Acular

Indications : Conjunctivitis, seasonal allergic; Pain, moderately severe

Pregnancy Category B

FDA Class 1B (“Modest Therapeutic Advantage”); Top 200 Drugs

FDA Approved 1989 Nov

DRUG CLASS : Analgesics, General; Analgesics-Non-Narcotic; NSAID; Ocular Anti-Inflammatory

BRAND NAMES : Acular (US); Alidol (Mexico); Dolac (Benin, Burkina-Faso, Ethiopia, Gambia, Ghana, Guinea, Ivory-Coast, Kenya, Liberia, Malawi, Mali, Mauritania, Mauritius, Morocco, Niger, Nigeria, Senegal, Seychelles, Sierra-Leone, South-Africa, Sudan, Tanzania, Tunia, Uganda, Zambia, Zimbabwe, Mexico); Dolorex (Peru); Infladol (Colombia); Kelac (India); Ketanov (India); Ketonic (India); Ketron (Colombia); Nodine (Bahrain, Cyprus, Egypt, Iran, Iraq, Jordan, Kuwait, Lebanon, Libya, Oman, Qatar, Republic-of-Yemen, Saudi-Arabia, Syria, United-Arab-Emirates); Rolesen (Ecuador, Peru); Tabel (Korea); Tarasyn (Korea); Supradol (Mexico); Tora-Dol (South-Africa); Toradol (US); Torolac (India); Tradak (Japan);
(International brand names outside U.S. in italics)

COST OF THERAPY : $ 22.64 (Pain; Tablet; 10 mg; 4/day; 5 days)

HCFA JCODES : J1885 per 15 mg IM, IV

DESCRIPTION :

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

Toradol is a racemic mixture of [-]S and [+]R ketorolac tromethamine. ketorolac tromethamine may exist in three crystal forms. All forms are equally soluble in water. ketorolac tromethamine has a pKa of 3.5 and an n-octanol/water partition coefficient of 0.26. The molecular weight of ketorolac tromethamine is 376.41.

Toradol IV : 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 IM administration only. The solutions contain 10% (w/v) alcohol, 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 or hydrochloric acid and the solutions are packaged with nitrogen. The sterile solutions are clear and slightly yellow in color.

Toradol Oral: Available as round, white, film-coated, red-printed tablets. Each tablet contains 10 mg ketorolac tromethamine, the active ingredient, with added lactose, magnesium stearate, and microcrystalline cellulose. The white film-coating contains hydroxypropyl methylcellulose, polyethylene glycol, and titanium dioxide.

The tablets are printed with red ink which includes FD&C red no. 40 aluminum lake as the colorant. There is a large “T” printed on both sides of the tablet, as well as the word “Toradol” on one side, and the word “SYNTEX” on the other.

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

Acular is supplied as a sterile isotonic aqueous 0.5% solution, with a pH of 7.4. Acular is a racemic mixture of R (+) and S (-) 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. The white to off-white crystalline substance discolors on prolonged exposure to light. The molecular weight of ketorolac tromethamine is 376.41. The osmolity of ketorolac tromethamine is 376.41.

CLINICAL PHARMACOLOGY :

Pharmacodynamics : Ketorolac is a nonsteroidal anti-inflammatory drug (NSAID). ketorolac tromethamine inhibits synthesis of prostaglandins and may be considered a peripherally-acting analgesic. The biological activity of ketorolac is associated with the S-form. ketorolac tromethamine possesses no sedative or anxiolytic properties.

Pain relief was statistically different after ketorolac tromethamine dosing from that of placebo at ½ hour (the first time point at which it was measured) following the largest recommended doses of ketorolac tromethamine, and by 1 hour following the smallest recommended doses. The peak analgesic effect occurred within 2 to 3 hours and was 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 was 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, IM, and oral doses of ketorolac tromethamine, are compared in TABLE 1A, TABLE 1B, and TABLE 1C.The extent of bioavailability following administration of the oral and IM forms of ketorolac tromethamine was equal to that following an IV bolus.

Linear Kinetics : Following administration of single oral, 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 humans, following single or multiple IM, IV, or recommended oral doses of ketorolac tromethamine, are linear. At the higher recommended doses, there is a proportional increase in the concentrations of free and bound racemate.

Binding and Distribution : The ketorolac tromethamine racemate has been shown to be highly protein-bound (99%). Nevertheless, even 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.

The mean apparent volume (V_beta) of ketorolac tromethamine following complete distribution was approximately 13 liters. This parameter was determined from single-dose data.

