Indomethacin

Indomethacin is an Analgesic/ anti inflammatory belonging to Non-Steroidal anti-inflammatory Drug

Indomethacin is used in the treatment of Acute pain, Ankylosing spondylitis, Bursitis/tendinopathy of the shoulder, Gout, treatment, Osteoarthritis, Patent ductus arteriosus, Rheumatoid arthritis. It is also used to treat Pericarditis, acute or recurrent; Prevention of pancreatitis post-endoscopic retrograde cholangiopancreatography; Tocolysis.

Indomethacin is Readily and almost completely absorbed from the gastrointestinal tract. Food may decrease absorption. It is Distributed into synovial fluid and CNS. Crosses the placenta; enters breast milk (small amounts). Volume of distribution: 0.34-1.57 L/kg. Plasma protein binding: Approx 99% and get Metabolised in the liver into glucuronide conjugate form and metabolites (desmethyl, desbenzoyl, and desmethyl-desbenzoyl), and their glucuronides. Undergoes extensive enterohepatic circulation. It is Mainly excreted via urine (60%; 26% as unchanged drug and glucuronide conjugates); faeces (33%, mainly as metabolites; 1.5% as unchanged drug). Terminal elimination half-life: 2.6-11.2 hours.

The onset of action of Indomethacin was about 30 minutes.

The Duration of action of Indomethacin was about 4-6 hours.

Indomethacin shows common side effects like headache. Dizziness. Vomiting. Diarrhea. Constipation. Ringing in the ears.

Indomethacin is available in Capsules, Oral solution, Suspension, Suppository

Indomethacin is available in India, Germany, Canada, France, USA.

Indomethacin, an NSAID, has analgesic, antipyretic and anti-inflammatory properties. It reduces prostaglandin synthesis by inhibiting cyclooxygenase (COX)-1 and 2. It also stimulates the secretion of β-endorphins by the pituitary hypothalamus, reduces the level of endogenous pyrogens and affects the thermoregulation centre in the hypothalamus.

Indomethacin is available in the form of Capsules, Oral solution, Suspension, Suppository, Powder.

Indomethacin is used in the treatment of Acute pain, Ankylosing spondylitis, Bursitis/tendinopathy of the shoulder, Gout, treatment, Osteoarthritis, Patent ductus arteriosus, Rheumatoid arthritis. It is also used to treat Pericarditis, acute or recurrent; Prevention of pancreatitis post-endoscopic retrograde cholangiopancreatography; Tocolysis.

Indometacin is an indole acetic derivative with analgesic, antipyretic, and anti-inflammatory effects. It reversibly inhibits cyclooxygenase-1 and -2 (COX-1 and -2) isoenzymes, thereby reducing the synthesis of prostaglandins in body tissues.

Indomethacin is approved for use in the following clinical indications

• Acute pain, mild to moderate: Treatment of mild to moderate acute pain in adults.

• Ankylosing spondylitis: Treatment of moderate to severe ankylosing spondylitis.

• Bursitis/tendinopathy of the shoulder: Treatment of acute painful bursitis and/or tendinopathy of the shoulder.

• Gout, treatment (acute flares) (generic IR Capsules, Oral solution, Suspension, Suppository, oral suspension, rectal suppositories): Treatment of acute gout flares.

• Osteoarthritis: Treatment of moderate to severe osteoarthritis.

• Patent ductus arteriosus (IV only): To close a hemodynamically significant patent ductus arteriosus in premature infants weighing between 500 and 1,750 g when 48 hours’ usual medical management (eg, fluid restriction, diuretics, digitalis, respiratory support) is ineffective.

• Rheumatoid arthritis: Treatment of moderate to severe rheumatoid arthritis, including acute flares of chronic disease.

Although not approved there have been certain off label uses documented for Indomethacin which include:

Pericarditis, acute or recurrent; Prevention of pancreatitis post-endoscopic retrograde cholangiopancreatography; Tocolysis.

• Acute pain (mild to moderate): Oral: 20 mg 3 times daily or 40 mg 2 or 3 times daily.

Ankylosing spondylosis, osteoarthritis, or rheumatoid arthritis: Note: Use lowest effective dose for the shortest duration possible.

