DESCRIPTION

Ketorolac Tromethamine Injection, USP 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 structural formula is presented in Figure 1.   

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 376.40.

Ketorolac Tromethamine Injection, USP 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 intramuscular administration only. The solutions contain 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 range is 6.9 to 7.9 and is adjusted with sodium hydroxide and/or hydrochloric acid. The sterile solutions are clear and slightly yellow in color.

CLINICAL PHARMACOLOGY

Pharmacodynamics

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 completely understood 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 by either route is in the duration of analgesia.

Pharmacokinetics

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

Comparison of Intravenous, Intramuscular and Oral Pharmacokinetics

 

The pharmacokinetics of ketorolac tromethamine, following intravenous, intramuscular, and oral doses of ketorolac tromethamine are compared in Table 1. In adults, the extent of bioavailability following administration of the oral and intramuscular forms of ketorolac tromethamine was equal to that following an intravenous bolus.

 Table 1 : Table of Approximate Average Pharmacokinetic Parameters (Mean±SD) Following Oral, Intramuscular and Intravenous Doses of Ketorolac Tromethamine

	Oral†	Intramuscular*			Intravenous Bolus ‡
Pharmacokinetic Parameters (units)	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
Cmin3 (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±0.2**	0.94±0.29**	1.88±0.59**	N/A	1.09±0.3**	2.17±0.59
Vβ5 (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 † Derived from oral pharmacokinetic studies in 77 normal fasted volunteers * Derived from intramuscular pharmacokinetic studies in 54 normal volunteers ‡ Derived from intravenous pharmacokinetic studies in 24 normal volunteers †† Not applicable because 60 mg is only recommended as a single dose ** 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					1Time-to-peak plasma concentration 2Peak plasma concentration 3Trough plasma concentration 4Average plasma concentration 5Volume of distribution

Linear Kinetics

In adults, following administration of single oral, intramuscular or intravenous doses of ketorolac tromethamine in the recommended dosage ranges, the clearance of the racemate does not change. This implies that the pharmacokinetics of ketorolac tromethamine in adults, following single or multiple intramuscular, intravenous, 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 PRECAUTIONS – Nursing Mothers).

Metabolism

Ketorolac tromethamine is largely metabolized in the liver. The metabolic products are hydroxylated and conjugated 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 plasma concentrations 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 2 (see CLINICAL PHARMACOLOGY – Kinetics in Special Populations).

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 intravenous bolus, every 6 hours, for 5 days, to healthy subjects (n = 13), showed no significant difference in Cmax on Day 1 and Day 5. Trough levels averaged 0.29 mcg/mL (SD ± 0.13) on Day 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 patients, 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 35 years) (see Table 2). 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 PRECAUTIONS – Geriatric Use).

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 children 4 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 of distribution 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 1). There are no pharmacokinetic data available for administration of ketorolac tromethamine by the intramuscular route in pediatric patients.

Renal Insufficiency

Based on single-dose data only, the mean half-life of ketorolac tromethamine in renally impaired 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 enantiomer increased by approximately 100% compared with healthy volunteers. The volume of distribution doubles for the S-enantiomer and increases by 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 WARNINGS – Renal Effects).

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 PRECAUTIONS – Hepatic Effects and Table 2).

Race

Pharmacokinetic differences due to race have not been identified.

 Table 2    : The Influence of Age, Liver and Kidney Function, on the Clearance and Terminal Half-life of Ketorolac Tromethamine (Intramuscular1 and Oral2) in Adult Populations

	Total Clearance [in L/h/kg]3		Terminal Half-life  [in hours]
Type of Subjects	Intramuscular Mean (range)	Oral Mean (range)	Intramuscular Mean (range)	Oral Mean (range)
Normal Subjects Intramuscular (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 Intramuscular (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 Intramuscular 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 Intramuscular (n = 25), Oral (n = 9) serum creatinine = 1.9-5.0 mg/dL, mean age (Intramuscular) = 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 Intramuscular and Oral (n = 9) mean age = 40, range = 27-63	0.016 (0.003- 0.036)	–	13.6 (8.0-39.1)	–

1 Estimated from 30 mg single intramuscular doses of ketorolac tromethamine
2 Estimated from 10 mg single oral doses of ketorolac tromethamine
3 Liters/hour/kilogram

Intravenous-Administration:

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

CLINICAL STUDIES

 

Adult Patients

In a postoperative study, where all patients received morphine by a PCA device, patients treated with ketorolac tromethamine intravenous as fixed intermittent boluses (e.g., 30 mg initial dose followed by 15 mg every 3 hours), required significantly less morphine (26%) than the placebo group. Analgesia was significantly superior, at various postdosing pain assessment times, in the patients receiving ketorolac tromethamine intravenous plus PCA morphine as compared to patients receiving PCA-administered morphine alone.

