Dosing and uses of Indocin, Tivorbex (indomethacin)
Adult dosage forms and strengths
capsule
- 20mg (Tivorbex)
- 25mg
- 40mg (Tivorbex)
- 50mg
capsule, extended-release
- 75mg
powder for injection
- 1mg
oral suspension
- 25mg/5mL
suppository
- 50mg
Inflammatory/Rheumatoid Disorders
Immediate release: 25-50 mg PO/PR q8-12hr; not to exceed 200 mg/day
Extended release: 75-150 mg/day PO in single daily dose or divided q12hr; not to exceed 150 mg/day
Bursitis/Tendinitis
Immediate-release: 75-150 mg/day PO/PR divided q6-8hr
Extended-release: 75-150 mg/day PO in single daily dose or divided q12hr
Acute Gouty Arthritis
50 mg PO/PR q8hr for 3-5 days; reduced once pain is under controL
Nephrogenic Diabetes Insipidus
2 mg/kg/day PO divided q8hr
Pain
Tivorbex: Indicated for mild-to-moderate acute pain
20 mg PO TID or 40 mg PO BID/TId
Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals
Pediatric dosage forms and strengths
capsule
- 25mg
- 50mg
capsule, extended-release
- 75mg
powder for injection
- 1mg
oral suspension
- 25mg/5mL
suppository
- 50mg
Inflammatory/Rheumatoid Disorders
<2 years: Safety and efficacy not established
2-14 years: 1-2 mg/kg/day PO divided q6-12hr; not to exceed 4 mg/kg/day or 150-200 mg/day
>14 years: 25-50 mg IR PO/PR q8-12hr; not to exceed 200 mg/day; 75-150 mg/day ER PO in single daily dose or divided q12hr; not to exceed 150 mg/day
Closure of Ductus Arteriosus
Neonates <28 days: 0.2 mg/kg IV over 20-30 minutes initially, THEN 2 subsequent doses, depending on postnatal age
Doses 2 and 3 (<48 hours): 0.1 mg/kg IV over 20-30 minutes at 12 and 24hr intervals
Doses 2 and 3 (2-7 days): 0.2 mg/kg IV over 20-30 minutes at 12 and 24hr intervals
Doses 2 and 3 (>7 days): 0.25 mg/kg IV over 20-30 minutes at 12 and 24hr intervals
After dose 3 (infants <1.5 kg): 0.1-0.2 mg/kg IV over 20-30 minutes once daily for 3-5 days
Geriatric dosage forms and strengths
Monitor renal function (drug is renally excreted); decreased renal function more likely in elderly
Indomethacin is a nonsteroidal anti-inflammatory drug (NSAID) producing mostly central nervous system (CNS) adverse reactions in elderly
Lowest dose and frequency recommended
Indocin, Tivorbex (indomethacin) adverse (side) effects
>10%
Transient renal insufficiency (40%)
Jaundice (≤15%)
Elevated liver function test values (≤15%)
Headache (12%)
1-10%
Dizziness (3-9%)
Dyspepsia (3-9%)
Epigastric pain (3-9%)
Indigestion (3-9%)
Nausea (3-9%)
Symptomatic upper GI ulcers, gross bleeding/perforation (4% of patients treated for 1 year; 1% of patients treated for 3-6 months).
Abnormal pain/cramps/distress (<3%)
Constipation (1-3%)
Depression (1-3%)
Diarrhea (1-3%)
Fatigue (1-3%)
Somnolence (1-3%)
Tinnitus (1-3%)
Vertigo (1-3%)
<1%
Acute interstitial nephritis with hematuria/proteinuria
Acute respiratory distress
Agranulocytosis
Angioedema
Aplastic anemia
Asthma
Bone marrow depression
Congestive heart failure (CHF)
Hemolytic anemia
Leukopenia
Macular and morbilliform eruptions
Pulmonary edema
Thrombocytopenia
Thrombocytopenic purpura
Ulcerative stomatitis
Urticaria
Warnings
Black box warnings
Cardiovascular risk
- NSAIDs may increase risk of serious cardiovascular thrombotic events, myocardial infarction (MI), and stroke, which can be fatal
- Risk may increase with duration of use
- Patients with existing cardiovascular disease or risk factors for such disease may be at greater risk
- NSAIDs are contraindicated for perioperative pain in setting of coronary artery bypass graft (CABG) surgery
Gastrointestinal risk
- NSAIDs increase risk of serious GI adverse events, including bleeding, ulceration, and gastric or intestinal perforation, which can be fatal
- GI adverse events may occur at any time during use and without warning symptoms
- Elderly patients are at greater risk for serious GI events
Contraindications
Absolute
- Hypersensitivity
- Aspirin allergy
- History of aspirin triad
- Preoperative pain associated with CABG surgery
Relative
- Bleeding disorder
- Duodenal/gastric/peptic ulcer
- Stomatitis
- Ulcerative colitis
- Upper GI disease
- Late pregnancy (may cause premature closure of ductus arteriosus)
Neonates
- Renal impairment
- Untreated infection
- Necrotizing enterocolitis
- Active bleeding (GI bleeding or intracranial hemorrhage)
- Thrombocytopenia