• Oral , rectal: 25 mg 2 to 3 times daily; if well tolerated, increase daily dosage by 25 or 50 mg at weekly intervals until satisfactory response or a total daily dose of 150 to 200 mg/day (maximum dose: 200 mg/day) is reached. In patients with arthritis and persistent night pain and/or morning stiffness may give the larger portion (up to maximum of 100 mg) of the total daily dose at bedtime.
• Oral (ER Capsules, Oral solution, Suspension, Suppository): Initial: 75 mg once daily, may increase to 75 mg twice daily (maximum dose: 150 mg/day).
• Bursitis/tendinopathy of the shoulder: Oral , rectal: Initial dose: 75 to 150 mg/day in 3 to 4 divided doses or 1 to 2 divided doses for extended release; usual treatment is 7 to 14 days; discontinue after signs/symptoms of inflammation have been controlled for several days.
• Gout, treatment (acute flares):
• Note: Some experts reserve use for patients who are not candidates for intra-articular glucocorticoids or when intra-articular glucocorticoid administration is not feasible .

• Oral (generic IR Capsules, Oral solution, Suspension, Suppository, suspension), rectal (suppository): 50 mg 3 times daily within 24 to 48 hours of flare onset; may reduce dose as symptoms improve; discontinue 2 to 3 days after resolution of clinical signs; usual duration: 5 to 7 days .

• Pericarditis, acute or recurrent (off-label use):

• Note: In patients with an indication for aspirin (eg, coronary artery disease), aspirin is preferred over other nonsteroidal anti-inflammatory drugs (NSAIDs). Non-aspirin NSAIDs should be avoided in patients with pericarditis secondary to acute myocardial infarction given lack of benefit and potential harm .

• Oral: Initial: 25 to 50 mg every 8 hours until resolution of symptoms for at least 24 hours and normalization of inflammatory biomarkers (eg, C-reactive protein) if monitored; initial therapy typically lasts for ≥1 to 2 weeks. Gradually taper by decreasing each dose by 25 mg every 1 to 2 weeks (eg, if initially 50 mg every 8 hours, taper to 25 mg every 8 hours, then discontinue); some clinicians may taper more slowly before discontinuing therapy (eg, if inititally 25 mg every 8 hours, taper to 25 mg every 12 hours, then 25 mg once daily, then discontinue); during taper, ensure patient remains asymptomatic and inflammatory biomarkers remain normal (if monitored). Use in combination with colchicine. In patients at risk of NSAID-related GI toxicity, prophylaxis (generally with a proton pump inhibitor) is recommended .

• Prevention of pancreatitis post-endoscopic retrograde cholangiopancreatography (off-label use): Rectal: 100 mg immediately before or after endoscopic retrograde cholangiopancreatography (Ref).

• Tocolysis (off-label use): Oral, rectal: Initial: 50 to 100 mg orally or rectally, followed by 25 mg every 4 to 6 hours orally in women between 24 and 32 weeks' gestation. Duration of treatment is generally limited to 48 to 72 hours

Indomethacin is available in the dosage strength of 20 mg ,25 mg, 50 mg, 75 mg, 1 mg, 50 mg , 25 mg/ 5 ml.

Indomethacin is available in the form of Capsules, Oral solution, Suspension, Suppository, powder.

Dosage Adjustment in Kidney Patient

• Oral/rectal: There are no dosage adjustments provided in the manufacturer's labeling; not recommended in patients with advanced kidney disease.
• Injection: If anuria or marked oliguria (urinary output <0.6 mL/kg/hour) evident at the scheduled time of the second or third dose, hold dose until kidney function returns to normal. Use is contraindicated in neonates with significant kidney impairment.
• KDIGO 2012 guidelines provide the following recommendations for NSAIDs:
• eGFR 30 to <60 mL/minute/1.73 m²: Temporarily discontinue in patients with intercurrent disease that increases risk of acute kidney injury.
• eGFR <30 mL/minute/1.73 m²: Avoid use.

Dosage Adjustment for Pediatric Patients:-

• Inflammatory/rheumatoid disorders: Note: Use lowest effective dose for the shortest duration:

Immediate release: Children ≥2 years and Adolescents (limited data available in ages <15 years): Oral (immediate release): Initial: 1 to 2 mg/kg/day in 3 to 4 divided doses; usual initial adult dose range: 50 to 75 mg/day; maximum daily dose: 4 mg/kg/day or 200 mg/day, whichever is less.

Extended release: Adolescents ≥15 years: Oral: Initial: 75 mg once daily, may increase to 75 mg twice daily; maximum daily dose: 150 mg/day

• Gout, acute flares (alternative agent): Adolescents ≥15 years: Immediate release (Capsules, Oral solution, Suspension, Suppository, suspension, suppository): Oral, Rectal: 50 mg 3 times daily; once pain is tolerable, rapidly reduce until completely discontinued; pain relief begins 2 to 4 hours after initiating therapy with tenderness and warmth beginning to subside in 24 to 36 hours and swelling gradually resolving in 3 to 5 days.

Take after eating and with a full glass of water to decrease gastric upset.

