 and 0.55 mcg/mL (SD ± 0.23) on Day 6. Steady state was approached after the fourth dose.

Accumulation of ketorolac tromethamine has not been studied in special populations (geriatric, pediatric, renal failure or hepatic disease patients).

Kinetics in Special Populations

Geriatric Patients: Based on single-dose data only, the half-life of the ketorolac tromethamine racemate increased from 5 to 7 hours in the elderly (65 to 78 years) compared with young healthy volunteers (24 to 35years) (see Table 4). There was little difference in the Cmax for the two groups (elderly, 2.52 mcg/mL ± 0.77; young, 2.99 mcg/mL ± 1.03) (see section 4.4).

Pediatric Patients: Limited information is available regarding the pharmacokinetics of dosing of ketorolac tromethamine in the pediatric population. Following a single intravenous bolus dose of 0.5 mg/kg in 10 children4 to 8 years old, the half-life was 5.8 ± 1.6 hours, the average clearance was 0.042 ± 0.01 L/hr/kg, the volume ofdistribution during the terminal phase (Vβ) was 0.34 ± 0.12 L/kg and the volume of distribution at steady state(Vss) was 0.26± 0.08 L/kg. The volume of distribution and clearance of ketorolac in pediatric patients was higher than those observed in adult subjects (see Table 3). There are no pharmacokinetic data available for administration of ketorolac tromethamine by the IM route in pediatric patients.

Renally Insufficiency: Based on single-dose data only, the mean half-life of ketorolac tromethamine in renallyimpaired patients is between 6 and 19 hours, and is dependent on the extent of the impairment. There is poor correlation between creatinine clearance and total ketorolac tromethamine clearance in the elderly and populations with renal impairment (r = 0.5). In patients with renal disease, the AUC∞ of each enantiomerincreased by approximately 100% compared with healthy volunteers. The volume of distribution doubles for the S- enantiomer and increasesby 1/5th for the R-enantiomer. The increase in volume of distribution of ketorolac tromethamine implies an increase in unbound fraction.

The AUC∞-ratio of the ketorolac tromethamine enantiomers in healthy subjects and patients remained similar, indicating there was no selective excretion of either enantiomer in patients compared to healthy subjects (see section 4.4).

Hepatic Insufficiency: There was no significant difference in estimates of half-life, AUC∞ and Cmax in 7 patients with liver disease compared to healthy volunteers (see section 4.4 and Table 4).

Race: Pharmacokinetic differences due to race have not been identified.

Table 4 The Influence of Age, Liver and Kidney Function, on the Clearance and Terminal Half-life of Ketorolac Tromethamine (IM1 and ORAL2) in AdultPopulations
	Total Clearance [in L/h/kg]3		Terminal Half-life [in hours]
Type of Subjects	IM Mean (range)	ORAL Mean (range)	IM Mean range)	ORAL Mean range)
Normal Subjects IM (n=54) mean age=32, range=18-60 Oral (n=77) mean age=32, range=20-60	0.023 (0.010-0.046)	0.025 (0.013-0.050)	5.3 (3.5-9.2)	5.3 (2.4-9)
Healthy Elderly Subjects IM (n=13), Oral (n=12) mean age=72, range=65-78	0.019 (0.013-0.034)	0.024 (0.018-0.034)	7 (4.7-8.6)	6.1 (4.3-7.6)
Patients with Hepatic Dysfunction IM and Oral (n=7) mean age=51, range=43-64	0.029 (0.013-0.066)	0.033 (0.019-0.051)	5.4 (2.2-6.9)	4.5 (1.6-7.6)
Patients with Renal Impairment IM (n=25), Oral (n=9) serum creatinine=1.9-5.0 mg/dL mean age (IM)=54, range 35-71 mean age (Oral)=57, range=39-70	0.015 (0.005-0.043)	0.016 (0.007-0.052)	10.3 (5.9-19.2)	10.8 (3.4-18.9)

Renal Dialysis Patients IM and Oral (n=9) mean age=40, range=27-63.

0.016   (0.003-0.036)

-

13.6.   (8.0-39.1).

-

¹Estimated from 30 mg single IM doses of ketorolac tromethamine 
²Estimated from 10 mgsingle oral doses of ketorolac tromethamine 
³Liters/hours/kilogram

IV Administration: In normal subjects (n=37), the total clearance of 30 mg IV-administered ketorolactromethamine was 0.030 (0.017 to 0.051) L/h/kg. The terminal half-life was 5.6 (4.0 to 7.9) hours. (See Kinetics in Special Population for use of IV dosing of ketorolac tromethamine in pediatric patients).

 

An 18-month study in mice with oral doses of ketorolac tromethamine tablets 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.

Ethanol

Sodium Chloride

Hydrochloric Acid

Sodium Hydroxide

Water for Injection

Not Applicable

24 months

Store below 30°C

Ketorolac Tromethamine TBM is a clear, colourless to slightly yellow colour solution, free from visibleparticulates, presented in 2 mL amber tubular Type I glass vial, stoppered with 13 mm Dark Grey coloured bromo butyl rubber stoppers and sealed with 13 mm aluminium flip off seals.

Ketorolac tromethamine TBM 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.

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