Prescription Drug Information: Ketorolac Tromethamine (Page 2 of 7)

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 (V β ) 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 IM 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 Effect and Table 2).

Race

Pharmacokinetic differences due to race have not been identified.

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

Pharmacokinetic Parameters (units)

Oral 1

Intramuscular 2

Intravenous Bolus 3

10 mg

15 mg

30 mg

60 mg

15 mg

30 mg

Bioavailability (extent)

100%

T max6 (min)

44 ± 34

33 ± 214

44 ± 29

33 ± 214

1.1 ± 0.74

2.9 ± 1.8

C max7 (mcg/mL) [single-dose]

0.87 ± 0.22

1.14 ± 0.324

2.42 ± 0.68

4.55 ± 1.274

2.47 ± 0.514

4.65 ± 0.96

C max (mcg/mL) [steady state qid]

1.05 ± 0.264

1.56 ± 0.444

3.11 ± 0.874

N/A5

3.09 ± 1.174

6.85 ± 2.61

C min8 (mcg/mL) [steady state qid]

0.29 ± 0.074

0.47 ± 0.134

0.93 ± 0.264

N/A

0.61 ± 0.214

1.04 ± 0.35

C avg9 (mcg/mL) [steady state qid]

0.59 ± 0.204

0.94 ± 0.294

1.88 ± 0.594

N/A

1.09 ± 0.304

2.17 ± 0.59

V β10 (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

1. Derived from PO pharmacokinetic studies in 77 normal fasted volunteers

2. Derived from IM pharmacokinetic studies in 54 normal volunteers

3. Derived from IV pharmacokinetic studies in 24 normal volunteers

4. 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

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

6. Time-to-peak plasma concentration

7. Peak plasma concentration

8. Trough plasma concentration

9. Average plasma concentration

10. Volume of distribution

Table 2: The Influence of Age, Liver, and Kidney Function on the Clearance and Terminal Half-Life of Ketorolac Tromethamine (IM 1 and ORAL 2) in Adult Populations

Total Clearance [in L/h/kg] 3

Terminal Half-Life [in hours]

Type of Subjects

IM

ORAL

IM

ORAL

Mean (range)

Mean (range)

Mean (range)

Mean (range)

Normal Subjects

IM (n = 54)

mean age = 32, range = 18 to 60

Oral (n = 77)

mean age = 32, range = 20 to 60

0.023

0.025

5.3

5.3

(0.010 to 0.046)

(0.013 to 0.050)

(3.5 to 9.2)

(2.4 to 9)

Healthy Elderly Subjects

IM (n = 13),

Oral (n = 12)

mean age = 72, range = 65 to 78

0.019

0.024

7

6.1

(0.013 to 0.034)

(0.018 to 0.034)

(4.7 to 8.6)

(4.3 to 7.6)

Patients With Hepatic Dysfunction

IM and Oral (n = 7)

mean age = 51, range = 43 to 64

0.029

0.033

5.4

4.5

(0.013 to 0.066)

(0.019 to 0.051)

(2.2 to 6.9)

(1.6 to 7.6)

Patients With Renal Impairment

IM (n = 25),

Oral (n = 9)

serum creatinine = 1.9 to 5 mg/dL,

mean age (IM) = 54, range = 35 to 71

mean age (Oral) = 57, range = 39 to 70

0.015

0.016

10.3

10.8

(0.005 to 0.043)

(0.007 to 0.052)

(5.9 to 19.2)

(3.4 to 18.9)

Renal Dialysis Patients

IM and Oral (n = 9)

mean age = 40, range = 27 to 63

0.016

13.6

(0.003 to 0.036)

(8 to 39.1)

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

IV Administration

In normal adult subjects (n = 37), the total clearance of 30 mg IV-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 IV 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 IV 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 IV plus PCA morphine as compared to patients receiving PCA-administered morphine alone.

Pediatric Patients

There are no data available to support the use of ketorolac tromethamine tablets in pediatric patients.

INDICATIONS AND USAGE

Carefully consider the potential benefits and risks of ketorolac tromethamine tablets, USP and other treatment options before deciding to use ketorolac tromethamine tablets, USP. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals.

Acute Pain in Adult Patients

Ketorolac tromethamine tablets, USP are indicated for the short-term (≤ 5 days) management of moderately severe acute pain that requires analgesia at the opioid level, usually in a postoperative setting. Therapy should always be initiated with IV or IM dosing of ketorolac tromethamine and ketorolac tromethamine tablets, USP are to be used only as continuation treatment, if necessary.

The total combined duration of use of ketorolac tromethamine tablets, USP and 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 Tablet USP 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, Preexisting 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 contractions, 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.

WARNINGS

(See also Boxed WARNING.)

The total combined duration of use of ketorolac tromethamine tablets and IV or IM dosing of ketorolac tromethamine is not to exceed 5 days in adults. Ketorolac tromethamine tablets are 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 GI bleeding. Ketorolac tromethamine can cause serious gastrointestinal (GI) adverse events including bleeding, ulceration and perforation, of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with ketorolac tromethamine.

Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Minor upper gastrointestinal problems, such as dyspepsia, are common and may also occur at any time during NSAID therapy. The incidence and severity of gastrointestinal complications increases with increasing dose of, and duration of treatment with, ketorolac tromethamine. Do not use ketorolac tromethamine for more than five days. However, even short-term therapy is not without risk. In addition to past history of ulcer disease, other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids, or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population.

To minimize the potential risk for an adverse GI event, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of ketorolac tromethamine until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered.

NSAIDs should be given with care to patients with a history of inflammatory bowel disease (ulcerative colitis, Crohn’s disease) as their condition may be exacerbated.

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