Pharmacokinetics, Safety, and Efficacy of SPRIX in 12 to 17 Year Old Patients vs. Adult Patients Undergoing Open Surgical Procedures

This is a study of intranasal (IN) ketorolac tromethamine (SPRIX) in pediatric subjects age
12-17 years vs. adults ages 18-64 years undergoing open surgical procedures that are expected
to result in at least a moderate level of pain (i.e., 40 or above on a 0-100 Visual Analog
Scale (VAS) in which 0 is no pain and 100 is the worst pain imaginable). Following surgery
subjects will receive their 1st dose of SPRIX, if and when pain reaches a VAS of 40 or more,
followed by SPRIX administration every 6 hours. Blood samples for PK assessment will then be
collected for PK assessment pre-dose, at 0.25, 0.5, 0.75, 1, 2, and 4 hours after the first
dose, at 6 hours (immediately before the 2nd dose), and immediately before each of the next
several subsequent q6h doses up to the dose to be administered on the morning of
post-operative day 2. Blood samples will then be collected at 1, 2, 4, 6, 8, 12, and 24 hours
after receiving the morning dose on day 2 (i.e., last blood sample for PK will be collected
on the morning of post-operative day 3). Pain intensity (PI) will be assessed using the 0-100
VAS at 0.5, 1, 2, 4, and 6 hours post dose, at 2 hours after the 2nd dose, and then
immediately prior to each dose at 12, 18, and 24 hours from baseline. Patients may elect to
continue taking SPRIX for a total of 5 days with daily assessments of pain intensity using a
diary. A final follow-up phone interview will be conducted 14 days after the final dose of
study drug. Thus, each subject's study participation will consist of a screening visit, a
treatment/assessment period of up to 5 days, and a follow-up interview.

Inclusion Criteria:

- Male of female patients age 12-64 years.

- Undergoing an open surgical procedure expected to result in at least moderate pain (at
least 40 on 0-100 VAS).

- Body mass index (BMI)≤ 95th percentile for age.

- Surgical procedures that would allow the subject to likely remain in the hospital
until the morning of post-operative day 3 (to complete PK sample collection).

- Willing and able to complete the study procedures and pain scales and to communicate
meaningfully with the study personnel (with parental assistance if pediatric).

- In generally good health and capable of undergoing surgery.

- Females at risk of pregnancy were to use an acceptable form of birth control and have
a negative serum or urine pregnancy test.

- Willing to refrain from use of non-study analgesics for the duration of the study,
from the day of surgery up to post-operative day 4.

- Assents to participation (if pediatric) and his/her parent or guardian is willing and
able to sign the informed consent approved by the IRB. Consents to participation and
willing and able to sign the informed consent approved by the IRB if adult.

Exclusion Criteria:

- Surgical procedure performed exclusively by laparoscopy.

- Known allergy or sensitivity to ketorolac, ethylene diamine tetraacetic acid (EDTA),
or any nonsteroidal anti-inflammatory drug (NSAID).

- Prior nasal-septal injury or surgery.

- History of peptic ulcer, gastro-esophageal reflux, or gastrointestinal bleeding.

- History of advanced renal impairment or a risk for renal failure due to volume
depletion.

- Clinically significant (in the Investigator's opinion) laboratory test value outside
the normal range.

- Use of either (a) oxycodone at a dose of 30 mg/day or more or (b) an equivalent dose
of another opioid analgesic for a total of more than half of the days during the
preceding month.

- The patient requires regular use (daily use in at least 25 days per month) in the 3
months prior to surgery of NSAIDs, COX2 inhibitors, tramadol, or acetaminophen at a
daily dose of more than 2 g for the management of pain.

- Contraindication to the use of morphine, general anesthetics, bupivacaine,
ropivacaine, lidocaine, other local anesthetics, muscle relaxants, hydrocodone,
ondansetron, or acetaminophen (eg, significant history of allergic reactions or
intolerance to these or related substances).

- Known bleeding diathesis or other disorder or current use of agents affecting
coagulation. Deep venous thrombosis prophylaxis of the surgeon's choice is permitted
postoperatively.

- Current use of CNS active drugs such as benzodiazepines, tricyclic antidepressants, or
SSRIs for pain. These drugs are permitted for non-pain indications if the dose has
been stable for at least 30 days. The use of lorazepam and other sleep medications,
except those containing analgesic properties, are permitted.

- Current diabetes mellitus and HbA1C > 9.5 or a history of prolonged uncontrolled
diabetes.

- Use of an antihypertensive agent or diabetic regimen at a dose that has not been
stable for at least 30 days.

- Any medical condition that in the investigator's opinion could adversely impact the
patient's participation or safety, conduct of the study, or interfere with the pain
assessments, including active infection.

- History of drug, prescription medicine, or alcohol abuse that would interfere with the
subject's safety or the assessments of efficacy in this trial, in the judgement of the
investigator.

- History of nasal mucosal damage or active seasonal allergies, nasal congestion, or
upper respiratory tract infection sufficient to interfere with intranasal drug
delivery.

- Administration of an investigational product within 3 months prior to the first dose
of study drug, or scheduled to receive an investigational product, while participating
in the study.

- Use of Toradol (ketorolac tromethamine) in any formulation within the past 30 days
prior to study entry and throughout study participation.