SPRIX (Page 6 of 7)

12.4 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. Subjects received a single dose of oxymetazoline nasal spray followed by a single dose (31.5 mg) of SPRIX 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 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 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.

Geriatric Patients: A single-dose study was conducted to compare the pharmacokinetics of SPRIX (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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility

Carcinogenesis: An 18-month study in mice with oral doses of ketorolac at 2 mg/kg/day (approximately 1.5 times the human systemic exposure at the recommended maximum IN dose of 31.5 mg qid, based on area-under-the-plasma-concentration curve [AUC]), and a 24-month study in rats at 5 mg/kg/day (approximately 0.8 times the human AUC) showed no evidence of tumorigenicity.

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

Impairment of fertility: Impairment of fertility did not occur in male or female rats at oral doses of 9 mg/kg (approximately 1.5 times the human AUC) and 16 mg/kg (approximately 2.7 times the human AUC) of ketorolac, respectively.

14 CLINICAL STUDIES

14.1 Postoperative Pain

The effect of SPRIX 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 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 as compared to those receiving placebo. The clinical relevance of this is reflected in the finding that patients treated with SPRIX 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 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 as compared to those receiving placebo. The clinical relevance of this is reflected in the finding that patients treated with SPRIX required 26% less morphine over 48 hours than patients treated with placebo.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Preservative-free SPRIX Nasal Spray is supplied in boxes containing 5 single-day nasal spray bottles (NDC 54868-6284-0). Each single-day nasal spray bottle contains a sufficient quantity of solution to deliver 8 sprays for a total of 126 mg of ketorolac tromethamine. Each spray delivers 15.75 mg of ketorolac tromethamine. The delivery system is designed to administer precisely metered doses of 100 μL per spray.

16.2 Storage

Protect from light and freezing. Store unopened SPRIX between 36°F and 46°F (2°C and 8°C). During use, keep containers of SPRIX Nasal Spray at controlled room temperature, between 59°F and 86°F (15°C and 30°C), out of direct sunlight. Bottles of SPRIX should be discarded within 24 hours of priming.

17 PATIENT COUNSELING INFORMATION

Instruct patients to read the NSAID Medication Guide that accompanies each prescription dispensed. Inform patients of the following information before initiating therapy with SPRIX.

Instruct all patients to read and closely follow the FDA-approved SPRIX Patient Instructions to ensure proper administration of SPRIX. When prescribing SPRIX, inform patients or their caregivers of the potential risks of ketorolac treatment, instruct patients to seek medical advice if they develop treatment-related adverse events, advise patients not to give SPRIX to other family members, and advise patients to discard any unused drug.

17.1 Limitations of Use

Instruct patients not to use SPRIX for more than 5 days. Use of SPRIX alone or in combination with any other ketorolac product for more than 5 days increases the risk for serious complications including GI bleeding and renal injury.

17.2 Gastrointestinal Effects

Ketorolac is a potent NSAID and, like other NSAIDs, may cause serious side effects, such as gastrointestinal bleeding, which may result in hospitalization and even fatal outcome. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, instruct patients to be alert for the signs and symptoms of ulcerations and bleeding, and to ask for medical advice when observing any indicative sign or symptom, including epigastric pain, dyspepsia, melena, and hematemesis. Instruct patients of the importance of this follow-up [see Contraindications (4), Warnings and Precautions (5.2)].

17.3 Renal Effects

SPRIX is eliminated by the kidneys. Advise patients to maintain adequate fluid intake and request medical advice if urine output decreases significantly [see Contraindications (4), Warnings and Precautions (5.4)].

17.4 Cardiovascular Effects

Ketorolac, like other NSAIDs, may cause serious CV events, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, advise patients to be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and that they should ask for medical advice when observing any indicative sign or symptoms. Inform patients of the importance of this follow-up [see Warnings and Precautions (5.6)].

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