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.

Clearance and Excretion : 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.

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 5-6 hours.

Accumulation : ketorolac tromethamine administered as an IV bolus, every 6 hours, for 5 days, to healthy subjects (n=13), showed no significant difference in C_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 (elderly patients, renal failure patients, or hepatic disease patients).

Effects of Food : 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.

Kinetics in Special Populations Elderly Patients : Based on single-dose data only, the half-life of the ketorolac tromethamine racemate increased from 5 to 7 hours in the elderly (65-78 years) compared with young healthy volunteers (24-35 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, Use in the Elderly).

Renally Impaired Patients : Based on single-dose data only, the mean half-life of ketorolac tromethamine in renally impaired patients in between 6 and 19 hours, and is dependent on the extent of the impairment. There is poor correlation between creatine 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 PRECAUTIONS, Hepatic Effects ).

Hepatic Effects : 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).

TABLE 1A Table of Approximate Average Pharmacokinetic Parameters (Mean ± SD) Oral, Intramuscular and Intravenous Doses of ketorolac tromethamine

Pharmacokinetic Parameter (units)	Oral* 10 mg
Bioavailability (extent)	100%
Tmax (min)	44 ± 34
Cmax§(mug/ml)[single dose]	0.87 ± 0.22
Cmax (mug/ml)[steady state qid]	1.05 ± 0.26
Cmin¤ (mug/ml)[steady state qid]	0.29 ± 0.07
Cavg¶ (mug/ml)[steady state qid]	0.59 ± 0.20
Vbeta** (L/kg)	0.175 ± 0.039
* Derived from PO pharmacokinetic studies in 77 normal fasted volunteers.
Mean value was simulated from observed plasma concentration data and standard deviation was simulated from percent coefficient of variation for observed Cmax and Tmax data.
Time-to-peak plasma concentration.
§ Peak plasma concentration.
¤ Trough plasma concentration
¶ Average plasma concentration.
** Volume of distribution.

TABLE 1B Table of Approximate Average Pharmacokinetic Parameters (Mean ± SD) Oral, Intramuscular and Intravenous Doses of ketorolac tromethamine

	Intramuscular*
Pharmacokinetic Parameter (units)	15 mg	30 mg	60 mg
Bioavailability (extent)	100%
Tmax§ (min)	33 ± 21	44 ± 29	33 ± 21
Cmax¤ (mug/ml)[single dose]	1.14 ± 0.32	2.42 ± 0.68	4.55 ± 1.27
Cmax (mug/ml)[steady state qid]	1.56 ± 0.44	3.11 ± 0.87	N/A
Cmin¶ (mug/ml)[steady state qid]	0.47 ± 0.13	0.93 ± 0.26	N/A
Cavg** (mug/ml)[steady state qid]	0.94 ± 0.29	1.88 ± 0.59	N/A
Vbeta (L/kg)	0.175-0.039
* Derived from IM pharmacokinetic studies in 54 normal volunteers.
Mean value was simulated from observed plasma concentration data and standard deviation was simulated from percent coefficient of variation for observed Cmax and Tmax data.
Not applicable because 60 mg is only recommended as a single dose.
§ Time-to-peak plasma concentration.
¤ Peak plasma concentration.
¶ Trough plasma concentration.
** Average plasma concentration.
Volume of distribution.

TABLE 1C Table of Approximate Average Pharmacokinetic Parameters (Mean ± SD) Oral, Intramuscular and Intravenous Doses of ketorolac tromethamine

	Intravenous Bolus*
Pharmacokinetic Parameter (units)	15 mg	30 mg
Bioavailability (extent)	100%
Tmax (min)	1.1 ± 0.7	2.9 ± 1.8
Cmax§ (mug/ml)[single dose]	2.47 ± 0.51	4.65 ± 0.96
Cmax (mug/ml)[steady state qid]	3.09 ± 1.17	6.85 ± 2.61
Cmin¤ (mug/ml)[steady state qid]	0.61 ± 0.21	1.04 ± 0.35
Cavg¶ (mug/ml)[steady state qid]	1.09 ± 0.30	2.17 ± 0.59
Vbeta** (L/kg)	0.210 ± 0.044
% Dose metabolized = <50	% Dose excreted in feces = 6
% Dose excreted in urine = 91	% Plasma protein binding = 99
* Derived from IV pharmacokinetic studies in 24 normal volunteers.
Mean value was simulated from observed plasma concentration data and standard deviation was simulated from percent coefficient of variation for observed Cmax and Tmax data.
Time-to-peak plasma concentration.
§ Peak plasma concentration.
¤ Trough plasma concentration.
¶ Average plasma concentration.
** Volume of distribution.

