KETOROLAC TROMETHAMINE INJECTION USP
SPL UNCLASSIFIED SECTION
| WARNINGKetorolac tromethamine, a nonsteroidal anti-inflammatory drug (NSAID), is indicated for the short-term (up to 5 days in adults), management of moderately severe acute pain that requires analgesia at the opioid level. Oral ketorolac tromethamine is indicated only as continuation treatment following IV or IM dosing of ketorolac tromethamine, if necessary. The total combined duration of use of oral ketorolac tromethamine and ketorolac tromethamine injection should not exceed 5 days.Ketorolac tromethamine is not indicated for use in pediatric patients and it is NOT indicated for minor or chronic painful conditions. Increasing the dose of ketorolac tromethamine beyond the label recommendations will not provide better efficacy but will increase the risk of developing serious adverse events.GASTROINTESTINAL RISKKetorolac tromethamine 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, ketorolac tromethamine 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 WARNINGS).CARDIOVASCULAR RISKNSAIDs 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 CLINICAL TRIALS).Ketorolac tromethamine is CONTRAINDICATED for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).RENAL RISKKetorolac tromethamine is CONTRAINDICATED in patients with advanced renal impairment and in patients at risk for renal failure due to volume depletion (see WARNINGS).RISK OF BLEEDINGKetorolac 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 WARNINGS and PRECAUTIONS).Ketorolac tromethamine is CONTRAINDICATED as prophylactic analgesic before any major surgery.HYPERSENSITIVITYHypersensitivity reactions, ranging from bronchospasm to anaphylactic shock, have occurred and appropriate counteractive measures must be available when administering the first dose of ketorolac tromethamine injection (see CONTRAINDICATIONS and WARNINGS). Ketorolac tromethamine is CONTRAINDICATED in patients with previously demonstrated hypersensitivity to ketorolac tromethamine or allergic manifestations to aspirin or other nonsteroidal antiinflammatory drugs (NSAIDs).INTRATHECAL OR EPIDURAL ADMINISTRATIONKetorolac tromethamine is CONTRAINDICATED for intrathecal or epidural administration due to its alcohol content.RISK DURING LABOR AND DELIVERYThe use of ketorolac tromethamine in labor and delivery is CONTRAINDICATED because it may adversely affect fetal circulation and inhibit uterine contractions. The use of ketorolac tromethamine is contraindicated in nursing mothers because of the potential adverse effects of prostaglandin-inhibiting drugs on neonates.CONCOMITANT USE WITH NSAIDsKetorolac tromethamine is CONTRAINDICATED in patients currently receiving aspirin or NSAIDs because of the cumulative risk of inducing serious NSAID-related side effects.SPECIAL POPULATIONSDosage should be adjusted for patients 65 years or older, for patients under 50 kg (110 lbs.) of body weight (see DOSAGE AND ADMINISTRATION) and for patients with moderately elevated serum creatinine (see WARNINGS). Doses of ketorolac tromethamine injection are not to exceed 60 mg (total dose per day) in these patients.DOSAGE AND ADMINISTRATIONKetorolac Tromethamine TabletsKetorolac tromethamine tablets are indicated only as continuation therapy to ketorolac tromethamine injection, and the combined duration of use of ketorolac tromethamine injection and ketorolac tromethamine tablets is not to exceed 5 (five) days, because of the increased risk of serious adverse events.The recommended total daily dose of ketorolac tromethamine tablets (maximum 40 mg) is significantly lower than for ketorolac tromethamine injection (maximum 120 mg) (see DOSAGE AND ADMINISTRATION). |
DESCRIPTION
CLINICAL PHARMACOLOGY
Pharmacodynamics
Pharmacokinetics
| Bioavailability (extent) | 100% | |||||
| Tmax1 (min) | 44 ± 34 | 33 ± 21§ | 44 ± 29 | 33 ± 21§ | 1.1 ± 0.7§ | 2.9 ± 1.8 |
| Cmax2 (mcg/mL) [single-dose] | 0.87 ± 0.22 | 1.14 ± 0.32§ | 2.42 ± 0.68 | 4.55 ± 1.27§ | 2.47 ± 0.51§ | 4.65 ± 0.96 |
| Cmax (mcg/mL) [steady state qid] | 1.05 ± 0.26§ | 1.56 ± 0.44§ | 3.11 ± 0.87§ | N/A|| | 3.09 ± 1.17§ | 6.85 ± 2.61 |
| Cmin3 (mcg/mL) [steady state qid] | 0.29 ± 0.07§ | 0.47 ± 0.13§ | 0.93 ± 0.26§ | 0.61 ± 0.21§ | 1.04 ± 0.35 | |
| Cavg4 (mcg/mL) [steady state qid] | 0.59 ± 0.20§ | 0.94 ± 0.29§ | 1.88 ± 0.59§ | 1.09 ± 0.30§ | 2.17 ± 0.59 | |
| Vβ5 (L/kg) | 0.175 ± 0.039 | 0.210 ± 0.044 |
| Normal SubjectsIM (n=54)mean age=32, range=18–60Oral (n=77)mean age=32, range=20–60 | 0.023(0.010–0.046) | 0.025(0.013–0.050) | 5.3(3.5–9.2) | 5.3(2.4–9.0) |
| Healthy Elderly SubjectsIM (n=13), Oral (n=12)mean age=72, range=65–78 | 0.019(0.013–0.034) | 0.024(0.018–0.034) | 7.0(4.7–8.6) | 6.1(4.3–7.6) |
| Patients with Hepatic DysfunctionIM and Oral (n=7)mean age=51, range=43–64 | 0.029(0.013–0.066) | 0.033(0.019–0.051) | 5.4(2.2–6.9) | 4.5(1.6–7.6) |
| Patients with Renal ImpairmentIM (n=25), Oral (n=9)serum creatinine=1.9–5.0 mg/dL,mean age (IM)=54, range=35–71mean age (Oral)=57, range=39–70 | 0.015(0.005–0.043) | 0.016(0.007–0.052) | 10.3(5.9–19.2) | 10.8(3.4–18.9) |
| Renal Dialysis PatientsIM and Oral (n=9)mean age=40, range=27–63 | 0.016(0.003–0.036) | — | 13.6(8.0–39.1) | — |
Clinical Studies
INDICATIONS AND USAGE
Acute Pain in Adult Patients
CONTRAINDICATIONS
WARNINGS
PRECAUTIONS
General
Hepatic Effects
Hematological Effects
Preexisting Asthma
Information for patients
- Ketorolac tromethamine, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS: Cardiovascular Effects).
