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Ketorolac Tromethamine Tablets, USP

10 mg

PHARMACIST: Dispense the accompanying Medication Guide to each patient.

Rx only

DESCRIPTION

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


C15H13NO3**.**C4H11NO3 M.W. 376.40

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

Ketorolac tromethamine tablets, USP are white, round, convex, unscored, film- coated tablets. Each tablet, for oral administration, contains 10 mg ketorolac tromethamine, USP, the active ingredient. In addition, each tablet contains the following inactive ingredients: hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, and titanium dioxide.

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 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 IV, IM and Oral Pharmacokinetics

The pharmacokinetics of ketorolac tromethamine, following IV and IM doses of ketorolac tromethamine and oral doses of ketorolac tromethamine, are compared inTable 1. In adults, the extent of bioavailability following administration of the ORAL form of ketorolac tromethamine and the IM form of ketorolac tromethamine was equal to that following an IV bolus.

Linear Kinetics

In adults, following administration of single ORAL doses of ketorolac tromethamine or IM or IV 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 IM or IV doses of ketorolac tromethamine 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.

Absorption

Ketorolac tromethamine is 100% absorbed after oral administration (seeTable 1). Oral administration of ketorolac tromethamine after a high-fat meal resulted in decreased peak and delayed time-to-peak concentrations of ketorolac tromethamine by about 1 hour. Antacids did not affect the extent of absorption.

Distribution

The mean apparent volume (Vß) 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 (seePRECAUTIONS, 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 (seeCLINICAL 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 IV 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 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) (seePRECAUTIONS,Geriatric Use (≥ 65 Years of Age)).

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 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 (seeWARNINGS, 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 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)	Oral1	Intramuscular2	Intravenous Bolus3
	10 mg	15 mg	30 mg	60 mg	15 mg	30 mg
Bioavailability (extent)	100%
Tmax6 (min)	44 ± 34	33 ± 214	44 ± 29	33 ± 214	1.1 ± 0.74	2.9 ± 1.8
Cmax7 (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
Cmax (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
Cmin8 (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
Cavg9 (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
Vβ10 (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 (IM1and ORAL2) 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 (seeKinetics 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 tromethamineIV 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 tromethamineIV 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.

HOW SUPPLIED

Ketorolac tromethamine tablets, USP are available as follows:

10 mg: White, round, convex, unscored, film-coated tablets, debossed "93" on one side and "314" on the other side. They are available in bottles of 100 tablets (NDC 0093-0314-01).

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).

PROTECT FROM LIGHT AND EXCESSIVE HUMIDITY.

KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.

Dispense with Medication Guide available at: www.tevausa.com/medguides

Manufactured For:
Teva Pharmaceuticals
****Parsippany, NJ 07054

Rev. N 7/2021

Medication Guide for Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

Dispense with Medication Guide available at: www.tevausa.com/medguides
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. 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	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
diarrhea	is black and sticky like tar
itching	unusual weight gain
your skin or eyes look yellow	skin rash or blisters with fever
indigestion or stomach pain	swelling of the arms, legs, hands and feet
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.

Manufactured For:
Teva Pharmaceuticals
****Parsippany, NJ 07054

Rev. B 7/2021