TABLE 2 The Influence of Age, Liver and Kidney Function, on the Clearance and Terminal Half-Life of ketorolac tromethamine (IM* and ORAL)

		Total Clearance (in l/h/kg)		Terminal Half-life (in hours)
	Type of Subjects	IM Mean (range)	Oral Mean (range)	IM Mean (range)	Oral Mean (range)
Normal Subjects
	IM (n=54) mean age=32, range=18-60, Oral (n=77), mean age=32, range=20-60	0.023 (0.010-0.046)	0.025 (0.013-0.050)	5.3 (3.5-9.2)	5.3 (2.4-9.0)
Healthy Elderly Subjects
	IM (n=13), Oral (n=12) mean age=72, range=65-78	0.019 (0.013-0.034)	0.024 (0.018-0.034)	7.0 (4.7-8.6)	6.1 (4.3-7.6)
Patients with Hepatic Dysfunction
	IM and Oral (n=7) mean age=51, range=43-64	0.029 (0.013-0.066)	0.033 (0.019-0.051)	5.4 (2.2-6.9)	4.5 (1.6-7.6)
Patients with Renal Impairment
	IM (n=25) and Oral (n=9) serum creatinine 1.9-5.0 mg/dl mean age (IM )=54, range=35-71 mean age (Oral )=5, range=39-70	0.015 (0.005-0.043)	0.016 (0.007-0.052)	10.3 (5.9-19.2)	10.8 (3.4-18.9)
Renal Dialysis Patients
	IM and Oral (n=9) mean age=40, range=27-63	0.016 (0.003-0.036)	—	13.6 (8.0-39.1)	—
* Estimated from 30 mg single IM doses of ketorolac tromethamine.
Estimated from 10 mg single oral doses of ketorolac tromethamine.
Liters/hour/kilogram.
IV Administration: In normal studies (n=37), the total clearance of 30 mg IV-administered ketorolac tromethamine was 0.030 (0.017-0.051) l/h/kg. The terminal half-life was 5.6 (4.0-7.9) hours.

CLINICAL STUDIES :

The analgesic efficacy of intramuscularly, intravenously and orally administered ketorolac tromethamine was investigated in two postoperative pain models: general surgery (orthopedic, gynecologic and abdominal) and oral surgery (removal of impacted third molars). The studies were primarily double-blind, single- and multi-dose, parallel trial designs, in patients with moderate to severe pain at baseline. ketorolac tromethamine IV/IM was compared as follows: IM to meperidine or morphine administered intramuscularly, and IV to morphine administered either directly IV or through a PCA (Patient-Controlled Analgesia) pump.

Short Term Use (up to 5 days) : In the comparisons of intramuscular administration during the first hour, the onset of analgesic action was similar for ketorolac tromethamine and the narcotics, but the duration of analgesia was longer with ketorolac tromethamine than with the opioid comparators meperidine or morphine.

In a multi-dose, postoperative (general surgery) double-blind trial of ketorolac tromethamine IM 30 mg versus morphine 6 and 12 mg IM, each drug given on an “as needed” basis for up to 5 days, the overall analgesic effect of ketorolac tromethamine IM 30 mg was in between that of morphine 6 and 12 mg. ketorolac tromethamine 30 mg caused less drowsiness, nausea and vomiting than morphine 12 mg. The majority of patients treated with either ketorolac tromethamine or morphine were dosed for up to 3 days; a small percentage of patients received 5 days of dosing.

In clinical settings where perioperative morphine was allowed, ketorolac tromethamine IV 30 mg, given once or twice as needed, provided analgesia comparable to morphine 4 mg IV once or twice as needed.

There was relatively limited experience with 5 consecutive days of ketorolac tromethamine IV use in controlled clinical trials, as most patients were given the drug for 3 days or less. The adverse events seen with IV- administered ketorolac tromethamine were similar to those observed with IM-administered ketorolac tromethamine, as would be expected based on the similar pharmacokinetics and bioequivalence (AUC, clearance, plasma half-life) of IV and IM routes of ketorolac tromethamine administration.

Clinical Studies with Concomitant Use of Opioids : Clinical studies in postoperative pain management have demonstrated that ketorolac tromethamine IV/IM, when used in combination with opioids, significantly reduced opioid consumption. This combination may be useful in the subpopulation of patients especially prone to opioid-related complications. ketorolac tromethamine and narcotics should not be administered in the same syringe.

