ketorolac tromethamine
Dosage Form: nasal spray
FULL PRESCRIBING INFORMATION
Limitations of Use
SPRIX (ketorolac tromethamine), a nonsteroidal anti-inflammatory drug (NSAID), is indicated for short-term (up to 5 days in adults) management of moderate to moderately severe pain that requires analgesia at the opioid level. Do not exceed a total combined duration of use of SPRIX and other ketorolac formulations (IM/IV or oral) of 5 days [see Dosage and Administration, (2.1) and Warnings and Precautions (5.1)].
SPRIX is not indicated for use in pediatric patients and it is not indicated for minor or chronic painful conditions.
Gastrointestinal Risk
Ketorolac tromethamine, including SPRIX, can cause peptic ulcers, gastrointestinal bleeding and/or perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Therefore, SPRIX is contraindicated in patients with active peptic ulcer disease, in patients with recent gastrointestinal bleeding or perforation, and in patients with a history of peptic ulcer disease or gastrointestinal bleeding. Elderly patients are at greater risk for serious gastrointestinal events [see Contraindications (4), Warnings and Precautions (5.2)].
Bleeding Risk
Ketorolac tromethamine inhibits platelet function and is, therefore, contraindicated in patients with suspected or confirmed cerebrovascular bleeding, patients with hemorrhagic diathesis, incomplete hemostasis and those at high risk of bleeding [see Contraindications (4), Warnings and Precautions (5.3)].
Cardiovascular Risk
NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk [see Warnings and Precautions (5.6)].
Sprix Nasal Spray is contraindicated for treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4)].
Renal Risk
SPRIX is contraindicated in patients with advanced renal impairment and in patients at risk for renal failure due to volume depletion [see Contraindications (4), Warnings and Precautions (5.4)].
Indications and Usage for Sprix Nasal Spray
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 Nasal Spray Dosage and Administration
Limitations of Use
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 (5.1)]. Treat patients for the shortest duration possible, and do not exceed 5 days of therapy with SPRIX.
Do not use SPRIX concomitantly with other formulations of ketorolac or other NSAIDs [see Warnings and Precautions (5.1)].
SPRIX has not been shown to be safe and effective in pediatric patients 17 years of age and younger.
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 (5.2, 5.4)].
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.
Dosage Forms and Strengths
Nasal spray: 15.75 mg of ketorolac tromethamine in each 100 μL spray. Each 1.7 g bottle contains 8 sprays.
Contraindications
- Known hypersensitivity to ketorolac tromethamine [see Warnings and Precautions (5.5, 5.7, 5.11)]
- Use in patients with active peptic ulcer disease, in patients with recent gastrointestinal bleeding or perforation, and in patients with a history of peptic ulcer disease or gastrointestinal bleeding [see Warnings and Precautions (5.2)]
- Use in patients with a history of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs [see Warnings and Precautions (5.5, 5.7, 5.11)]
- Use as a prophylactic analgesic before any major surgery [see Warnings and Precautions (5.3)]
- Use during the perioperative period in the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.6)]
- Use in patients with advanced renal disease or patients at risk for renal failure due to volume depletion [see Warnings and Precautions (5.4,5.6)]
- 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 Warnings and Precautions (5.8), Use in Specific Populations (8.1, 8.2)]
- Use in nursing mothers because of the potential adverse effects of prostaglandin-inhibiting drugs on neonates
- Use in patients with suspected or confirmed cerebrovascular bleeding, hemorrhagic diathesis, incomplete hemostasis, or those for whom hemostasis is critical [see Warnings and Precautions (5.3), Drug Interactions (7.1, 7.10)]
- Known hypersensitivity to aspirin or to other NSAIDs [see Warnings and Precautions (5.5, 5.7, 5.11)]
- Known hypersensitivity to ethylenediamine tetraacetic acid (EDTA) [see Description (11)]
- Concomitant use with probenecid [see Drug Interactions (7.4)]
- Concomitant use with pentoxifylline [see Drug Interactions (7.10)]
Warnings and Precautions
Limitations of Use
The total duration of use of SPRIX alone or sequentially with other forms of ketorolac is not to exceed 5 days. SPRIX must not be used concomitantly with other forms of ketorolac or other NSAIDs [see Dosage and Administration (2.1)].
