KETOROLAC TROMETHAMINE INJECTION, SOLUTION [CARDINAL HEALTH, INC.]

KETOROLAC TROMETHAMINE INJECTION, SOLUTION [CARDINAL HEALTH, INC.]
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NDC 55154-9368-5
Set ID f335a030-ffa8-4f42-8166-2f06e036b40d
Category HUMAN PRESCRIPTION DRUG LABEL
Packager Cardinal Health, Inc.
Generic Name
Product Class
Product Number
Application Number ANDA075784
  • SPL UNCLASSIFIED SECTION

    Rx only

  • BOXED WARNING (What is this?)

    WARNING

    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.  Oral ketorolac tromethamine is indicated only as continuation treatment following intravenous or intramuscular dosing of ketorolac tromethamine, if necessary.  The total combined duration of use of oral ketorolac tromethamine and ketorolac tromethamine injection should not exceed 5 days.

    Ketorolac tromethamine is not indicated for use in pediatric patients and it is NOT indicated for minor or chronic painful conditions.  Increasing the dose of ketorolac tromethamine beyond the label recommendations will not provide better efficacy but will increase the risk of developing serious adverse events.

    Gastrointestinal Risk

    Ketorolac tromethamine can cause peptic ulcers, gastrointestinal bleeding and/or perforation of the stomach or intestines, which can be fatal.  These events can occur at any time during use and without warning symptoms.  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.  Elderly patients are at greater risk for serious gastrointestinal events (see WARNINGS).

    Cardiovascular Thrombotic Events

    Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal.  This risk may occur early in treatment and may increase with duration of use (see  WARNINGS and PRECAUTIONS).
    Ketorolac Tromethamine Injection, USP, is CONTRAINDICATED in the setting of coronary artery bypass graft (CABG) surgery (see  CONTRAINDICATIONS and WARNINGS). 

    Renal Risk

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

    Risk of Bleeding

    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.

    Hypersensitivity

    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 (see  CONTRAINDICATIONS 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).

    Intrathecal or Epidural Administration

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

    Risk During Labor and Delivery 

    The use of ketorolac tromethamine in labor and delivery is CONTRAINDICATED because it may adversely affect fetal circulation and inhibit uterine contractions.

    Concomitant Use with NSAIDs

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

    Special Populations

    Dosage should be adjusted for patients 65 years or older, for patients under 50 kg (110 lbs.) of body weight (see DOSAGE 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.

    DOSAGE AND ADMINISTRATION

    Ketorolac Tromethamine Tablets

    Ketorolac tromethamine tablets are indicated only as continuation therapy to ketorolac tromethamine injection, and the combined duration of use of ketorolac tromethamine injection and ketorolac tromethamine tablets is not to exceed 5 (five) days, because of the increased risk of serious adverse events.
    The recommended total daily dose of ketorolac tromethamine tablets (maximum 40 mg) is significantly lower than for ketorolac tromethamine injection (maximum 120 mg) (see DOSAGE AND ADMINISTRATION).
  • 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-1 H-pyrrolizine-1-carboxylic acid, compound with 2-amino-2-(hydroxymethyl)-1,3-propanediol (1:1), and the chemical structure is:

    structure

    C19H24N2O6                                                          M.W. 376.41

    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.

    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 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 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%

    T max1 (min)

    44±34

    33±21 **

    44±29

    33±21 **

    1.1±0.7 **

    2.9±1.8

    C max2 (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

    C max (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

    C min3 (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

    C avg4 (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

    V β5(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 PO 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 C max and T max 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 (V β) 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 C max  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 C max  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 (V ss) 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 C max, 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 to 60
    Oral (n=77)
    mean age= 32, range= 20 to 60

    0.023
    (0.010 to 0.046)

    0.025
    (0.013 to 0.050)

    5.3
    (3.5 to 9.2)

    5.3
    (2.4 to 9)

    Healthy Elderly Subjects
    Intramuscular (n=13),
    Oral (n=12)
    mean age= 72, range= 65 to 78

    0.019
    (0.013 to 0.034)