In 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.

TABLE 3A Incidence of Clinically Serious G.I. Bleeding as Related to Age, Total Daily Dose, and History of G.I. Perforation, Ulcer, Bleeding (PUB) After up to 5 Days of Treatment with ketorolac tromethamine IV/IM A. Patients without History of PUB

Age of Patients	Total Daily Dose of ketorolac tromethamineIV/IM
	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%

TABLE 3B Incidence of Clinically Serious G.I. Bleeding as Related to Age, Total Daily Dose, and History of G.I. Perforation, Ulcer, Bleeding (PUB) After up to 5 Days of Treatment with ketorolac tromethamine IV/IM B. Patients with History of PUB

Age of Patients	Total Daily Dose of ketorolac tromethamine IV/IM
	60 mg	>60 to 90 mg	>90 to 120 mg	>120 mg
<65 years of age	2.1%	4.6%	7.8%	15.4%
65 years of age	4.7%	3.7%	2.8%	25.0%

Ophthalmic Solution : Ocular administration of ketorolac tromethamine reduces the prostaglandin E₂ levels in aqueous humor. The mean concentration of PGE₂ was 80 pg/ml in the aqueous humor of the eyes receiving vehicle and 28 pg/ml in the eyes receiving 0.5% Acular (ketorolac tromethamine) ophthalmic solution.

ketorolac tromethamine given systemically does not cause pupil constriction.

Results from clinical studies indicate that Acular ophthalmic solution has no significant effect upon intraocular pressure.

Two controlled studies showed that Acular (ketorolac tromethamine) ophthalmic solution was significantly more effective than its vehicle in receiving ocular itch caused by seasonal allergic conjunctivitis.

Two drops (0.1 ml) of 0.5% Acular (ketorolac tromethamine) ophthalmic solution instilled into the patient 12 hours and 1 hour prior to cataract extraction achieved measurable levels in 8 of 9 patients’ eyes (mean ketorolac concentration 95 ng/ml aqueous humor, range 40 to 170 ng/ml).

One drop (0.05 ml) of 0.5% of Acular ophthalmic solution was instilled into one eye and one drop of vehicle into the other eye t.i.d. in 26 normal subjects. Only 5 of 26 subjects had a detectable amount of ketorolac in their plasma (range 10.7 to 22.5 ng/ml) at Day 10 during topical ocular treatment. When ketorolac tromethamine 10 mg is administered systemically every 6 hours, peak plasma levels at steady state are round 960 ng/ml.

Acular ophthalmic solution has been safely administered in conjunction with other ophthalmic medications, such as antibiotics, beta blockers, carbonic anhydrase inhibitors, cycloplegics, and mydriatics.

INDICATIONS AND USAGE :

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 ketorolac tromethamine IV/IM and oral ketorolac tromethamine is to be used only as continuation treatment, if necessary. Combined use of ketorolac tromethamine IV/IM and oral ketorolac tromethamine is not to exceed 5 days of use because of the potential of increasing the frequency and severity of adverse reactions associated with the recommended doses (see WARNINGS, PRECAUTIONS, DOSAGE AND ADMINISTRATION, and ADVERSE REACTIONS). Patients should be switched to alternative analgesics as soon as possible, but ketorolac tromethamine therapy is not to exceed 5 days.

ketorolac tromethamine IV/IM 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 IV/IM dosage range with low doses of narcotics prn, unless otherwise contraindicated. ketorolac tromethamine IV/IM and narcotics should not be administered in the same syringe (see DOSAGE AND ADMINISTRATION), Pharmaceutical Information for ketorolac tromethamine IV/IM.

Ophthalmic Solution : Acular ophthalmic solution is indicated for the relief of ocular itching due to seasonal allergic conjunctivitis.

CONTRAINDICATIONS :

See also BOXED WARNING.

Ophthalmic Solution : ketorolac tromethamine ophthalmic solution is contraindicated in patients with previously demonstrated hypersensitivity to any of the ingredients in the formulation.

WARNINGS :

(See also BOXED WARNING.)

The combined use of ketorolac tromethamine IV/IM and oral ketorolac tromethamine is not to exceed 5 days.