Indomethacin is contraindicated in patients with:

Hypersensitivity (eg, anaphylactic reactions, serious skin reactions) to indomethacin or any component of the formulation; use in the setting of coronary artery bypass graft (CABG) surgery; history of asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAID agents; patients with a history of proctitis or recent rectal bleeding (suppositories).

Neonates (IV only): Necrotizing enterocolitis (proven or suspected); significant kidney impairment; active bleeding (including intracranial hemorrhage and gastrointestinal bleeding), thrombocytopenia, coagulation defects; untreated infection (proven or suspected); congenital heart disease where patency of the ductus arteriosus is necessary for adequate pulmonary or systemic blood flow (eg, pulmonary atresia, severe tetralogy of Fallot, severe coarctation of the aorta).

Concerns related to adverse effects:

Anaphylactoid reactions: Even in patients without prior exposure anaphylactoid reactions may occur; patients with "aspirin triad" (bronchial asthma, aspirin intolerance, rhinitis) may be at increased risk. Contraindicated in patients who experience bronchospasm, asthma, rhinitis, or urticaria with nonsteroidal anti-inflammatory drug (NSAID) or aspirin therapy.

Cardiovascular events: [US Boxed Warning]: NSAIDs cause an increased risk of serious (and potentially fatal) adverse cardiovascular thrombotic events, including MI and stroke. Risk may occur early during treatment and may increase with duration of use. Relative risk appears to be similar in those with and without known cardiovascular disease or risk factors for cardiovascular disease; however, absolute incidence of serious cardiovascular thrombotic events (which may occur early during treatment) was higher in patients with known cardiovascular disease or risk factors and in those receiving higher doses. New-onset hypertension or exacerbation of hypertension may occur (NSAIDs may also impair response to ACE inhibitors, thiazide diuretics, or loop diuretics); may contribute to cardiovascular events; monitor blood pressure; use with caution in patients with hypertension. May cause sodium and fluid retention, use with caution in patients with edema. Avoid use in heart failure (FDA 2015). Avoid use in patients with recent MI unless benefits outweigh risk of cardiovascular thrombotic events. Use the lowest effective dose for the shortest duration of time, consistent with individual patient goals, to reduce risk of cardiovascular events; alternate therapies should be considered for patients at high risk.

CNS effects: May cause drowsiness, dizziness, blurred vision, and other neurologic effects, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery, driving). Headache may occur; cessation of therapy required if headache persists after dosage reduction.

Drug reaction with eosinophilia and systemic symptoms: Potentially serious, sometimes fatal, drug reaction with eosinophilia and systemic symptoms (DRESS), also known as multiorgan hypersensitivity reactions, has been reported with NSAIDs. Monitor for signs and symptoms (eg, fever, rash, lymphadenopathy, eosinophilia) in association with other organ system involvement (eg, hepatitis, nephritis, hematological abnormalities, myocarditis, myositis). Early symptoms of hypersensitivity reaction (eg, lymphadenopathy, fever) may occur without rash; discontinue therapy and further evaluate if DRESS is suspected.

GI events: [US Boxed Warning]: NSAIDs cause increased risk of serious GI inflammation, ulceration, bleeding, and perforation (may be fatal); elderly patients and patients with history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events. These events may occur at any time during therapy and without warning. Avoid use in patients with active GI bleeding. In patients with a history of acute lower GI bleeding, avoid use of non-aspirin NSAIDs, especially if due to angioectasia or diverticulosis (Strate 2016). Use caution with a history of GI ulcers, concurrent therapy known to increase the risk of GI bleeding (eg, aspirin, anticoagulants and/or corticosteroids, selective serotonin reuptake inhibitors), advanced hepatic disease, coagulopathy, smoking, use of alcohol, or in older or debilitated patients. Use the lowest effective dose for the shortest duration of time, consistent with individual patient goals, to reduce risk of GI adverse events; alternate therapies should be considered for patients at high risk. When used concomitantly with aspirin, a substantial increase in the risk of GI complications (eg, ulcer) occurs; concomitant gastroprotective therapy (eg, proton pump inhibitors) is recommended (Bhatt 2008).

Hematologic effects: Platelet adhesion and aggregation may be decreased; may prolong bleeding time; patients with coagulation disorders or who are receiving anticoagulants should be monitored closely. Anemia may occur; patients on long-term NSAID therapy should be monitored for anemia. Rarely, NSAID use has been associated with potentially severe blood dyscrasias (eg, agranulocytosis, thrombocytopenia, aplastic anemia).

