SPRIX (Page 5 of 7)

8.2 Labor and Delivery

The effects of SPRIX on labor and delivery in pregnant women are unknown. In rat studies, maternal exposure to NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, increased the incidence of dystocia and delayed parturition, and decreased pup survival.

8.3 Nursing Mothers

Ketorolac is excreted in human milk. Ten nursing mothers received 10 mg of oral ketorolac, four times a day, for two days. In four women, ketorolac was undetectable in milk (assay limit 5 ng/mL). In the remaining six women, ketorolac concentrations in milk ranged from 5.2 to 7.9 ng/mL. Based on these concentrations, the estimated maximum infant daily dose of ketorolac from breast milk is 1.185 mcg/kg/day. Exercise caution when administering SPRIX to a nursing woman.

8.4 Pediatric Use

The safety and effectiveness of ketorolac in pediatric patients 17 years of age and younger have not been established.

8.5 Geriatric Use (≥ 65 years of age)

Exercise caution when treating the elderly (65 years and older) with SPRIX. Carefully consider the potential benefits and risks of SPRIX and other treatment options before deciding to use SPRIX. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals [see Dosage and Administration (2.3), Warnings and Precautions (5.2), Clinical Pharmacology (12.4)]. After observing the response to initial therapy with SPRIX, then adjust the dose and frequency to suit an individual patient’s needs.

9 DRUG ABUSE AND DEPENDENCE

Ketorolac does not bind to opiate receptors. A study to evaluate the sedative and addictive potential of ketorolac in volunteers showed no withdrawal symptoms upon cessation of dosing with ketorolac 30 mg IM 4 times daily for 5 days. A single-dose clinical study of IM ketorolac showed no significant adverse effects on psychomotor measurements, including reaction time, computerized driving skills, ataxia, and sedation.

10 OVERDOSAGE

There has been no experience with overdosage of SPRIX. In controlled overdosage studies with IM ketorolac injection, daily doses of 360 mg given for five days (approximately 3 times the maximum daily dose of SPRIX) caused abdominal pain and peptic ulcers, which healed after discontinuation of dosing. Single overdoses of ketorolac tromethamine have been variously associated with abdominal pain, nausea, vomiting, hyperventilation, peptic ulcers and/or erosive gastritis, and renal dysfunction.

Symptoms and Signs

Symptoms following acute NSAID overdose are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression, and coma may occur, but are rare.

Treatment

Manage patients using symptomatic and supportive care following an NSAID overdose. There are no specific antidotes. Activated charcoal (60 g to 100 g in adults, 1 g/kg to 2 g/kg in children) may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large oral overdose (5 to 10 times the usual dose). Forced diuresis, alkalization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.

11 DESCRIPTION

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), and the structural formula is:

Structural Formula

The molecular weight of ketorolac tromethamine is 376.41. Ketorolac tromethamine is highly water-soluble, allowing its formulation in an aqueous nasal spray product at pH 7.2.

SPRIX is available as an intranasal spray product containing the active ingredient (ketorolac tromethamine) and the excipients edetate disodium (EDTA), monobasic potassium phosphate, sodium hydroxide, and water for injection.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

SPRIX contains ketorolac tromethamine, a nonsteroidal anti-inflammatory drug (NSAID). Ketorolac is an analgesic that inhibits the enzyme cyclooxygenase (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 6 mg and 12 mg. Ketorolac possesses no sedative or anxiolytic properties, and has no effect on gut motility.

12.2 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, has anti-inflammatory, analgesic, and anti-pyretic effects. Studies directly comparing the analgesic effects of SPRIX and opioids have not been conducted.

12.3 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

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.

Ketorolac Tromethamine Cmax (SD)ng/mL tmax (range)hours AUC 0-∞ (SD)ng•h/mL T½ (SD)hours
30 mg IM (1.0 mL of a 30 mg/mL solution) 2382.2(432.7) 0.75(0.25-1.03) 11152.8(4260.1) 4.80(1.18)
31.5 mg IN (SPRIX) (2 x 100 μL of a 15% w/w solution) 1805.8(882.8) 0.75(0.50-2.00) 7477.3(3654.4) 5.24(1.33)
15 mg IM (0.5 mL of a 30 mg/mL solution) 1163.4(279.9) 0.75(0.25-1.50) 5196.3(2076.7) 5.00(1.72)

Absorption: In a study in which SPRIX (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 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.

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