The Most Serious Risks Associated with Ketorolac Tromethamine are :

1. Gastrointestinal Ulcerations–Bleeding and Perforation : ketorolac tromethamine is CONTRAINDICATED in patients with previously documented peptic ulcers and/or G.I. bleeding. Serious gastrointestinal toxicity, such as bleeding ulceration, and perforation, can occur at any time, with or without warning symptoms, in patients treated with ketorolac tromethamine. Studies to date with NSAIDs have not identified any subset of patients not at risk of developing peptic ulceration and bleeding. Elderly or debilitated patients seem to tolerate ulceration or bleeding less well than other individuals, and most spontaneous reports of fatal GI events are in this population. Postmarketing experience with parenterally administered ketorolac tromethamine suggests that there may be a greater risk of gastrointestinal ulcerations, bleeding and perforation in the elderly.

The incidence and severity of gastrointestinal compilations increases with increasing dose of, and duration of treatment with, ketorolac tromethamine. In a non-randomized, in-hospital postmarketing surveillance study, comparing parental ketorolac tromethamine to parental opioids, higher rates of clinically serious G.I. bleeding were seen in patients <65 years of age who received an average total daily dose of more than 90 mg of ketorolac tromethamine IV/IM per day (see CLINICAL PHARMACOLOGY, Postmarketing Surveillance Study .

The same study showed that elderly (65 years of age), and debilitated patients are more susceptible to gastrointestinal complications. A history of peptic ulcer disease was revealed as another risk factor that increases the possibility of developing serious gastrointestinal complications during ketorolac tromethamine therapy (see TABLES 3A and TABLE 3B).

2.Impaired Renal Function: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.

Renal toxicity with ketorolac tromethamine has been seen in patients with conditions leading to a reduction in blood volume and/or renal blood flow, where renal prostaglandins have a supportive role in the maintenance of renal perfusion. In these patients, administration of ketorolac tromethamine may cause a dose- dependent reduction in renal prostaglandin formation and may precipitate acute renal failure. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, heart failure, liver dysfunction, those taking diuretics and the elderly. Discontinuation of ketorolac tromethamine therapy is usually followed by recovery to the pretreatment state.

Renal Effects : 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, nephritis, and nephrotic syndrome.

Because patients with underlying renal insufficiency are at increased risk of developing acute renal failure, the risks and benefits should be assessed prior to giving ketorolac tromethamine to these patients. Hence, in patients with moderately elevated serum creatinine, it is recommended that the daily dose of ketorolac tromethamine IV/IM be reduced by half, not to exceed 60 mg/day. ketorolac tromethamine IS CONTRAINDICATED IN PATIENTS WITH SERUM CREATININE CONCENTRATIONS INDICATING ADVANCED RENAL IMPAIRMENT (see CONTRAINDICATIONS).

Hypovolemia should be corrected before treatment with ketorolac tromethamine is initiated.

3. Fluid Retention and Edema : Fluid Retention, edema, retention of NaCl, oliguria, elevations of serum urea nitrogen and creatine have been reported in clinical trials with ketorolac tromethamine. Therefore, ketorolac tromethamine should be used only very cautiously in patients with cardiac decompensation, hypertension, or similar conditions.

4. 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 prophylactic low-dose heparin (2500-5000 units q12h), warfarin and dextrans have not been studied extensively, but may also be associated with an increased risk of bleeding. Until data from such studies are available, physicians should carefully weigh the benefits against the risks, and use such concomitant therapy in these patients only extremely cautiously. In patients who receive anticoagulants for any reason, there is an increased risk of intramuscular hematoma formation from administered ketorolac tromethamine IM (see DRUG INTERACTIONS). 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 perioperative use of ketorolac tromethamine IV/IM. Therefore, perioperative use of ketorolac tromethamine should be avoided and postoperative use be undertaken with caution when hemostasis is critical (see WARNINGSand PRECAUTIONS).

5. Anaphylactoid Reactions: Anaphylactoid reactions may occur in patients without a known previous exposure or hypersensitivity to aspirin, ketorolac tromethamine, or other NSAIDs, or in individuals with a history of angioedema, bronchospastic reactivity (e.g., asthma), and nasal polyps. Anaphylactoid reactions, like anaphylaxis, may have a fatal outcome.

Ophthalmic Solution

There is potential for cross sensitivity to acetylsalicylic acid, phenylacetic acid derivatives, and other nonsteroidal anti-inflammatory agents. Therefore, caution should be used when treating individuals who have previously exhibited sensitivities to these drugs.

With some nonsteroidal anti-inflammatory drugs, there exists the potential for increased bleeding time due to interference with thrombocyte aggregation. There have been reports that ocularly aplied nonsteroidal anti-inflammatory drugs may cause increased bleeding of ocular tissues (including hyphemas) in conjuction with ocular surgery.

