Sprix

General Dosing Instructions

Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions ].

The total duration of use of SPRIX alone or sequentially with other formulations of ketorolac (IM/IV or oral) must not exceed 5 days because of the potential for increasing the frequency and severity of adverse reactions associated with the recommended doses [see Warnings and Precautions ].

Do not use SPRIX concomitantly with other formulations of ketorolac or other NSAIDs [see Warnings and Precautions ].

Administration

SPRIX is not an inhaled product. Do not inhale when administering this product.

Instruct patients to administer as follows:

1. First hold the finger flange with fingers, and remove the clear plastic cover with opposite hand; then remove the blue plastic safety clip. Keep the clear plastic cover; and throw away the blue plastic safety clip.

2. Before using the bottle for the FIRST time, activate the pump. To activate the pump, hold the bottle at arm’s length away from the body with index finger and middle finger resting on the top of the finger flange and thumb supporting the base.

Press down evenly and release the pump 5 times. Patient may not see a spray the first few times he/she presses down.

The bottle is now ready to use. There is no need to activate the pump again if more doses are used from the bottle.

3. It’s important to get the medication to the correct place in the nose so it will be most effective.

    - Blow nose gently to clear nostrils.
    - Sit up straight or stand.  Tilt head slightly forward.
    - Insert the tip of the container into your right nostril.  
    - Point the container away from the center of your nose. 
    - Hold your breath and spray once into your right nostril, pressing down evenly on both sides.
    - Immediately after administration, resume breathing through mouth to reduce expelling the product.  Also pinch the nose to help retain the spray if it starts to drip.

    If only one spray per dose is prescribed, administration is complete; skip to Step 5 below.

4. If a dose of 2 sprays is prescribed, repeat the process in Step 3 for the left nostril. Again, be sure to point the spray away from the center of nose. Spray once into the left nostril.

5. Replace the clear plastic cover and place the bottle in a cool, dry location out of direct sunlight, such as inside a medication cabinet. Keep out of reach of children.

Adult Patients < 65 Years of Age

The recommended dose is 31.5 mg SPRIX (one 15.75 mg spray in each nostril) every 6 to 8 hours. The maximum daily dose is 126 mg (four doses).

Reduced Doses for Special Populations

For patients ≥ 65 years of age, renally impaired patients, and adult patients less than 50 kg (110 lbs), the recommended dose is 15.75 mg SPRIX (one 15.75 mg spray in only one nostril) every 6 to 8 hours. The maximum daily dose is 63 mg (four doses) [see Warnings and Precautions ].

Discard Used SPRIX Bottle after 24 Hours

Do not use any single SPRIX bottle for more than one day as it will not deliver the intended dose after 24 hours. Therefore, the bottle must be discarded no more than 24 hours after taking the first dose, even if the bottle still contains some liquid.

Pregnancy

Risk Summary
Use of NSAIDs, including SPRIX, can cause premature closure of the fetal ductus arteriosus and fetal renal
dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks,
limit dose and duration of SPRIX use between about 20 and 30 weeks of gestation, and avoid SPRIX use at about
30 weeks of gestation and later in pregnancy (see Clinical Considerations, Data).

      Premature Closure of Fetal Ductus Arteriosus

      Use of NSAIDs, including SPRIX, at about 30 weeks gestation or later in pregnancy increases the risk of
      premature closure of the fetal ductus arteriosus.

      Oligohydramnios/Neonatal Renal Impairment

      Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal
      renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment.

Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or
second trimesters of pregnancy are inconclusive. In animal reproduction studies in rabbits and rats tested at 0.6
and 1.5 times the human systemic exposure, respectively, at the recommended maximum IN dose of 31.5 mg four
times a day, there was no evidence of teratogenicity or other adverse developmental outcomes (see Data). Based
on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability,
blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis
inhibitors such as ketorolac, resulted in increased pre- and post-implantation loss. Prostaglandins also have been
shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis
inhibitors have been reported to impair kidney development when administered at clinically relevant doses.

The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown.
All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general
population, the estimated background risk of major birth defects and miscarriage in clinically recognized
pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

      Fetal/Neonatal Adverse Reactions

      Premature Closure of Fetal Ductus Arteriosus:

      Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs,
      including SPRIX, can cause premature closure of the fetal ductus arteriosus (see Data).

      Oligohydramnios/Neonatal Renal Impairment:

      If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest
      effective dose and shortest duration possible. If SPRIX treatment extends beyond 48 hours, consider
      monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue SPRIX and
      follow up according to clinical practice (see Data).

Data

      Human Data

      Premature Closure of Fetal Ductus Arteriosus:

      Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy
      may cause premature closure of the fetal ductus arteriosus.

      Oligohydramnios/Neonatal Renal Impairment:

      Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or
      later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases,
      neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment,
      although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In
      many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the
      drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal
      dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal
      dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis.

      Methodological limitations of these postmarketing studies and reports include lack of a control group;
      limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other
      medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and
      neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes
      involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant
      exposed to NSAIDs through maternal use is uncertain.

      Animal Data

      Reproduction studies have been performed during organogenesis using daily oral doses of ketorolac tromethamine at
      3.6 mg/kg (0.6 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]) in rabbits and at 10 mg/kg (1.5 times the human AUC) in rats.
      These studies did not reveal evidence of teratogenicity or other adverse developmental outcomes. However, because
      animal dosing was limited by maternal toxicity, these studies do not adequately assess ketorolac’s potential to cause
      adverse developmental outcomes in humans.

Lactation

Risk Summary

Ketorolac is excreted in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for SPRIX and any potential adverse effects on the breastfed infant from the SPRIX or from the underlying maternal condition.

Clinical Considerations

Exercise caution when administering SPRIX to a nursing woman. Available information has not shown any specific adverse events in nursing infants; however, instruct patients to contact their infant’s health care provider if they note any adverse events.

Data

Limited data from one published study involving ten nursing mothers 2-6 days postpartum showed low levels of ketorolac in breast milk. Levels were undetectable (less than 5 ng/mL) in 4 of the patients. After a single administration of 10 mg ketorolac, the maximum milk concentration observed was 7.3 ng/mL, and the maximum milk to plasma ratio was 0.037. After 1 day of dosing (10 mg every 6 hours), the maximum milk concentration was 7.9 ng/mL, and the maximum milk-to-plasma ratio was 0.025. Assuming a daily intake of 400-1000 mL of human milk per day and a maternal body weight of 60 kg, the calculated maximum daily infant exposure was 0.00263 mg/kg/day, which is 0.4% of the maternal weight adjusted dose.

Females and Males of Reproductive Potential

Infertility

Females

Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including SPRIX, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including SPRIX, in women who have difficulties conceiving or who are undergoing investigation of infertility.

Pediatric Use

Sprix is not for use in pediatric patients less than 2 years of age. The safety and effectiveness of ketorolac in pediatric patients 17 years of age and younger have not been established.

Geriatric Use

Exercise caution when treating the elderly (65 years and older) with SPRIX. Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Dosage and Administration , Warnings and Precautions , Clinical Pharmacology ]. After observing the response to initial therapy with SPRIX, adjust the dose and frequency to suit an individual patient’s needs.

Ketorolac and its metabolites are known to be substantially excreted by the kidneys, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, use caution in this patient population, and it may be useful to monitor renal function [see Clinical Pharmacology ].