    0.024
    (0.018 to 0.034)

    7
    (4.7 to 8.6)

    6.1
    (4.3 to 7.6)

    Patients with Hepatic Dysfunction Intramuscular and Oral (n=7)
    mean age= 51, range= 43 to 64

    0.029
    (0.013 to 0.066)

    0.033
    (0.019 to 0.051)

    5.4
    (2.2 to 6.9)

    4.5
    (1.6 to 7.6)

    Patients with Renal Impairment Intramuscular (n=25),
    Oral (n=9)
    serum creatinine=
    1.9 to 5 mg/dL,
    mean age (Intramuscular)=54,
    range= 35 to 71
    mean age (Oral)=57, range= 39 to 70

    0.015
    (0.005 to 0.043)

    0.016
    (0.007 to 0.052)

    10.3
    (5.9 to 19.2)

    10.8
    (3.4 to 18.9)

    Renal Dialysis Patients
    Intramuscular and Oral (n=9)
    mean age= 40, range= 27 to 63

    0.016
    (0.003 to 0.036)

    ------

    13.6
    (8 to 39.1)

    -------

    1Estimated from 30 mg single intramuscular doses of ketorolac tromethamine

    2Estimated from 10 mg single oral doses of ketorolac tromethamine

    3Liters/hour/kilogram

    Intravenous-Administration

    In normal adult subjects (n=37), the total clearance of 30 mg intravenous-administered ketorolac tromethamine was 0.030 (0.017 to 0.051) L/h/kg.  The terminal half-life was 5.6 (4 to 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 q3h), 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 AND 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 the 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.

    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).

  • 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.

    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 (GI) Effects – Risk of GI 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 (2,500 to 5,000 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 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 a 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 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 (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 of follow-up.

    Avoid the use of Ketorolac Tromethamine Injection, USP, in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events.  If Ketorolac Tromethamine Injection, USP 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  Drug Interactions).

    Avoid the use of Ketorolac Tromethamine Injection, USP, in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure.  If Ketorolac Tromethamine Injection, USP, 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.

    Hematologic 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 hematocrit 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 anti-inflammatory 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.

    Information for Patients

    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, WARNINGSPRECAUTIONS  and  ADVERSE REACTIONS  sections), instruct patients to seek medical advice if they develop treatment-related adverse events, and advise patients not to give oral ketorolac tromethamine  to other family members and to discard any unused drug.  Remember that 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. Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.   

    1.
    Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their healthcare provider immediately (see  WARNINGS).
    2.
    Ketorolac tromethamine, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see  WARNINGS, Gastrointestinal (GI) Effects, Risk of GI Ulceration, Bleeding, and Perforation).
    3.
    Ketorolac tromethamine, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible.
    4.
    Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur (see  WARNINGS).
    5.
    Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy.
    6.
    Patients should be informed of the signs of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see  WARNINGS).
    7.
    In late pregnancy, as with other NSAIDs, ketorolac tromethamine should be avoided because it will cause premature closure of the ductus arteriosus.

    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.

    Drug Interactions

    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 intravenous or intramuscular was given with two doses of 5,000 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 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  WARNINGS  and PRECAUTIONS, Hematologic Effects).

    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 WARNINGS, Renal Effects), 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 intravenous/intramuscular and nondepolarizing muscle 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 selective serotonin reuptake inhibitors (SSRIs) are combined with NSAIDs.  Caution should be used when NSAIDs are administered concomitantly with SSRIs.

    Carcinogenesis, Mutagenesis, Impairment of Fertility

    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 intramuscular or intravenous 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 1,590 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.

    Pregnancy

    Teratogenic Effects

    Pregnancy Category C

    Reproduction studies have been performed during organogenesis using daily oral doses of ketorolac tromethamine tablets at 3.6 mg/kg (0.37 times the human AUC) in rabbits and at 10 mg/kg (1 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.

    Nonteratogenic Effects

    Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided. Oral doses of ketorolac tromethamine tablets at 1.5 mg/kg (0.14 times the human AUC), administered after gestation day 17, caused dystocia and higher pup mortality in rats.

