indomethacin (Rx)

Brand and Other Names:Indocin, Indocin SR, more...Tivorbex
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Dosing & Uses

AdultPediatricGeriatric

Dosage Forms & 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

Dosage Forms & 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

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

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Interactions

Interaction Checker

and indomethacin

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            Adverse 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

            Postmarketing Reports

            Pancreatitis

            Drug reaction with eosinophilia and systemic symptoms (DRESS)

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            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

            • History of hypersensitivity (anaphylactic or serious skin reactions)
            • History of urticaria, asthma, or allergic type reactions with aspirin
            • Preoperative pain associated with CABG surgery
            • History of proctitis or recent rectal bleeding (suppositories)

            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

            Platelet adhesion and aggregation may decrease; may prolong bleeding time; monitor closely patients receiving anticoagulants; patients on long-term NSAID therapy should be monitored for anemia; agranulocytosis, aplastic anemia, thrombocytopenia reported (rarely)

            Transaminase elevations reported with use; patients with abnormal liver function test should be monitored closely; discontinue immediately if signs or symptoms of liver disease develop

            NASAID use my increase risk of hyperkalemia, particularly in the elderly, renal disease, diabetics, when administered concomitantly with agents that can induce hyperkalemia

            May increase risk of meningitis with patients with systemic lupus erythematosus and mixed connective tissue disorders being a at higher risk

            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

            Drug reaction with eosinophilia and systemic symptoms

            • Drug Reaction reported in patients taking NSAIDs; some of these events have been fatal or life-threatening; DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling
            • Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis; sometimes symptoms of DRESS may resemble an acute viral infection
            • Eosinophilia is often present; because this disorder is variable in its presentation, other organ systems not noted here may be involved
            • Early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident; if such signs or symptoms are present, discontinue therapy and evaluate the patient immediately
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            Pregnancy & Lactation

            Pregnancy

            Use of NSAIDs, including indomethacin capsules, can cause premature closure of fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment; because of these risks, limit dose and duration of therapy to between about 20 and 30 weeks of gestation, and avoid use at about 30 weeks of gestation and later in pregnancy

            Premature closure of fetal ductus arteriosus use of NSAIDs, including indomethacin capsules, at about 30 weeks gestation or later in pregnancy increases risk of premature closure of fetal ductus arteriosus; avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy

            Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment

            Data from observational studies regarding other potential embryofetal risks of NSAID use in women in first or second trimesters of pregnancy are inconclusive

            If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit use to lowest effective dose and shortest duration possible; if treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios; if oligohydramnios occurs, discontinue therapy and follow up according to clinical practice

            There are no studies on effects during labor or delivery; in animal studies, NSAIDS, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth

            Animal data

            • Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization
            • In animal reproduction studies retarded fetal ossification was observed with administration of indomethacin to mice and rats during organogenesis at doses 0.1 and 0.2 times, respectively, the maximum recommended human dose (MRHD, 200 mg)
            • In published studies in pregnant mice, indomethacin produced maternal toxicity and death, increased fetal resorptions, and fetal malformations at 0.1 times the MRHD; when rat and mice dams were dosed during last three days of gestation, indomethacin produced neuronal necrosis in the offspring at 0.1 and 0.05 times the MRHD, respectively
            • In animal studies, administration of prostaglandin synthesis inhibitors such as indomethacin, resulted in increased pre- and post-implantation loss
            • Prostaglandins also have been shown to have an important role in fetal kidney development; in published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses

            Reproductive potential

            • Based on mechanism of action, the use of prostaglandin-mediated NSAIDs, including indomethacin capsules, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women
            • Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation
            • Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation; consider withdrawal of NSAIDs, including, in women who have difficulties conceiving or who are undergoing investigation of infertility

            Lactation

            Based on available published clinical data, drug may be present in human milk; the developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for therapy and any potential adverse effects on breastfed infant from drug or from underlying maternal condition

            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.

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            Pharmacology

            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%)

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            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

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            Images

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            Formulary

            FormularyPatient Discounts

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            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
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            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.