DrugLib.com — Drug Information Portal

Rx drug information, pharmaceutical research, clinical trials, news, and more

Toradol (Ketorolac Tromethamine) - Description and Clinical Pharmacology

 
 



DESCRIPTION

TORADOL (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-1 H -pyrrolizine-1-carboxylic acid, compound with 2-amino-2-(hydroxy-methyl)-1,3-propanediol (1:1).

TORADOL is a racemix 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. Its molecular formula is C19H24N2O6.

TORADOL 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 IM 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 or hydrochloric acid, and the solutions are packaged with nitrogen. The sterile solutions are clear and slightly yellow in color.

TORADOLORALis 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 tables are printed with red ink that includes FD&C Red #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 ROCHE on the other.

CLINICAL PHARMACOLOGY

Pharmacodynamics: Ketorolac tromethamine is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits analgesic activity in animal models. Ketorolac tromethamine inhibits synthesis of prostaglandins and may be considered a peripherally acting analgesic. 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 TORADOL occurs within 2 to 3 hours and is not statistically significantly different over the recommended dosage range of TORADOL. The greatest difference between large and small doses of TORADOL 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 IV, IM and Oral Pharmacokinetics: The pharmacokinetics of ketorolac tromethamine, following IV, IM and oral doses of TORADOL, are compared in Table 1. In adults, the extent of bioavailability following administration of the ORAL and IM forms of TORADOL was equal to that following an IV bolus.

Linear Kinetics: In adults, following administration of single ORAL, IM or IV doses of TORADOL 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, IV or recommended oral doses of TORADOL, are linear. At the higher recommended doses, there is a proportional increase in the concentrations of free and bound racemate.

Absorption: TORADOL is 100% absorbed after oral administration (see Table 1). Oral administration of TORADOL 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 (V(beta)) 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, even plasma concentrations as high as 10 µg/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: Lactation and Nursing).

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 TORADOL (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: TORADOL 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 µg/mL (SD ± 0.13) on Day 1 and 0.55 µg/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 µg/mL ± 0.77; young, 2.99 µg/mL ± 1.03) (see PRECAUTIONS: Geriatric Use).

Pediatric Patients: Following a single intravenous bolus dose of 0.5 mg/kg in 10 children 4 to 8 years old, the half-life was 6 hours (range: 3.5 to 10 h), the average clearance was 0.042 L/hr/kg and the Vd was 0.26 L/kg (range: 0.19 to 0.44 L/kg). In a second study, following a single intravenous dose of 0.6 mg/kg in 24 children 3 to 18 years old, Cmax was 4.3 ± 1.7 mcg/mL, Tmax was 10.25 ± 1.15 minutes, half-life was 3.8 ± 2.6 hours, Cl was 0.0678 L/hr/kg and Vd was 0.25 L/kg. The volume of distribution and clearance of ketorolac in pediatric patients was twice that observed in adult subjects (see Tables 1 and 2). There are no pharmacokinetic data available for TORADOL administration 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(infinity) 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(infinity)-ratio of the ketorolac tromethamine each 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 and Table 2).

Hepatic Insufficiency: There was no significant difference in estimates of half-life, AUC(infinity) and Cmax in 7 patients with liver disease compared to healthy volunteers (see PRECAUTIONS: Hepatic Effects and Table 2).

Race: Pharmacokinetic differences due to race have not been identified.

Table 1. Table of Approximate Average Pharmacokinetic Parameters (Mean ± SD) Following Oral, Intramuscular and Intravenous Doses of TORADOL
Oral * Intramuscular **/* Intravenous Bolus **/**
Pharmacokinetic
Parameters (units) 10 mg 15 mg 30 mg 60 mg 15 mg 30 mg
Bioavailability (extent) 100%
Tmax 1 (min) 44 ± 34 33 ± 21 § 44 ± 29 33 ± 21 § 1.1 ± 0.7 § 2.9 ± 1.8
Cmax 2 (µg/mL) [single-dose] 0.87 ± 0.22 1.14 ± 0.32 § 2.42 ± 0.68 4.55 ± 1.27 § 2.47 ± 0.51 § 4.65 ± 0.96
Cmax(µg/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
Cmin 3 (µg/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
Cavg 4 (µg/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(beta) 5 (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 IM pharmacokinetic studies in 54 normal volunteers
**/** 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
#Not applicable because 60 mg is only recommended as a single dose
1 Time-to-peak plasma concentration
2 Peak plasma concentration
3 Trough plasma concentration
4 Average plasma concentration
5 Volume of distribution