Gastrointestinal (GI) Effects - Risk of Ulceration, Bleeding, and Perforation
SPRIX is contraindicated in patients with previously documented peptic ulcers and/or GI bleeding [see Contraindications (4)]. Ketorolac tromethamine can cause serious GI adverse events including bleeding, ulceration, and perforation of the 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 ketorolac.
Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Minor upper GI problems, such as dyspepsia, are common and may also occur at any time during NSAID therapy. The incidence and severity of GI complications increases with increasing dose of, and duration of treatment with, ketorolac. Even short-term therapy is not without risk. In addition to past history of ulcer disease, other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients, and therefore, special care should be taken in treating this population.
To minimize the potential risk for an adverse GI event, the lowest effective dose should be used for the shortest possible duration. Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy, and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of SPRIX until a serious GI adverse event is ruled out. For high risk patients, consider alternate therapies that do not involve NSAIDs. 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.
Hematological Effects
Because prostaglandins play an important role in hemostasis and NSAIDs affect platelet aggregation as well, use caution with use of ketorolac tromethamine in patients who have coagulation disorders, and monitor these patients carefully. The effects of NSAIDs other than aspirin on platelet function are reversible. Patients on therapeutic doses of anticoagulants (e.g., heparin or dicumarol derivatives) have an increased risk of bleeding complications if given ketorolac tromethamine concurrently; therefore, administer such concomitant therapy only with extreme caution. The concurrent use of ketorolac tromethamine and therapy that affects hemostasis, including prophylactic low dose heparin (2500 to 5000 units q12h), warfarin and dextrans, has not been studied extensively, but may also be associated with an increased risk of bleeding. Until data from such studies are available, carefully weigh the benefits against the risks and use such concomitant therapy in these patients only with extreme caution. Monitor patients receiving therapy that affects hemostasis closely.
In clinical trials, serious adverse events related to bleeding were more common in patients treated with SPRIX than placebo. In clinical trials and in postmarketing experience with ketorolac IV and IM dosing, postoperative hematomas and other signs of wound bleeding have been reported in association with peri-operative use. Therefore, use SPRIX with caution in the postoperative setting when hemostasis is critical.
Anemia is sometimes seen in patients receiving NSAIDs. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Do not use SPRIX in patients for whom hemostasis is critical [see Contraindications (4), Drug Interactions (7.1, 7.2, 7.10)].
Renal Effects
Ketorolac and its metabolites are eliminated primarily by the kidneys. Patients with reduced creatinine clearance will have diminished clearance of the drug [see Clinical Pharmacology (12.4)]. SPRIX is contraindicated in patients with advanced renal impairment [see Contraindications (4)].
In patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and renal blood flow, which may precipitate overt renal decompensation. Decreased intravascular volume such as when oral intake is poor increases the risks of renal toxicity with NSAIDs. Therefore, patients treated with SPRIX should be adequately hydrated. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.
Use SPRIX with caution in patients with impaired renal function, heart failure, liver dysfunction, those taking diuretics or ACE inhibitors, and the elderly. Assess the risks and benefits prior to giving SPRIX to these patients, and follow these patients closely during SPRIX therapy. Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury such as interstitial nephritis and nephrotic syndrome.
Anaphylactoid Reactions
As with other NSAIDs, anaphylactoid reactions may occur in patients with or without a history of allergic reactions to aspirin or NSAIDs and in patients without known prior exposure to ketorolac. SPRIX should be discontinued immediately in patients with allergic reactions. SPRIX should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs [see Contraindications (4), Warnings and Precautions (5.11)]. Emergency help should be sought in cases where an anaphylactoid reaction occurs.
Cardiovascular Effects
- Cardiovascular (CV) 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 CV thrombotic events, myocardial infarction and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or 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 increases the risk of serious GI events. 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 [see Contraindications (4), Warnings and Precautions (5.2), Drug Interactions (7.2, 7.3, 7.7)].
- Hypertension
NSAIDs can lead to onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7.3)].
- Congestive Heart Failure and Edema
Fluid retention, edema, retention of NaCl, oliguria, and elevations of serum urea nitrogen and creatinine have been reported in clinical trials with ketorolac. Therefore, only use SPRIX very cautiously in patients with cardiac decompensation or similar conditions.
Skin Reactions
NSAIDs, including ketorolac, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin manifestations, and discontinue use of the drug at the first appearance of skin rash or any other sign of hypersensitivity [see Contraindications (4)].
