KETOROLAC TROMETHAMINE AND PHENYLEPHRINE HYDROCHLORIDE
Clinical safety rating: avoid
ACE inhibitors and ARBs may have diminished antihypertensive effect Increases risk of serious bleeding and renal impairment.
Ketorolac is a nonsteroidal anti-inflammatory drug (NSAID) that inhibits cyclooxygenase (COX-1 and COX-2), reducing prostaglandin synthesis. Phenylephrine is a selective alpha-1 adrenergic receptor agonist, causing vasoconstriction.
| Metabolism | Ketorolac: Hepatic metabolism primarily via CYP2C9 and conjugation to inactive metabolites. Phenylephrine: Metabolized by monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) in the liver and extrahepatic tissues. |
| Excretion | Ketorolac: ~92% renal (60% as unchanged drug, 32% as metabolites), 6% fecal. Phenylephrine: primarily renal as metabolites (sulfate conjugates) with <1% unchanged. |
| Half-life | Ketorolac: 2.4-8.6 hours (mean 5.3 hours) in young adults; prolonged in elderly (up to 13.9 hours) and renal impairment. Phenylephrine: 2-3 hours. |
| Protein binding | Ketorolac: 99.4% bound to albumin. Phenylephrine: ~95% bound to albumin and α-1-acid glycoprotein. |
| Volume of Distribution | Ketorolac: 0.15-0.3 L/kg (rapid and extensive tissue distribution). Phenylephrine: 0.5-1.0 L/kg (primarily in extracellular fluid). |
| Bioavailability | Ketorolac: oral ~80-100%, IM ~100%, ophthalmic: negligible systemic (≤1%). Phenylephrine: ophthalmic: negligible systemic; oral: 38% (first-pass effect). |
| Onset of Action | Ophthalmic: within 30 minutes for mydriasis; systemic ketorolac: IV 1-30 min, IM 10 min, oral 30-60 min. |
| Duration of Action | Ophthalmic: mydriasis persists 2-4 hours; ketorolac: analgesic effect 4-6 hours (IM/IV) to 6-8 hours (oral). |
| Molecular Weight | Ketorolac tromethamine: 376.41 Da; Phenylephrine hydrochloride: 203.67 Da |
Ophthalmic: 1 drop of the combination (ketorolac tromethamine 0.45% and phenylephrine hydrochloride 1%) into the operative eye three times daily, beginning 1 day prior to surgery and continuing on the day of surgery and for 2 weeks postoperatively.
| Dosage form | SOLUTION |
| Renal impairment | No specific dose adjustment guidelines available for ophthalmic use. Systemic absorption is minimal; however, caution is advised in patients with severe renal impairment (CrCl <30 mL/min) due to potential for increased systemic exposure. |
| Liver impairment | No specific dose adjustment guidelines available for ophthalmic use. Caution in severe hepatic impairment (Child-Pugh class C) due to potential for increased systemic exposure, though absorption is minimal. |
| Pediatric use | Safety and efficacy in pediatric patients have not been established. Not recommended for use in children. |
| Geriatric use | No specific dose adjustment required; use same dose as for younger adults. Monitor for adverse effects due to potential age-related renal or hepatic impairment. |
| 1st trimester | Avoid: Ketorolac is contraindicated due to risk of oligohydramnios and premature ductus arteriosus closure; phenylephrine may reduce uterine blood flow. |
| 2nd trimester | Avoid: Same risks as t1; ketorolac associated with fetal nephrotoxicity and premature ductal closure. |
| 3rd trimester | Contraindicated: Ketorolac may cause premature closure of ductus arteriosus and oligohydramnios; phenylephrine may induce uterine contractions. |
Clinical note
ACE inhibitors and ARBs may have diminished antihypertensive effect Increases risk of serious bleeding and renal impairment.
| FDA category | Contraindicated |
| Placental transfer | Both components cross the placenta. Ketorolac is extensively bound to plasma proteins (99%) but crosses to fetal circulation; phenylephrine crosses placenta and may cause fetal hypoxia. |
■ FDA Black Box Warning
Ketorolac: Increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke; increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation. Phenylephrine: No black box warning.