    There are no adequate and well-controlled studies of ketorolac tromethamine in pregnant women. Ketorolac tromethamine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

    Labor and Delivery

    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).

    Effects on 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.

    Nursing Mothers

    Limited data from one published study that included 10 breastfeeding women 2 to 6 days postpartum showed low levels of ketorolac in breast milk and were undetectable (less than 5 ng/mL) in 4 of the patients. After a single administration of 10 mg of ketorolac tromethamine, 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 (10 mg every 6 hours), the maximum milk concentration was 7.9 ng/mL, and the maximum milk-to-plasma ratio was 0.025. Assuming a daily intake of 400 to 1,000 mL of human milk per day and a maternal body weight of 60 kg, the calculated maximum daily infant exposure was 0.00263 mg/kg/day, which is 0.4% of the maternal weight-adjusted dose.

    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 infant’s healthcare provider if they note any adverse events.

    Pediatric Use

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

    Geriatric Use

    (65 Years of Age)

    Because ketorolac tromethamine may be cleared more slowly by the elderly (see CLINICAL PHARMACOLOGY) who are also more sensitive to the dose-related adverse effects of NSAIDs (see WARNINGS, Gastrointestinal (GI) Effects – Risk of GI Ulceration, Bleeding, and Perforation), extreme caution and reduced dosages (see DOSAGE AND ADMINISTRATION) and careful clinical monitoring must be used when treating the elderly with ketorolac tromethamine.

  • ADVERSE REACTIONS:

    To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

    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.

    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, postoperative 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 GI Bleeding as Related to Age, Total Daily Dose, and History of GI 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%

  • 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.  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).  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 AND 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 “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 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 “prn” 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:

    FOR INTRAMUSCULAR OR INTRAVENOUS USE.

    packaging information

    The container closure is not made with natural rubber latex.

    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.

  • MEDICATION GUIDE

    Medication Guide for Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

    What is the most important information I should know about medicines called Nonsteroidal 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 use of NSAIDs
    taking medicines called “corticosteroids”, “anticoagulants”, “SSRIs”, or “SNRIs”
    increasing doses of NSAIDs
    older age
    longer use of NSAIDs
    poor health
    smoking
    advanced liver disease
    drinking alcohol
    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 have 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.  Talk to your healthcare provider if you are considering taking NSAIDs during pregnancy.   You should not take NSAIDs after 29 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
    slurred speech
    chest pain
    swelling of the face or throat
    weakness in one part or side of your body

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

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

    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 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.

  • SPL UNCLASSIFIED SECTION

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    Lake Zurich, IL 60047

    www.fresenius-kabi.com/us

    Distributed by:
    Cardinal Health

    Dublin, OH 43017

    45906H

    Revised:  September 2019

    L35331631220

  • Package/Label Display Panel

    Ketorolac Tromethamine Injection, USP

    30 mg per mL

    5 x 1 mL Single Use Vials

    bag label
  • INGREDIENTS AND APPEARANCE
    KETOROLAC TROMETHAMINE 
    ketorolac tromethamine injection, solution
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:55154-9368(NDC:63323-162)
    Route of AdministrationINTRAMUSCULAR
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    KETOROLAC TROMETHAMINE (UNII: 4EVE5946BQ) (KETOROLAC - UNII:YZI5105V0L) KETOROLAC TROMETHAMINE30 mg  in 1 mL
    Inactive Ingredients
    Ingredient NameStrength
    SODIUM CHLORIDE (UNII: 451W47IQ8X) 4.35 mg  in 1 mL
    CITRIC ACID MONOHYDRATE (UNII: 2968PHW8QP) 1 mg  in 1 mL
    SODIUM HYDROXIDE (UNII: 55X04QC32I)  
    HYDROCHLORIC ACID (UNII: QTT17582CB)  
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC:55154-9368-55 in 1 BAG10/18/2000
    11 mL in 1 VIAL, SINGLE-DOSE; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA07578410/18/2000
    Labeler - Cardinal Health, Inc. (603638201)

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