PRECAUTIONS :

Hepatic Effects: ketorolac tromethamine should be used with caution in patients with impaired hepatic function, or a history of liver disease. Treatment with ketorolac tromethamine may cause elevations of liver enzymes, and in patients with pre-existing liver dysfunction it may lead to the development of a more severe hepatic reaction. The administration of ketorolac tromethamine should be discontinued in patients in whom an abnormal liver test has occurred as a result of ketorolac tromethamine therapy.

Hematologic Effects : ketorolac tromethamine inhibits platelet aggregation and may prolong bleeding time; therefore, it is contraindicated as a preoperative medication and caution should be used when hemostasis is critical. Unlike aspirin, the inhibition of platelet function by ketorolac tromethamine disappears within 24 to 48 hours after the drug is discontinued. ketorolac tromethamine does not appear to affect platelet count, prothrombin time (PT) or partial thromboplastin time (PTT). In controlled clinical studies, where ketorolac tromethamine was administered intramuscularly or intravenously postoperatively, the incidence of clinically significant postoperative bleeding was 0.4% for ketorolac tromethamine compared to 0.2% in the control groups receiving narcotic analgesics.

Information for the Patient : 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 of the potential risks of ketorolac tromethamine treatment (see BOXED WARNING, WARNINGS, PRECAUTIONS, and ADVERSE REACTIONS). Advise patients not to give oral ketorolac tromethamine to other family members and to discard any unused drug. Remember that the total duration of ketorolac tromethamine therapy is not to exceed 5 (five) days.

Carcinogenesis, Mutagenesis, and Impairment of Fertility : An 18-month study in mice with oral doses of ketorolac tromethamine at 2 mg/kg/day (0.9 times the human systemic exposure at the recommended IM or IV dose of 30 mg qid, based on area-under-the-plasma-concentration curve {AUC}, and a 24-month study in rats at 5 mg/kg/day (0.5 times the human AUC), showed no evidence of tumorigenicity.

ketorolac tromethamine was not mutagenic in Ames test, unscheduled DNA synthesis and repair, and in forward mutation assays. ketorolac tromethamine did not cause chromosome breakage in the in vivo mouse micronucleus assay. At 1590 mcg/ml and at higher concentrations, ketorolac tromethamine increased the incidence of chromosomal aberrations in Chinese hamster ovarian cells.

Impairment of fertility did not occur in male or female rats at oral doses of 9 mg/kg (0.9 times the human AUC) and 16 mg/kg (1.6 times the human AUC) of ketorolac tromethamine, respectively.

Pregnancy Category C : Reproduction studies have been performed during organogenesis, using daily oral doses of ketorolac tromethamine at 3.6 mg/kg (0.37 times the human AUC) in rabbits and at 10 mg/kg (1.0 times the human AUC) in rats. Results of these studies did not reveal evidence of teratogenicity to the fetus. Oral doses of ketorolac tromethamine 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).

Nursing Mothers : After a single administration of 10 mg of oral ketorolac tromethamine to humans, the maximum milk concentration observed was 7.3 ng/ml and the maximum milk-to-plasma ratio was 0.037. After one day of dosing (qid), the maximum milk concentration was 7.9 ng/ml and the maximum milk-to-plasma ratio was 0.025. Because of the possible adverse effects of prostaglandin-inhibiting drugs on neonates, use in nursing mothers is contraindicated.

Pediatric Use : Safety and efficacy in children (less than 16 years of age) have not been established. Therefore, use of ketorolac tromethamine is not recommended for use in children is not recommended.

Use in the Elderly (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 adverse effects of NSAIDs (see WARNINGS, Renal Effects), extra caution and reduced dosages (see DOSAGE AND ADMINISTRATION) must be used when treating the elderly with ketorolac tromethamine IV/IM. The lower dosage range is recommended for patients over 65 years of age and total daily dose is not to exceed 60 mg. The incidence and severity of gastrointestinal complications increases with increasing dose of, and duration of treatment with, ketorolac tromethamine.

Additional Precautions for the Ophthalmic Solution

It is recommended that ketorolac tromethamine) 0.5% sterile ophthalmic solution be used with caution in patients with known bleeding tendencies or who are receiving other medication which may prolong bleeding time.

DRUG INTERACTIONS :

Ketorolac is highly bound to human plasma proteins (mean 99.2%).