Pregnancy
Starting at 30 weeks gestation, SPRIX can cause fetal harm when administered to a pregnant woman due to an increased risk of premature closure of the ductus arteriosus. If SPRIX is used at or after 30 weeks gestation, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)].
Hepatic Effects
Use SPRIX with caution in patients with impaired hepatic function or a history of liver disease. Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs, including ketorolac. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice, fulminant hepatitis, liver necrosis, and hepatic failure, some of them with fatal outcomes, have been reported [see Warnings and Precautions (5.4, 5.6),Clinical Pharmacology (12.4)].
Evaluate patients with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, for evidence of the development of a more severe hepatic reaction while on therapy with SPRIX. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue SPRIX.
Inflammation and Fever
The pharmacological activity of SPRIX in reducing inflammation and fever may diminish the utility of these diagnostic signs in detecting infections.
Preexisting Asthma
Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, do not administer SPRIX to patients with this form of aspirin sensitivity, and use with caution in patients with preexisting asthma [see Contraindications (4), Warnings and Precautions (5.5)].
Eye Exposure
Avoid contact of SPRIX with the eyes. If eye contact occurs, wash out the eye with water or saline, and consult a physician if irritation persists for more than an hour.
Adverse Reactions
The following serious adverse reactions are discussed elsewhere in the labeling:
- Gastrointestinal effects [see Boxed Warning and Warnings and Precautions (5.2)]
- Hemorrhage [see Boxed Warning and Warnings and Precautions (5.3)]
- Renal effects [see Boxed Warning and Warnings and Precautions (5.4)]
- Anaphylactoid reactions [see Warnings and Precautions (5.5)]
- Cardiovascular thrombotic events [see Boxed Warning and Warnings and Precautions (5.6)]
- Hypertension [see Warnings and Precautions (5.6)]
- Congestive heart failure and edema [see Warnings and Precautions (5.6)]
- Serious skin reactions [see Warnings and Precautions (5.7)]
- Hepatic effects [see Warnings and Precautions (5.9)]
The most frequently reported adverse reactions were related to local symptoms, i.e., nasal discomfort or irritation. These reactions were generally mild and transient in nature.
The most common drug-related adverse events leading to premature discontinuation were nasal discomfort or nasal pain (rhinalgia).
Experience from SPRIX Clinical Studies
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The data described below reflect exposure to SPRIX in patients enrolled in placebo-controlled efficacy studies of acute pain following major surgery. The studies enrolled 828 patients (183 men, 645 women) ranging from 18 years to over 75 years of age.
The patients in the postoperative pain studies had undergone major abdominal, orthopedic, gynecologic, or other surgery; 455 patients received SPRIX (31.5 mg) three or four times a day for up to 5 days, and 245 patients received placebo. Most patients were receiving concomitant opioids, primarily PCA morphine.
| SPRIX (N=455) | Placebo (N= 245) | |
| Nasal discomfort | 15% | 2% |
| Rhinalgia | 13% | <1% |
| Lacrimation increased | 5% | 0% |
| Throat irritation | 4% | <1% |
| Oliguria | 3% | 1% |
| Rash | 3% | <1% |
| Bradycardia | 2% | <1% |
| Urine output decreased | 2% | <1% |
| ALT and/or AST increased | 2% | 1% |
| Hypertension | 2% | 1% |
| Rhinitis | 2% | <1% |
In controlled clinical trials in major surgery, primarily knee and hip replacements and abdominal hysterectomies, seven patients (N=455, 1.5%) treated with SPRIX experienced serious adverse events of bleeding (4 patients) or hematoma (3 patients) at the operative site versus one patient (N=245, 0.4%) treated with placebo (hematoma). Six of the seven patients treated with SPRIX underwent a surgical procedure and/or blood transfusion and the placebo patient subsequently required a blood transfusion.
Adverse Reactions Reported in Clinical Trials with Other Dosage Forms of Ketorolac or Other NSAIDs
Adverse reaction rates increase with higher doses of ketorolac. It is necessary to remain alert for the severe complications of treatment with ketorolac, such as GI ulceration, bleeding, and perforation, postoperative bleeding, acute renal failure, anaphylactic and anaphylactoid reactions, and liver failure. These complications can be serious in certain patients for whom ketorolac is indicated, especially when the drug is used inappropriately.