- Congenital heart disease where patent ductus arteriosus is necessary
Cautions
Use caution in patients with history of bronchospasm, cardiac disease, CHF, hypertension, hepatic or renal impairment
Long-term administration of NSAIDs may result in renal papillary necrosis and other renal injury; patients at greatest risk include elderly individuals, those with impaired renal function, hypovolemia, heart failure, liver dysfunction, or salt depletion, and those taking diuretics, angiotensin-converting enzyme (ACE) inhibitors, or angiotensin receptor blockers
Prolonged use may cause corneal deposits and retinal disturbances; discontinue if visual changes observed
Risk of aggravation of psychiatric disturbances, epilepsy, fluid retention, or Parkinson disease
Reduction in cerebral blood flow associated with rapid IV infusion
Serious skin adverse events (eg, exfoliative dermatitis, Stevens-Johnson Syndrome, and toxic epidermal necrolysis) reported; discontinue is symptoms occur
Heart Failure(HF) risk
- NSAIDS have the potential to trigger HF by prostaglandin inhibition that leads to sodium and water retention, increased systemic vascular resistance, and blunted response to diuretics
- NSAIDS should be avoided or withdrawn whenever possible
- AHA/ACC Heart Failure Guidelines; Circulation. 2016; 134
Pregnancy and lactation
Pregnancy category: C
Quebec Pregnancy Registry identified 4705 women who had spontaneous abortions by 20 weeks' gestation; each case was matched to 10 control subjects (n=47,050) who had not had spontaneous abortions; exposure to nonaspirin NSAIDs during pregnancy was documented in approximately 7.5% of cases of spontaneous abortions and approximately 2.6% of controls
Lactation: Drug enters breast milk; use not recommended (American Academy of Pediatrics committee states that drug is compatible with nursing)
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Indocin, Tivorbex (indomethacin)
Mechanism of action
Inhibits synthesis of prostaglandins in body tissues by inhibiting at least 2 cyclo-oxygenase (COX) isoenzymes, COX-1 and COX-2
May inhibit chemotaxis, alter lymphocyte activity, decrease proinflammatory cytokine activity, and inhibit neutrophil aggregation; these effects may contribute to anti-inflammatory activity
Absorption
Bioavailability: ~100%
Onset: 30 min
Duration: 4-6 hr
Peak plasma time: 0.5-2 hr; 1.67 hr (Tivorbex)
Peak plasma concentration: 1.2 mcg/mL (20 mg PO); 0.8-2.5 mcg/mL (25 mg PO); 2.4 mcg/mL (40 mg PO); 2.5-4 mcg/mL (50 mg PO)
Tivorbex
- When taken under fasted conditions, a 20% lower dose of indomethacin in Tivorbex 40 mg capsules resulted in a 21% lower mean systemic exposure (AUCinf) and an equivalent mean peak concentration (Cmax) compared to 50 mg indomethacin IR capsules
- The median time to reach peak concentrations (Tmax) was 1.67 hr and 2.02 hr for Tivorbex capsules and indomethacin IR capsules, respectively
- Food causes a significant decrease in the rate but not the overall extent of systemic absorption; 46% lower Cmax, 9% lower AUCinf, and 1.33 hr delayed Tmax (1.67 hr during fasted vs 3 hr during fed)
Distribution
Protein bound: 99%
Vd: 0.34-1.57 L/kg
Metabolism
Metabolized in liver
Metabolites: Desmethyl, desbenzoyl, desmethyl-desbenzoyL
Enzymes inhibited: COX-1, COX-2
Elimination
Half-life: 4.5 hr (prolonged in neonates)
Excretion: Urine (60%), feces (>33%)
Administration
Oral Administration
Take with food or 8-12 oz of water to avoid gastrointestinal (GI) effects
Tivorbex: Food causes a significant decrease in the rate but not the overall extent of systemic absorption and 1.33 hr delayed Tmax (1.67 hr during fasted vs 3 hr during fed)
IV Incompatibilities
Y-site: Amino acid injection, calcium gluconate, cimetidine, dobutamine, dopamine, gentamicin, levofloxacin, tobramycin, tolazoline
IV Preparation
Reconstitute just before administration
Discard any unused portion
Do not use preservative-containing diluents for reconstitution
IV Administration
Infuse over 20-30 min at concentration of 0.5-1 mg/mL in preservative-free SWI or Ns
Avoid bolus administration or infusion via umbilical catheter into vessels near superior mesenteric artery; this may cause vasoconstriction and can compromise blood flow to intestines
Do not administer intra-arterially
IV Storage
Store below 30°C (86°F)
Protect from light