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 two-fold 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 volunteers, oral ketorolac tromethamine was co-administered with a single dose of 25 mg warfarin , causing no significant changes in pharmacokinetics or pharmacodynamics of warfarin. In another study, ketorolac tromethamine IV/IM was given with two doses of 5000 U of heparin to 11 healthy volunteers, resulting in a mean template bleeding time of 6.4 minutes (3.2-11.4 min) compared to a mean of 6.0 minutes (3.4-7.5 min) for heparin alone and 5.1 minutes (3.5-8.5 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).

ketorolac tromethamine IV/IM reduced the diuretic response to furosemide in normovolemic healthy subjects by approximately 20% (mean sodium and urinary output decreased 17%).

Concomitant administration of oral ketorolac tromethamineand probenecid resulted in decreased clearance of ketorolac and significant increases in ketorolac plasma levels (total AUC increased approximately 3-fold from 5.4 to 17.8 mcg/h/ml) and terminal half-life increased approximately 2-fold from 6.6 to 15.1 hours. Therefore, concomitant use of ketorolac tromethamine and probenecid is contraindicated.

Inhibition of renal lithium clearance, leading to an increase in plasma lithium concentration, has been reported with some prostaglandin synthesis-inhibiting drugs. The effect of ketorolac tromethamine on plasma lithium has not been studied, but cases of increased lithium plasma levels during ketorolac tromethamine therapy have been reported.

Concomitant administration of methotrexate and some NSAIDs has been reported to reduce the clearance of methotrexate, enhancing the toxicity of methotrexate. The effect of ketorolac tromethamine on methotrexate clearance has not been studied.

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

Concomitant use of ACE inhibitors may increase the risk of renal impairment, particularly in volume-depleted patients.

Sporadic cases of seizures have been reported during concomitant use of ketorolac tromethamine and antiepilectic drugs (Dilantin, Tegretol).

Hallucinations have been reported when ketorolac tromethamine was used in patients taking psychoactive drugs (Prozac, Navane, Xanax).

ketorolac tromethamine IV/IM has been administered concurrently with morphine in several clinical trials of postoperative pain without evidence of adverse interactions. Do not mix ketorolac tromethamine and morphine in the same syringe.

There is no evidence, in animal or human studies, that ketorolac tromethamine induces or inhibits hepatic enzymes capable of metabolizing itself or other drugs.

ADVERSE REACTIONS :

Adverse reaction rates increase with higher doses of ketorolac tromethamine. Practitioners should be alert for the severe complications of treatment with ketorolac tromethamine, such as G.I. ulceration, bleeding and perforation, postoperative bleeding, acute renal failure, anaphylactic and anaphylactoid reactions, and liver failure (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.

The adverse reactions listed below were reported in clinical trials as probably related to ketorolac tromethamine.

Incidence Greater Than 1% :

Incidence 1% or Less :

The following adverse events were reported from postmarketing experience:

Body as a Whole : Hypersensitivity reactions such as anaphylaxis, anaphylactoid reaction, laryngeal edema, tongue edema (see BOXED WARNING, WARNINGS), myalgia.
Cardiovascular : Hypotension and flushing.
Dermatologic : Lyell’s syndrome, Stevens-Johnson syndrome, exfoliative dermatitis, maculopapular rash, urticaria.
Gastrointestinal : Peptic, ulceration, GI hemorrhage, GI perforation (see BOXED WARNING, WARNINGS), melena, acute pancreatitis.
Hemic and Lymphatic : Postoperative wound hemorrhage (rarely requiring blood transfusion (see BOXED WARNING, WARNINGS and PRECAUTIONS), thrombocytopenia, leukopenia.
Hepatic : Hepatitis, liver failure, cholestatic, jaundice.
Nervous System : Convulsions, psychosis, aseptic meningitis.
Respiratory : Asthma, bronchospasm.
Urogenital : Acute renal failure (see BOXED WARNING, WARNINGS), flank pain with or without hematuria and/or azotemia, nephritis, hyponatremia, hyperkalemia, hemolytic, uremic syndrome.

Additional Information for Ophthalmic Solution

In patients with allergic conjunctivitis, the most adverse events reported with the use of Acular (ketorolac tromethamine) ophthalmic solution have been transient stinging and burning on instillation. These events were reported by approximately 40% of the patients treated with Acular ophthalmic solution. In all development studies conducted, other adverse events reported during treatment with Acular include ocular irritation (3%), allergic reactions (3%), superficial ocular infections (0.5%) and superficial keratitis (1%).

