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Sprix

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Sprix

CLINICAL PHARMACOLOGY

Mechanism of Action

SPRIX contains ketorolac tromethamine, a nonsteroidal anti-inflammatory drug (NSAID). Ketorolac is an analgesic that inhibits the enzyme cylooxygenase (COX), an early component of the arachidonic acid cascade, resulting in the reduced synthesis of prostaglandins, thromboxanes, and prostacyclin.

Ketorolac does not bind to the opiate receptor subtypes (mu, kappa, delta), but a 30 mg dose of ketorolac tromethamine IM has demonstrated an overall analgesic effect between that obtained with morphine 6mg and 12mg. Ketorolac possesses no sedative or anxiolytic properties, and has no effect on gut motility.

Pharmacodynamics

Ketorolac tromethamine is a racemic mixture of [-]S and [+]R-enantiomeric forms, with the S-form having analgesic activity. Ketorolac, the active component of SPRIX (ketorolac tromethamine nasal spray) , has anti-inflammatory, analgesic, and anti-pyretic effects. Studies directly comparing the analgesic effects of SPRIX (ketorolac tromethamine nasal spray) and opioids have not been conducted.

Pharmacokinetics

The half-lives of ketorolac by the IN and IM routes were similar. The bioavailability of ketorolac by the IN route of administration of a 31.5 mg dose was approximately 60% compared to IM administration. (See Table 2.)

Table 2: Pharmacokinetic Parameters of Ketorolac Tromethamine after Intramuscular (IM) and Intranasal (IN) Administration

Ketorolac Tromethamine Cmax(SD)
ng/mL
tmax(range)
hours
AUC0-∞(SD)
ng•h/mL
T½(SD)
hours
30mg IM (1.0 mL of a 30 mg/mL solution) 2382.2 0.75 11152.8 4.80
(432.7) (0.25-1.03) (4260.1) (1.18)
31.5mg IN (SPRIX) (100 μL of a 15% w/w solution) 1805.8 0.75 7477.3 5.24
(882.8) (0.50-2.00) (3654.4) (1.33)
15mg IM (0.5 mL of a 30 mg/mL solution) 1163.4 0.75 5196.3 5.00
(279.9) (0.25-1.50) (2076.7) (1.72)
Cmax = maximum plasma concentration; tmax = time of Cmax; AUC0-∞ = complete area under the concentration-time curve; T½ = half-life; SD = standard deviation. All values are means, except tmax, for which medians are reported.

Absorption

In a study in which SPRIX (ketorolac tromethamine nasal spray) (31.5 mg) was administered to healthy volunteers four times daily for 5 days, the Cmax, tmax, and AUC values following the final dose were comparable to those obtained in the single-dose study. Accumulation of ketorolac has not been studied in special populations, geriatric, pediatric, renal failure or hepatic disease patients.

Distribution

Scintigraphic assessment of drug disposition of ketorolac following SPRIX (ketorolac tromethamine nasal spray) intranasal dosing demonstrated that most of the ketorolac was deposited in the nasal cavity and pharynx, with less than 20 % deposited in the esophagus and stomach, and zero or negligible deposition in the lungs ( < 0.5%).

The mean apparent volume (Vβ) 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.

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 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.

Special Populations

Drug Interactions

A study was conducted in subjects with symptomatic allergic rhinitis to assess the effects of the commonly used nasal spray products oxymetazoline hydrochloride and fluticasone propionate on the pharmacokinetics of SPRIX (ketorolac tromethamine nasal spray) . Subjects received a single dose of oxymetazoline nasal spray followed by a single dose (31.5 mg) of SPRIX (ketorolac tromethamine nasal spray) 30 min later. Subjects also received fluticasone nasal spray (200 mcg as 2 x 50 mcg in each nostril) for seven days, with a single dose (31.5 mg) of SPRIX (ketorolac tromethamine nasal spray) on the 7th day. Administration of these common IN products had no effect of clinical significance on the rate or extent of ketorolac absorption. In addition, comparison of the pharmacokinetics of SPRIX (ketorolac tromethamine nasal spray) in subjects with allergic rhinitis to data from a previous study in healthy subjects showed no differences that would be of clinical consequence for the efficacy or safety of SPRIX (ketorolac tromethamine nasal spray) .

Geriatric Patients

A single-dose study was conducted to compare the pharmacokinetics of SPRIX (ketorolac tromethamine nasal spray) (31.5 mg) in subjects ≥ age 65 to the pharmacokinetics in subjects < age 65. Exposure to ketorolac was increased by 23% for the ≥ 65 population as compared to subjects < 65. Peak concentrations of 2028 and 1840 ng/mL were observed for the elderly and nonelderly adult populations, respectively, at 0.75 h after dosing. In the elderly population a longer terminal half-life was observed as compared to the nonelderly adults (4.5 h vs. 3.3 h, respectively).

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.

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.

Race

Pharmacokinetic differences due to race have not been identified.

Clinical Studies

Postoperative Pain

The effect of SPRIX (ketorolac tromethamine nasal spray) on acute pain was evaluated in two multi-center, randomized, double-blind, placebo-controlled studies.

In a study of adults who had undergone elective abdominal or orthopedic surgery, 300 patients were randomized and treated with SPRIX (ketorolac tromethamine nasal spray) or placebo administered every 8 hours and morphine administered via patient controlled analgesia on an as needed basis. Efficacy was demonstrated as a statistically significant greater reduction in the summed pain intensity difference over 48 hours in patients who received SPRIX (ketorolac tromethamine nasal spray) as compared to those receiving placebo. The clinical relevance of this is reflected in the finding that patients treated with SPRIX (ketorolac tromethamine nasal spray) required 36% less morphine over 48 hours than patients treated with placebo.

In a study of adults who had undergone elective abdominal surgery, 321 patients were randomized and treated with SPRIX (ketorolac tromethamine nasal spray) or placebo administered every 6 hours and morphine administered via patient controlled analgesia on an as needed basis. Efficacy was demonstrated as a statistically significant greater reduction in the summed pain intensity difference over 48 hours in patients who received SPRIX (ketorolac tromethamine nasal spray) as compared to those receiving placebo. The clinical relevance of this is reflected in the finding that patients treated with SPRIX (ketorolac tromethamine nasal spray) required 26% less morphine over 48 hours than patients treated with placebo.

Last reviewed on RxList: 10/21/2011
This monograph has been modified to include the generic and brand name in many instances.

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