"Nov. 2, 2012 -- Safety steps taken in the wake of the fungal meningitis outbreak have worsened drug shortages, raising questions about whether the U.S. must choose between the safety and the availability of crucial medicines.
The following serious adverse reactions are discussed elsewhere in the labeling:
- Gastrointestinal effects [see BOXED WARNING and WARNINGS AND PRECAUTIONS]
- Hemorrhage [see BOXED WARNING and WARNINGS AND PRECAUTIONS]
- Renal effects [see BOXED WARNING and WARNINGS AND PRECAUTIONS]
- Anaphylactoid reactions [see WARNINGS AND PRECAUTIONS]
- Cardiovascular thrombotic events [see BOXED WARNING and WARNINGS AND PRECAUTIONS]
- Hypertension [see WARNINGS AND PRECAUTIONS]
- Congestive heart failure and edema [see WARNINGS AND PRECAUTIONS]
- Serious skin reactions [see WARNINGS AND PRECAUTIONS]
- Hepatic effects [see WARNINGS AND PRECAUTIONS]
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.
Table 1: Post-operative Patients with Adverse Reactions Observed
at a rate of 2% or more and at least twice the incidence of the placebo group.
|Throat irritation||4%||< 1%|
|Urine output decreased||2%||< 1%|
|ALT and/or AST increased||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:
|flatulence||GI fullness||GI ulcers (gastric /duodenal)|
|gross bleeding /perforation||heartburn||nausea*|
|abnormal renal function||anemia||dizziness|
|drowsiness||edema||elevated liver enzymes|
|headache*||hypertension||increased bleeding time|
|injection site pain||pruritus||purpura|
*Incidence greater than 10%
Additional adverse experiences reported occasionally ( < 1% in patients taking ketorolac or other NSAIDs in clinical trials) include:
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
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:
Respiratory: bronchospasm, respiratory depression, pneumonia
Special Senses: conjunctivitis
Read the Sprix (ketorolac tromethamine nasal spray) Side Effects Center for a complete guide to possible side effects »
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.
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].
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], as well as to assure diuretic efficacy.
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.
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.
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].
Sporadic cases of seizures have been reported during concomitant use of ketorolac and antiepileptic drugs (phenytoin, carbamazepine).
Hallucinations have been reported when ketorolac was used in patients taking psychoactive drugs (fluoxetine, thiothixene, alprazolam).
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 and WARNINGS AND PRECAUTIONS].
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.
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].
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].
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.
Last reviewed on RxList: 10/21/2011
This monograph has been modified to include the generic and brand name in many instances.
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