INDICATIONS & USAGE

Carefully consider the potential benefits and risks of 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 WARNINGS).

Acute Pain in Adult Patients
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 intravenous or intramuscular 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 WARNINGS, 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.

CONTRAINDICATIONS

(see also Boxed WARNING)
Ketorolac Tromethamine is contraindicated in patients with previously demonstrated hypersensitivity to ketorolac tromethamine.

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 should not be given to 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 (see WARNINGS – Anaphylactoid Reactions, and PRECAUTIONS – Pre-existing Asthma).

Ketorolac tromethamine is contraindicated as prophylactic analgesic before any major surgery.

Ketorolac tromethamine is contraindicated in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).

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 musculature, thus increasing the risk of uterine hemorrhage.

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 aspirin or NSAIDs because of the cumulative risks of inducing serious NSAID-related adverse events.

The concomitant use of ketorolac tromethamine and probenecid is contraindicated.

The concomitant use of ketorolac tromethamine and pentoxifylline is contraindicated.

Ketorolac tromethamine injection is contraindicated for neuraxial (epidural or intrathecal) administration due to its alcohol content.

WARNINGS

(see also Boxed WARNING)

The total combined duration of use of oral ketorolac tromethamine and intravenous or intramuscular dosing of ketorolac tromethamine is not to exceed 5 days in adults. Ketorolac tromethamine is not indicated for use in pediatric patients.

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 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 every 12 hours), 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 intravenous or intramuscular 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 PRECAUTIONS).

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 CLINICAL PHARMACOLOGY). Therefore, ketorolac tromethamine should be used with caution in patients with impaired renal function (see DOSAGE AND ADMINISTRATION) 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 CONTRAINDICATIONS). 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 CONTRAINDICATIONS and PRECAUTIONS - Pre-existing Asthma). 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. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first few weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses.

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 tromethamine, increases the risk of serious gastrointestinal (GI) events (see WARNINGS).

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 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG surgery (see CONTRAINDICATIONS).

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, CV-related 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 NSAID-treated 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 follow-up.

Avoid the use of ketorolac tromethamine in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If ketorolac tromethamine is used in patients 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 pre-existing 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 PRECAUTIONS - Drug Interactions).

Avoid the use of ketorolac tromethamine in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If ketorolac tromethamine 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.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as ketorolac tromethamine. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue ketorolac tromethamine and evaluate the patient immediately.

Fetal Toxicity

Premature Closure of Fetal Ductus Arteriosus:

Avoid use of NSAIDs, including ketorolac tromethamine, in pregnant women at about 30 weeks gestation and later. NSAIDs including ketorolac tromethamine, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age.

Oligohydramnios/Neonatal Renal Impairment:

Use of NSAIDs, including ketorolac tromethamine, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required.

If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit ketorolac tromethamine use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if ketorolac tromethamine treatment extends beyond 48 hours. Discontinue ketorolac tromethamine if oligohydramnios occurs and follow up according to clinical practice (see PRECAUTIONS; Pregnancy).

PRECAUTIONS

ADVERSE REACTIONS

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 G.I. ulceration, bleeding and perforation, postoperative bleeding, acute renal failure, anaphylactic and anaphylactoid reactions and liver failure (seeBoxed 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.

In patients taking ketorolac tromethamine or other NSAIDs in clinical trials, the most frequently reported adverse experiences in approximately 1% to 10% of patients are:

Gastrointestinal (GI) experiences including:
abdominal pain	constipation/diarrhea	dyspepsia
flatulence	GI fullness	GI ulcers (gastric/duodenal)
gross bleeding/perforation	heartburn	nausea*
stomatitis	vomiting

Other experiences:

abnormal renal function	anemia	dizziness
drowsiness	edema	elevated liver enzymes
headaches*	hypertension	increased bleeding time
injection site pain	pruritus	purpura
rashes	tinnitus	sweating

 *  Incidence greater than 10%

Additional adverse experiences reported occasionally (<1% in patients taking ketorolac tromethamine or other NSAIDs in clinical trials) include:

Body as a Whole: fever, infections, sepsis

Cardiovascular: congestive heart failure, palpitation, pallor, tachycardia, syncope

Dermatologic: alopecia, photosensitivity, urticaria

Gastrointestinal: anorexia, dry mouth, eructation, esophagitis, excessive thirst, gastritis, glossitis, hematemesis, hepatitis, increased appetite, jaundice, melena, rectal bleeding