| Common Effects | Skin peeling Application site reactions burning irritation itching and redness Nausea Vomiting Abdominal pain Increased liver enzymes Application site redness Itching Diarrhea Abnormal liver function tests Adrenal insufficiency Application site burning |
| Serious Effects |
Hypersensitivity to ketorolac, phenylephrine, or any componentActive peptic ulcer disease or gastrointestinal bleedingHistory of asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDsSevere renal impairment (CrCl <30 mL/min) or at risk for renal failureAdvanced hepatic disease or coagulopathyConcurrent use of probenecid, pentoxifylline, or any NSAID (including aspirin)During labor and delivery (risk of uterine atony and fetal harm)Patients undergoing coronary artery bypass graft (CABG) surgeryUncontrolled hypertension or hypertensive crisis (from phenylephrine)
| Precautions |
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| Breastfeeding | Ketorolac is excreted into breast milk in low amounts but due to risk of adverse effects in infants (e.g., bleeding, renal impairment), use is not recommended. Phenylephrine is excreted in breast milk in minimal amounts but may cause irritability and sleep disturbances in infants. Avoid breastfeeding during treatment and for at least 24 hours after last dose. |
| Lactation Rating | L5 - Contraindicated |
| Teratogenic Risk | First trimester: Ketorolac, like other NSAIDs, is associated with increased risk of spontaneous abortion and cardiac defects. Avoid use. Second trimester: Use only if clearly needed; may cause oligohydramnios. Third trimester: Contraindicated due to risk of premature closure of ductus arteriosus and pulmonary hypertension in the neonate. Phenylephrine is a sympathomimetic; animal studies show fetal abnormalities at high doses, but human data are limited. Avoid in first trimester due to potential teratogenicity; in second and third trimesters, use only if benefit outweighs risk, as it may reduce uteroplacental blood flow. |
| Fetal Monitoring | Monitor maternal blood pressure and fetal heart rate during administration. Assess for signs of oligohydramnios with prolonged ketorolac use; perform ultrasound if indicated. Monitor neonatal status for ductus arteriosus patency if used near term. |
| Fertility Effects | Ketorolac may impair female fertility by inhibiting prostaglandin synthesis, affecting ovulation and implantation; reversible upon discontinuation. Phenylephrine effects on fertility are not well studied; high doses may impair spermatogenesis in animal models. |
| Bleeding risk (due to inhibition of platelet aggregation), ocular infection risk with topical use, delayed wound healing, hypersensitivity reactions, renal toxicity, hypertension, and rebound congestion with prolonged use. |
| Food/Dietary | No specific food interactions for ophthalmic use. However, avoid alcohol and NSAIDs (e.g., ibuprofen) as they may increase risk of gastrointestinal bleeding due to ketorolac's systemic absorption. |
| Clinical Pearls | Ketorolac tromethamine is a nonsteroidal anti-inflammatory drug (NSAID) used for its analgesic effects; phenylephrine hydrochloride is an alpha-1 adrenergic receptor agonist used as a mydriatic and decongestant. In ophthalmic formulations, this combination is used to prevent intraoperative miosis during cataract surgery. Systemic absorption of ketorolac can cause renal impairment, especially in elderly or volume-depleted patients. Phenylephrine may cause transient hypertension; monitor blood pressure in patients with cardiovascular disease. Contraindicated in patients with bleeding diathesis or concurrent NSAID use. |
| Patient Advice | This medication is used to prevent pupil constriction during eye surgery. · Do not touch the dropper tip to any surface, including your eye, to avoid contamination. · You may experience temporary blurred vision after administration; avoid driving until vision clears. · Report any eye pain, redness, or changes in vision to your doctor. · Inform your doctor if you have a history of bleeding problems, asthma, or heart disease. · Avoid taking aspirin or other NSAIDs while using this medication unless directed by your doctor. · If you miss a dose, use it as soon as possible unless it is almost time for your next dose. |