Table 2. The Influence of Age, Liver, and Kidney Function on the Clearance
and Terminal Half-life of TORADOL (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 0.023 0.025 5.3 5.3
IM (n=54) (0.010-0.046) (0.013-0.050) (3.5-9.2) (2.4-9.0)
mean age=32, range=18-60
Oral (n=77)
mean age=32, range=20-60
Healthy Elderly Subjects 0.019 0.024 7.0 6.1
IM (n=13), Oral (n=12) (0.013-0.034) (0.018-0.034) (4.7-8.6) (4.3-7.6)
mean age=72, range=65-78
Patients with Hepatic 0.029 0.033 5.4 4.5
Dysfunction (0.013-0.066) (0.019-0.051) (2.2-6.9) (1.6-7.6)
IM and Oral (n=7)
mean age=51, range=43-64
Patients with Renal 0.015 0.016 10.3 10.8
Impairment (0.005-0.043) (0.007-0.052) (5.9-19.2) (3.4-18.9)
IM (n=25), Oral (n=9)
serum creatinine=1.9-5.0 mg/dL,
mean age (IM)=54, range=35-71
mean age (Oral)=57, range=39-70
Renal Dialysis Patients 0.016 -- 13.6 --
IM and Oral (n=9) (0.003-0.036) (8.0-39.1)
mean age=40, range=27-63
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 TORADOL was 0.030 (0.0.17-0.051) L/h/kg. The terminal half-life was 5.6 (4.0-7.9) hours. (See Kinetics in Special Populations for use of TORADOLIVin pediatric patients.)

CLINICAL STUDIES

Adult Patients: The analgesic efficacy of intramuscularly, intravenously and orally administered TORADOL was investigated in two postoperative pain models: general surgery (orthopedic, gynecologic and abdominal) and oral surgery (removal of impacted third molars). The studies were double-blind, single- and multiple-dose, parallel trial designs in patients with moderate to severe pain at baseline. TORADOLIV/IMwas 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) Studies: In adults, the comparisons of intramuscular administration during the first hour, the onset of analgesic action was similar for TORADOL and the narcotics, but the duration of analgesia was longer with TORADOL than with the opioid comparators meperidine or morphine.

In a multidose, postoperative (general surgery) double-blind trial of TORADOLIM30 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 TORADOLIM30 mg was between that of morphine 6 and 12 mg. The majority of patients treated with either TORADOL 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, TORADOLIV30 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 TORADOLIVuse in controlled clinical trials, as most patients were given the drug for 3 days or less. The adverse events seen with IV-administered TORADOL were similar to those observed with IM-administered TORADOL, as would be expected based on the similar pharmacokinetics and bioequivalence (AUC, clearance, plasma half-life) of IV and IM routes of TORADOL administration.

Pediatric Patients: The analgesic efficacy of single doses of TORADOLIV/IMhas been demonstrated by showing a decrease in the need for supplemental narcotic in pediatric patients receiving ketorolac as compared to placebo. See discussion of these results under Clinical Studies With Concomitant Use of Opioids below.

CLINICAL STUDIES WITH CONCOMITANT USE OF OPIOIDS

Adults Patients: Clinical studies in postoperative pain management have demonstrated that TORADOLIV/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. TORADOL and narcotics should not be administered in the same syringe.

In a postoperative study, where all patients received morphine by a PCA device, patients treated with TORADOLIVas fixed intermittent boluses (eg, 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 TORADOLIVplus PCA morphine as compared to patients receiving PCA-administered morphine alone.

Pediatric Patients: TORADOLIMinjection reduced the need for supplemental opioid (fentanyl) when a 1 mg/kg dose was administered immediately following tonsillectomy compared to saline controls (see WARNINGS: Hemorrhage). In another study, when a single bolus dose of 0.9 mg/kg of TORADOLIVwas given to pediatric patients ages 5 to 12 years, compared to saline, a reduction in supplemental opioid was needed following various surgical procedures. In a third study less supplemental morphine was needed in pediatric patients ages 8 to 16 years, who received a 0.8 mg/kg IV injection of TORADOL in conjunction with morphine following orthopedic surgical procedures, compared to morphine alone. In a study in pediatric patients ages 3 to 12 years, TORADOLIVdemonstrated a slower onset of analgesia, but a longer duration of action compared to morphine. There is limited data available to support the use of multiple doses of TORADOLIV/IMin pediatric patients. There are also insufficient data available to support the use of TORADOLORALin pediatric patients.

Postmarketing Surveillance Study: A large postmarketing observational, nonrandomized study, involving approximately 10,000 patients receiving TORADOL, 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 TORADOL (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 TORADOLIV/IM
A. Adult Patients Without History of PUB
Age of Patients Total Daily Dose of TORADOLIV/IM
>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 TORADOLIV/IM
>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%

-- advertisement -- The American Red Cross
 
Home | About Us | Contact Us | Site usage policy | Privacy policy

All Rights reserved - Copyright DrugLib.com, 2006-2014