Sprix

• Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use [

  see Warnings and Precautions (

  5.1 Cardiovascular Thrombotic Events

  Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses.

  To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur.

  There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as ketorolac, increases the risk of serious gastrointestinal (GI) events [

  see Warnings and Precautions

  ].

  Status Post Coronary Artery Bypass Graft (CABG) Surgery

  Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [

  see Contraindications

  ].

  Post-MI Patients

  Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up.

  Avoid the use of SPRIX in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If SPRIX is used in patients with a recent MI, monitor patients for signs of cardiac ischemia.

  )

  ].
• SPRIX^® is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [

  see Contraindications (

  4 CONTRAINDICATIONS

  SPRIX is contraindicated in the following patients:

  • Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to ketorolac or any components of the drug product [
    see Warnings and Precautions
    ]
  • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [
    see Warnings and Precautions
    ]
  • In the setting of coronary artery bypass graft (CABG) surgery [
    see Warnings and Precautions
    ]
  • Use in patients with active peptic ulcer disease and in patients with recent gastrointestinal bleeding or perforation [
    see Warnings and Precautions
    ]
  • Use as a prophylactic analgesic before any major surgery [
    see Warnings and Precautions
    ]
  • Use in patients with advanced renal disease or patients at risk for renal failure due to volume depletion [
    see Warnings and Precautions
    ]
  • Use in labor and delivery. Through its prostaglandin synthesis inhibitory effect, ketorolac may adversely affect fetal circulation and inhibit uterine contractions, thus increasing the risk of uterine hemorrhage [
    see Use in Specific Populations
    ]
  • Use in patients with suspected or confirmed cerebrovascular bleeding, hemorrhagic diathesis, incomplete hemostasis, or those for whom hemostasis is critical [
    see Warnings and Precautions , Drug Interactions
    ]
  • Concomitant use with probenecid [
    see Drug Interactions
    ]
  • Concomitant use with pentoxifylline [
    see Drug Interactions
    ]

  • Known hypersensitivity to ketorolac or any components of the drug product
  • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs
  • In the setting of CABG surgery
  • Use in patients with active peptic ulcer disease or with recent GI bleeding or perforation
  • Use as a prophylactic analgesic before any major surgery
  • Use in patients with advanced renal disease or patients at risk for renal failure due to volume depletion
  • Use in patients with suspected or confirmed cerebrovascular bleeding, patients with hemorrhagic diathesis, incomplete hemostasis, and those at high risk of bleeding
  • Use in labor and delivery

  ) and Warnings and Precautions (

  5.1 Cardiovascular Thrombotic Events

  Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses.

  To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur.

  There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as ketorolac, increases the risk of serious gastrointestinal (GI) events [

  see Warnings and Precautions

  ].

  Status Post Coronary Artery Bypass Graft (CABG) Surgery

  Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [

  see Contraindications

  ].

  Post-MI Patients

  Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up.

  Avoid the use of SPRIX in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If SPRIX is used in patients with a recent MI, monitor patients for signs of cardiac ischemia.

  )

  ].

• NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events [

  see Warnings and Precautions (

  5.2 Gastrointestinal Bleeding, Ulceration, and Perforation

  SPRIX is contraindicated in patients with active peptic ulcers and/or GI bleeding and in patients with recent gastrointestinal bleeding or perforation [

  see Contraindications

  ].

  NSAIDs, including ketorolac, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3-6 months, and in about 2%-4% of patients treated for one year. However, even short-term NSAID therapy is not without risk.

  Risk Factors for GI Bleeding, Ulceration, and Perforation

  Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding.

  Strategies to Minimize the GI Risks in NSAID-treated patients:

  • Use the lowest effective dosage for the shortest possible duration.
  • Avoid administration of more than one NSAID at a time.
  • Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, consider alternate therapies other than NSAIDs. Do not use Sprix in those with active GI bleeding.
  • Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy.
  • If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue SPRIX until a serious GI adverse event is ruled out.
  • In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [
    see Drug Interactions
    ].
  • Use great care when giving SPRIX to patients with a history of inflammatory bowel disease (ulcerative colitis, Crohn’s disease) as their condition may be exacerbated.

  )

  ].

SPRIX is indicated in adult patients for the short term (up to 5 days) management of moderate to moderately severe pain that requires analgesia at the opioid level.

•       Sprix is not for use in pediatric patients less than 2 years of age.

• Use the lowest effective dosage for shortest duration consistent with individual patient treatment goals. (
  2.1 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

  ].
  )
• SPRIX is not an inhaled product. For adult patients < 65 years of age: 31.5 mg (one 15.75 mg spray in each nostril) every 6 to 8 hours. The maximum daily dose is 126 mg. (
  2.2 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.
  ,
  2.3 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).
  )
• For patients ≥ 65 years of age, renally impaired patients, and patients less than 50 kg (110 lbs): 15.75 mg (one 15.75 mg spray in only one nostril) every 6 to 8 hours. The maximum daily dose is 63 mg. (
  2.4 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

  ].
  )
• SPRIX nasal spray should be discarded within 24 hours of taking the first dose, even if the bottle still contains some medication. (
  2.5 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.
  )

SPRIX (ketorolac tromethamine) Nasal spray: 15.75 mg of ketorolac tromethamine in each 100 μL spray. Each 1.7 g bottle contains 8 sprays.