In patients taking ketorolac or other NSAIDs in clinical trials, the most frequently reported adverse experiences in approximately 1% to 10% of patients are:
Gastrointestinal (GI) experiences including:
*Incidence greater than 10% | ||
| abdominal pain | constipation/diarrhea | dyspepsia |
| flatulence | GI fullness | GI ulcers (gastric/duodenal) |
| gross bleeding/perforation | heartburn | nausea* |
| stomatitis | vomiting | |
| Other experiences: | ||
| abnormal renal function | anemia | dizziness |
| drowsiness | edema | elevated liver enzymes |
| headache* | hypertension | increased bleeding time |
| injection site pain | pruritus | purpura |
| rash | tinnitus | sweating |
Additional adverse experiences reported occasionally (<1% in patients taking ketorolac or other NSAIDs in clinical trials) include:
Body as a Whole: fever, infection, sepsis
Cardiovascular System: congestive heart failure, palpitation, pallor, tachycardia, syncope
Digestive System: anorexia, dry mouth, eructation, esophagitis, excessive thirst, gastritis, glossitis, hematemesis, hepatitis, increased appetite, jaundice, melena, rectal bleeding
Hemic and Lymphatic: ecchymosis, eosinophilia, epistaxis, leukopenia, thrombocytopenia
Metabolic and Nutritional: weight change
Nervous System: abnormal dreams, abnormal thinking, anxiety, asthenia, confusion, depression, euphoria, extrapyramidal symptoms, hallucinations, hyperkinesis, inability to concentrate, insomnia, nervousness, paresthesia, somnolence, stupor, tremors, vertigo, malaise
Respiratory: asthma, dyspnea, pulmonary edema, rhinitis
Special Senses: abnormal taste, abnormal vision, blurred vision, hearing loss
Urogenital: cystitis, dysuria, hematuria, increased urinary frequency, interstitial nephritis, oliguria/polyuria, proteinuria, renal failure, urinary retention
Adverse Reactions from Postmarketing Experience with Other Dosage Forms of Ketorolac or Other NSAIDs
Other observed reactions (reported from postmarketing experience in patients taking ketorolac or other NSAIDs) are:
Body as a Whole: angioedema, death, hypersensitivity reactions such as anaphylaxis, anaphylactoid reaction, laryngeal edema, tongue edema, myalgia
Cardiovascular: arrhythmia, bradycardia, chest pain, flushing, hypotension, myocardial infarction, vasculitis
Dermatologic: exfoliative dermatitis, erythema multiforme, Lyell's syndrome, bullous reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis
Gastrointestinal: acute pancreatitis, liver failure, ulcerative stomatitis, exacerbation of inflammatory bowel disease (ulcerative colitis, Crohn's disease)
Hemic and Lymphatic: agranulocytosis, aplastic anemia, hemolytic anemia, lymphadenopathy, pancytopenia, postoperative wound hemorrhage (rarely requiring blood transfusion)
Metabolic and Nutritional: hyperglycemia, hyperkalemia, hyponatremia
Nervous System: aseptic meningitis, convulsions, coma, psychosis
Respiratory: bronchospasm, respiratory depression, pneumonia
Special Senses: conjunctivitis
Urogenital: flank pain with or without hematuria and/or azotemia, hemolytic uremic syndrome
Drug Interactions
Ketorolac is highly bound to human plasma protein (mean 99.2%). There is no evidence in animal or human studies that ketorolac induces or inhibits hepatic enzymes capable of metabolizing itself or other drugs.
Warfarin, Digoxin, Salicylate, and Heparin
The in vitro binding of warfarin to plasma proteins is only slightly reduced by ketorolac (99.5% control vs. 99.3%) when ketorolac plasma concentrations reach 5 to 10 mcg/mL. Ketorolac does not alter digoxin protein binding. In vitro studies indicate that, at therapeutic concentrations of salicylate (300 mcg/mL), the binding of ketorolac was reduced from approximately 99.2% to 97.5%, representing a potential twofold increase in unbound ketorolac plasma levels. Therapeutic concentrations of digoxin, warfarin, ibuprofen, naproxen, piroxicam, acetaminophen, phenytoin, and tolbutamide did not alter ketorolac protein binding.
The effects of warfarin and NSAIDs, in general, on GI bleeding are synergistic, such that the users of both drugs together have a risk of serious GI bleeding higher than the users of either drug alone.