- Ketorolac tromethamine, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS: Gastrointestinal Effects- Risk of Ulceration, Bleeding, and Perforation).
- Ketorolac tromethamine, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible.
- Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians.
- Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy.
- Patients should be informed of the signs of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS).
- In late pregnancy, as with other NSAIDs, ketorolac tromethamine should be avoided because it will cause premature closure of the ductus arteriosus.
Laboratory tests
Drug interactions
Carcinogenesis, mutagenesis, impairment of fertility
Pregnancy
Nursing mothers
Pediatric use
ADVERSE REACTIONS
Postmarketing Surveillance Study
| Table 3 Incidence of Clinically Serious G.I. Bleeding as Related to Age, Total Daily Dose, and History of G.I. Perforation, Ulcer, Bleeding (PUB) after up to 5 Days of Treatment with Ketorolac Tromethamine Injection | ||||
| A. Patients without History of PUB | ||||
| Age of Patients | Total Daily Dose of Ketorolac Tromethamine Injection | |||
| ≤60 mg | >60 to 90 mg | >90 to 120 mg | >120 mg | |
| <65 years of age | 0.4% | 0.4% | 0.9% | 4.6% |
| ≥65 years of age | 1.2% | 2.8% | 2.2% | 7.7% |
| B. Patients with History of PUB | ||||
| Age of Patients | Total Daily Dose of Ketorolac Tromethamine Injection | |||
| ≤60 mg | >60 to 90 mg | >90 to 120 mg | >120 mg | |
| <65 years of age | 2.1% | 4.6% | 7.8% | 15.4% |
| ≥65 years of age | 4.7% | 3.7% | 2.8% | 25.0% |
OVERDOSAGE
DOSAGE AND ADMINISTRATION
- Patients < 65 years of age: One dose of 60 mg.
- Patients ≥ 65 years of age, renally impaired and/or less than 50 kg (110 lbs) of body weight: One dose of 30 mg.
HOW SUPPLIED
INFORMATION FOR PATIENTS SECTION
| Serious side effects include: heart attackstrokehigh blood pressureheart failure from body swelling (fluid retention)kidney problems including kidney failurebleeding and ulcers in the stomach and intestinelow red blood cells (anemia)life-threatening skin reactionslife-threatening allergic reactionsliver problems including liver failureasthma attacks in people who have asthma | Other side effects include:stomach painconstipationdiarrheagasheartburnnauseavomitingdizziness |
| Celecoxib | Celebrex |
| Diclofenac | Cataflam, Voltaren, Arthrotec (combined with misoprostol) |
| Diflunisal | Dolobid |
| Etodolac | Lodine, Lodine XL |
| Fenoprofen | Nalfon, Nalfon 200 |
| Flurbirofen | Ansaid |
| Ibuprofen | Motrin, Tab-Profen, Vicoprofen* (combined with hydrocodone), Combunox (combined with oxycodone) |
| Indomethacin | Indocin, Indocin SR, Indo-Lemmon, Indomethagan |
| Ketoprofen | Oruvail |
| Ketorolac | Toradol |
| Mefenamic Acid | Ponstel |
| Meloxicam | Mobic |
| Nabumetone | Relafen |
| Naproxen | Naprosyn, Anaprox, Anaprox DS, EC-Naproxyn, Naprelan, Naprapac (copackaged with lansoprazole) |
| Oxaprozin | Daypro |
| Piroxicam | Feldene |
| Sulindac | Clinoril |
| Tolmetin | Tolectin, Tolectin DS, Tolectin 600 |
- with longer use of NSAID medicines
- in people who have heart disease