Hemic and Lymphatic: ecchymosis, eosinophilia, epistaxis, leukopenia, thrombocytopenia

Metabolic and Nutritional: weight change

Nervous System: abnormal dreams, abnormal thinking, anxiety, asthenia, confusion, depression, euphoria, extrapyramidal symptoms, hallucinations, hyperkinesis, inability to concentrate, insomnia, nervousness, paresthesia, somnolence, stupor, tremors, vertigo, malaise

Reproductive, female: infertility

Respiratory: asthma, cough, dyspnea, pulmonary edema, rhinitis

Special Senses: abnormal taste, abnormal vision, blurred vision, hearing loss

Urogenital: cystitis, dysuria, hematuria, increased urinary frequency, interstitial nephritis, oliguria/polyuria, proteinuria, renal failure, urinary retention

Other rarely observed reactions (reported from postmarketing experience in patients taking ketorolac tromethamine or other NSAIDs) are:

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

Cardiovascular: arrhythmia, bradycardia, chest pain, flushing, hypotension, myocardial infarction, vasculitis

Dermatologic: exfoliative dermatitis, erythema multiforme, Lyell's syndrome, bullous reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis.

Gastrointestinal: acute pancreatitis, liver failure, ulcerative stomatitis, exacerbation of inflammatory bowel disease (ulcerative colitis, Crohn's disease)

Hemic and Lymphatic: agranulocytosis, aplastic anemia, hemolytic anemia, lymphadenopathy, pancytopenia, post operative wound hemorrhage (rarely requiring blood transfusion — see Boxed WARNING, WARNINGS, and PRECAUTIONS)

Metabolic and Nutritional: hyperglycemia, hyperkalemia, hyponatremia

Nervous System: aseptic meningitis, convulsions, coma, psychosis

Respiratory: bronchospasm, respiratory depression, pneumonia

Special Senses: conjunctivitis

Urogenital: flank pain with or without hematuria and/or azotemia, hemolytic uremic syndrome

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 3A and 3B). This was particularly true in elderly patients who received an average daily dose greater than 60 mg/day of ketorolac tromethamine (see Table 3A).

Table 3: 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 Treatment with 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%

To report SUSPECTED ADVERSE REACTIONS, contact Caplin Steriles Limited at 1-866-978-6111 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 

OVERDOSAGE

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. Anaphylactoid reactions 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. Forced diuresis, alkalization of urine, hemodialysis or hemoperfusion 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.

DOSAGE & ADMINISTRATION

Carefully consider the potential benefits and risks of ketorolac tromethamine and other treatment options before deciding to use ketorolac tromethamine. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals. In adults, the combined duration of use of intravenous or intramuscular 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 intravenous or intramuscular dosing of ketorolac tromethamine. See package insert for ketorolac tromethamine tablets for transition from intravenous or intramuscular dosing of ketorolac tromethamine (single- or multiple-dose) to multiple-dose oral 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 intravenous or intramuscular dosing of ketorolac tromethamine and oral ketorolac tromethamine is not to exceed 5 days.

KETOROLAC TROMETHAMINE INJECTION
Ketorolac tromethamine injection may be used as a single or multiple dose on a regular or "as needed" 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 WARNINGS – Renal Effects). 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 intravenous bolus must be given over no less than 15 seconds. The intramuscular 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 intravenous or intramuscular. Duration of analgesic effect is usually 4 to 6 hours.

 

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

Intramuscular 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.

Intravenous 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 (Intravenous or Intramuscular)

• Patients <65 years of age: The recommended dose is 30 mg ketorolac tromethamine injection 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 WARNINGS), 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 "as needed" unless otherwise contraindicated.

Pharmaceutical Information for Ketorolac Tromethamine Injection

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.

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

HOW SUPPLIED

Ketorolac Tromethamine Injection, USP is supplied as follows:

NDC	Strength of product	Package Factor
65145- 146-25	15 mg/mL Single-dose vial	25 Vials per Carton
65145- 145-25	30 mg/mL Single-dose vial	25 Vials per Carton
65145-147-25	60 mg/2 mL (30 mg/mL) Single-dose-vial	25 Vials per Carton

Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.]
Protect from light.
Retain in carton until time of use.

Made in India

Distributed by :

Caplin Steriles USA Inc,
Hamilton, NJ 08619.

Code: TN/Drugs/TN00003457

22200861

Revised: 05/2024

Medication Guide for Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

What is the most important information I should know about medicines called Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?

NSAIDs can cause serious side effects, including:

• Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and may increase:
  • with increasing doses of NSAIDs
  • with longer use of NSAIDs

Do not take NSAIDs right before or after a heart surgery called a "coronary artery bypass graft (CABG)."

Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack.

• Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines:
  • anytime during use
  • without warning symptoms
  • that may cause death

The risk of getting an ulcer or bleeding increases with:

• past history of stomach ulcers, or stomach or intestinal bleeding with the use of NSAIDs
• taking medicines called "corticosteroids", "anticoagulants", "SSRIs", or "SNRIs"
• increasing doses of NSAIDs
• longer use of NSAIDs
• smoking
• drinking alcohol
• older age
• poor health
• advanced liver disease
• bleeding problems

NSAIDS should only be used:

• exactly as prescribed
• at the lowest dose possible for your treatment
• for the shortest time needed

What are NSAIDs?

NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps, and other types of short-term pain.

Who should not take NSAIDs?

Do not take NSAIDs:

• if you had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs.
• right before or after heart bypass surgery.

Before taking NSAIDs, tell your healthcare provider about all of your medical conditions, including if you:

 

• have liver or kidney problems
• have high blood pressure
• have asthma
• are pregnant or plan to become pregnant. Taking NSAIDs at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to take NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. You should not take NSAIDs after about 30 weeks of pregnancy.
• are breastfeeding or plan to breast feed

Tell your healthcare provider about all of the medicines you take, including prescription or over-the-counter medicines, vitamins or herbal supplements.

 NSAIDs and some other medicines can interact with each other and cause serious side effects. Do not start taking any new medicine without talking to your healthcare provider first.

What are the possible side effects of NSAIDs?
NSAIDs can cause serious side effects, including:

See "What is the most important information I should know about medicines called NonSteroidal Anti-inflammatory Drugs (NSAIDs)?"

•  new or worse high blood pressure
• heart failure
• liver problems including liver failure
• kidney problems including kidney failure
• low red blood cells (anemia)
• life-threatening skin reactions
• life-threatening allergic reactions
• Other side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness.

Get emergency help right away if you get any of the following symptoms:

• shortness of breath or trouble breathing
• chest pain
• weakness in one part or side of your body
• slurred speech
• swelling of the face or throat

Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms:

•  nausea
• more tired or weaker than usual
• diarrhea
• itching
• your skin or eyes look yellow
• indigestion or stomach pain
• flu-like symptoms
• vomit blood
• there is blood in your bowel movement or it is black and sticky like tar
• unusual weight gain
• skin rash or blisters with fever
• swelling of the arms and legs, hands and feet

If you take too much of your NSAID, call your healthcare provider or get medical help right away.

These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Other information about NSAIDs

 

•  Aspirin is an NSAID medicine but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines.
• Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days.

General information about the safe and effective use of NSAIDs

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them.

If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals.

 

This Medication Guide has been approved by the U.S. Food and Drug Administration.

 Made in India

Distributed by :

 Caplin Steriles USA Inc,

Hamilton, NJ 08619.

Code: TN/Drugs/TN00003457

22200861
Revised: 05/2024

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

Container Label for 15 mg/mL:

NDC 65145-146-01

Rx only

Ketorolac Tromethamine

Injection, USP

15 mg/mL

For Intravenous or

Intramuscular Use

1 mL Single-Dose Vial

Carton Label for 15 mg/mL:

NDC 65145-146-25

Rx only

Ketorolac Tromethamine

Injection, USP

15 mg/mL

For Intravenous or Intramuscular Use

Dispense the enclosed Medication Guide to each patient.

25 X 1 mL Single-Dose Vial

Container Label for 30 mg/mL:

NDC 65145-145-01

Rx only

Ketorolac Tromethamine

Injection, USP

30 mg/mL

For Intravenous or

Intramuscular Use

1 mL Single-Dose Vial

Carton Label for 30 mg/mL:

NDC 65145-145-25

Rx only

Ketorolac Tromethamine

Injection, USP

30 mg/mL

For Intravenous or Intramuscular Use

Dispense the enclosed Medication Guide to each patient.

25 X 1 mL Single-Dose Vial

Container Label for 60 mg/2 mL (30 mg/mL):

NDC 65145-147-01
Rx only
Ketorolac Tromethamine
Injection, USP
60 mg/2 mL (30 mg/mL)
For Intramuscular Use Only.
2 mL Single-Dose Vial

  

Carton Label for 60 mg/2 mL (30 mg/mL):
NDC 65145-147-25
Rx only
Ketorolac Tromethamine
Injection, USP
60 mg/2 mL (30 mg/mL)
For Intramuscular Use Only
Dispense the enclosed Medication Guide to each patient.
25 X 2 mL Single-Dose Vial