Aspirin
When ketorolac is administered with aspirin, its protein binding is reduced, although the clearance of free ketorolac is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of SPRIX and aspirin is not generally recommended because of the potential of increased adverse effects [see Warnings and Precautions (5.2, 5.5, 5.11)].
Diuretics
Clinical studies, as well as postmarketing observations, have shown that ketorolac can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with SPRIX, observe the patient closely for signs of renal failure [see Warnings and Precautions (5.4, 5.6)], as well as to assure diuretic efficacy.
Probenecid
Concomitant administration of oral ketorolac and probenecid resulted in decreased clearance and volume of distribution of ketorolac and significant increases in ketorolac plasma levels (total AUC increased approximately threefold from 5.4 to 17.8 mcg/h/mL), and terminal half-life increased approximately twofold from 6.6 to 15.1 hours. Therefore, concomitant use of SPRIX and probenecid is contraindicated.
Lithium
NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when SPRIX and lithium are administered concurrently, observe patients carefully for signs of lithium toxicity.
Methotrexate
NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Use caution when SPRIX is administered concomitantly with methotrexate.
ACE Inhibitors/Angiotensin II Receptor Antagonists
Concomitant use of ACE inhibitors and/or angiotensin II receptor antagonists may increase the risk of renal impairment, particularly in volume-depleted patients. Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE inhibitors and/or angiotensin II receptor antagonists. Consider this interaction in patients taking SPRIX concomitantly with ACE inhibitors and/or angiotensin II receptor antagonists [see Warnings and Precautions (5.4, 5.6)].
Antiepileptic Drugs
Sporadic cases of seizures have been reported during concomitant use of ketorolac and antiepileptic drugs (phenytoin, carbamazepine).
Psychoactive Drugs
Hallucinations have been reported when ketorolac was used in patients taking psychoactive drugs (fluoxetine, thiothixene, alprazolam).
Pentoxifylline
When ketorolac is administered concurrently with pentoxifylline, there is an increased tendency to bleeding. Therefore, concomitant use of SPRIX and Pentoxifylline is contraindicated [see Contraindications (4) and Warnings and Precautions (5.3)].
Nondepolarizing Muscle Relaxants
In postmarketing experience there have been reports of a possible interaction between ketorolac and nondepolarizing muscle relaxants that resulted in apnea. The concurrent use of ketorolac with muscle relaxants has not been formally studied.
Selective Serotonin Reuptake Inhibitors (SSRIs)
There is an increased risk of gastrointestinal bleeding when selective serotonin reuptake inhibitors (SSRIs) are combined with NSAIDs. Use caution when SPRIX is administered concomitantly with SSRIs.
Fluticasone
The rate and extent of absorption of ketorolac from SPRIX administration (31.5 mg dose) were assessed in subjects with allergic rhinitis before and after the administration of a single daily dose of 200 mcg (as 2 x 50 mcg in each nostril) of fluticasone propionate nasal spray for 7 consecutive days. There was no effect on the pharmacokinetic characteristics of SPRIX that can be considered clinically significant [see Clinical Pharmacology (12.4)].
Oxymetazoline
The rate and extent of absorption of ketorolac from SPRIX administration were assessed in subjects with allergic rhinitis before and 30 min after a single dose (3 sprays in each nostril) of oxymetazoline hydrochloride nasal spray. There was no effect on the pharmacokinetic characteristics of SPRIX that can be considered clinically significant [see Clinical Pharmacology (12.4)].
USE IN SPECIFIC POPULATIONS
Pregnancy
Teratogenic Effects: Pregnancy Category C prior to 30 weeks gestation; Category D starting at 30 weeks gestation.
SPRIX can cause fetal harm when administered to a pregnant woman. Human data demonstrate that use of NSAIDs at or after 30 weeks gestation increases the risk of premature closure of the ductus arteriosus. If SPRIX is used at or after 30 weeks gestation, the patient should be apprised of the potential hazard to a fetus. There are no adequate, well-controlled studies in pregnant women. Prior to 30 weeks gestation, SPRIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
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 (1.7 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.
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.
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.
Pediatric Use
The safety and effectiveness of ketorolac in pediatric patients 17 years of age and younger have not been established.
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.
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.
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.
Sprix Nasal Spray 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:
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.
Sprix Nasal Spray - Clinical Pharmacology
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.
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.
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.)
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 trom
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