Other adverse events reported rarely with the use of ketorolac tromethamine ophthalmic solution include: eye dryness, corneal infiltrates, corneal ulcer, and visual disturbance (blurry vision).

OVERDOSAGE :

In controlled overdosage, daily doses of 360 mg of ketorolac tromethamine IV/IM given for five days (3 times the highest recommended dose), caused abdominal pain and peptic ulcers which healed after discontinuation of doses. Metabolic acidosis has been reported following intentional overdosage.

Dialysis does not significantly clear ketorolac tromethamine from the blood stream.

DOSAGE AND ADMINISTRATION :

IV/IM

THE COMBINED DURATION OF USE OF ketorolac tromethamine IV/IM AND ketorolac tromethamine ORAL IS NOT TO EXCEED FIVE (5) DAYS.

THE USE OF ketorolac tromethamine ORAL IS ONLY INDICATED AS CONTINUATION THERAPY TO ketorolac tromethamine IV/IM .

ketorolac tromethamine IV/IM may be used as a single or multiple dose, on a regular or “pm” 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 IV/IM, the IV bolus must be given over no less than 15 seconds. The IM administration should be given slowly and deeply into the muscle. The analgesic effect begins in 30 minutes with maximum effect 1 to 2 hours after dosing IV or IM. Duration of analgesic effect is usually 4 to 6 hours.

Single-Dose Treatment

The following regimen should be limited to single administration use only.

IM Dosing :

	Patients <65 Years of Age : One dose of 60 mg.
	Patients 65 Years of Age, Renally Impaired and/or Less Than 50 kg (110 lbs) of Body Weight : One dose of 30 mg.

IV Dosing :

	Patients <65 Years of Age: One dose of 30 mg.
	Patients 65 Years of Age, Renally Impaired and/or Less Than 50 kg (110 lbs) of Body Weight: One dose of 15 mg.

Multiple-Dose Treatment

	Patients <65 Years of Age: The recommended dose is 30 mg ketorolac tromethamine IV/IM every 6 hours. The maximum daily dose 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 IV/IM 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 regiments with low doses of opioids “pm” unless otherwise contraindicated.

Preparation of Solution

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

ketorolac tromethamine IV/IM 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.

Oral

Oral ketorolac tromethamine is indicated ONLY as continuation therapy to ketorolac tromethamine IV/IM for the management of moderately severe, acute pain that requires analgesia at the opioid level. See also PRECAUTIONS, Information for Patients.

Transition from ketorolac tromethamine IV/IM to ketorolac tromethamine Oral

The recommended oral ketorolac tromethamine dose is as follows:

	Patients <65 years of age: Two (2) tablets as a first oral dose for patients who received 60 mg IM single dose, 30 mg IV single dose or 30 mg multiple dose ketorolac tromethamine IV/IM followed by one (1) tablet oral ketorolac tromethamine every 4 to 6 hours, not to exceed 40 mg/24 h of oral ketorolac tromethamine.
	Patients 65 years of age, renally impaired and/or less than 50 kg (110 lbs) of body weight: One (1) tablet as a first oral dose for patients who received 30 mg IM single dose, 15 mg IV single dose or 15 mg multiple dose ketorolac tromethamine IV/IM followed by one (1) tablet oral ketorolac tromethamine every 4 to 6 hours, not to exceed 40 mg/24 h of oral ketorolac tromethamine.

Shortening the recommended dosing intervals may result in increased frequency and severity of adverse reactions.

The maximum combined duration of use (parenteral and oral ketorolac tromethamine) is limited to 5 days.

Ophthalmic Solution

The recommended dose of Acular is one drop (0.25 mg) four times a day for relief of ocular itching due to seasonal allergic conjunctivitis.

ANIMAL PHARMACOLOGY :

Ophthalmic Solution Only : ketorolac tromethamine prevented the development of increased intraocular pressure induced in rabbits with topically applied arachidonic acid. Ketorolac did not inhibit rabbit lens aldose reductase in vivo .

ketorolac tromethamine ophthalmic solution did not enhance the spread of ocular infections induced in rabbits with Candida albicans, Herpes Simplex virus type one, or pseudomonas aeruginosa .

HOW SUPPLIED :

IM/IV : Store injectionables at controlled room temperature 15-30°C (59-86°F) with protection from light.
Oral : Store oral tablets and blister packages at controlled room temperature, 15-30°C (59-86°F). Protect from excessive humidity and light.
Acular Ophthalmic Solution : Store at controlled room temperature, 15-30°C (59-86°F) with protection from light.