Hepatic effects: Transaminase elevations have been reported with use; closely monitor patients with any abnormal liver function test (LFT). Rare, sometimes fatal severe hepatic reactions (eg, fulminant hepatitis, hepatic necrosis, hepatic failure) have occurred with NSAID use; discontinue immediately if clinical signs or symptoms of liver disease develop or if systemic manifestations occur.

Hyperkalemia: NSAID use may increase the risk of hyperkalemia, particularly in older patients, diabetic patients, patients with kidney disease, and with concomitant use of other agents capable of inducing hyperkalemia (eg, ACE inhibitors). Monitor potassium closely.

Kidney effects: NSAID use may compromise existing kidney function; dose-dependent decreases in prostaglandin synthesis may result from NSAID use, reducing renal blood flow which may cause kidney decompensation (usually reversible). Patients with impaired kidney function, dehydration, hypovolemia, heart failure, hepatic impairment, those taking diuretics, and ACE inhibitors, and older patients are at greater risk of kidney toxicity. Rehydrate patient before starting therapy; monitor kidney function closely. Long-term NSAID use may result in renal papillary necrosis and other kidney injury.

Ophthalmic effects: Prolonged therapy may cause corneal deposits and retinal disturbances, including those of the macula. Discontinue use with blurred or diminished vision and perform ophthalmologic exam. Periodically evaluate vision in all patients receiving long-term therapy.

Skin reactions: NSAIDs may cause potentially fatal serious skin adverse events, including drug reaction with eosinophilia and systemic symptoms, exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis; may occur without warning; discontinue use at first sign of skin rash (or any other hypersensitivity).

Indomethacin may cause liver problems, and using it with substantial quantities of ethanol may increase that risk.

Indomethacin is present in breast milk.

The relative infant dose (RID) of indomethacin is 8.6% when calculated using the highest breast milk concentration located and compared to an IV infant therapeutic dose of 0.2 mg/kg/day.

In general, breastfeeding is considered acceptable when an RID of a medication is <10%.

The RID of indomethacin was calculated using a milk concentration of 115 mcg/L, providing an estimated infant dose via breast milk of 0.017 mg/kg/day. This milk concentration was obtained following maternal administration of indomethacin 1.43 mg/kg/day. Using all data from this study, the average concentration in breast milk is 0.27% of the weight-adjusted maternal dose (dose range: 0.94 to 4.29 mg/kg/day). Indomethacin was also detected in the plasma of a breastfeeding infant.

Food may decrease the rate but not the extent of absorption. Indomethacin peak serum levels may be delayed if taken with food. Management: Administer with food or milk to minimize GI upset.

• Common Adverse effects:

Headache. dizziness. vomiting. diarrhea. constipation. ringing in the ears.

• Less Common Adverse effects:

Abdominal or stomach cramping, burning, or tenderness. back or leg pains. blistering, peeling, or loosening of the skin. bloody or black, tarry stools. blue lips and fingernails. breast enlargement and tenderness. burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings.

• Rare Adverse effects

Ulcers, bleeding, or holes in the stomach or intestine.

• May diminish the antihypertensive effects of ACE inhibitors (e.g. captopril), β-blockers (e.g. propranolol, atenolol), diuretics (loop, K-sparing, thiazides), and angiotensin II receptor antagonists (e.g. losartan). Reduced clearance and increased the risk of toxicity of methotrexate and lithium.
• May increase plasma concentrations with probenecid. Increased serum concentrations of digoxin and aminoglycosides (e.g. amikacin, gentamicin). Increased risk of adverse effects with corticosteroids, antiplatelet agents (e.g. aspirin, clopidogrel), anticoagulants (e.g. warfarin), SSRIs, and other NSAIDs.
• May enhance the effect of desmopressin. Enhanced drowsiness with haloperidol.
• May reduce the effect of mifepristone. Indometacin may enhance the nephrotoxic effects of ciclosporin, tacrolimus and triamterene. Increased bioavailability of tiludronic acid.
• May enhance the seizure-potentiating adverse effect of quinolones.

Potentially Fatal: Decreased renal clearance and increased plasma concentration with diflunisal.

The common side effects of Indomethacin include the following :

Atrial fibrillation, atrial flutter, peripheral edema.

Symptoms: Nausea, vomiting, epigastric pain, severe headache, dizziness, drowsiness, disorientation, mental confusion, lethargy, paraesthesia, numbness, convulsions, excitation, tinnitus, fainting, gastrointestinal bleeding; rarely, hypertension, acute renal failure, respiratory depression, and coma.

Management: Symptomatic and supportive treatment. Empty stomach contents immediately if ingestion is recent. Induce emesis with syrup of ipecac if vomiting has not occurred spontaneously; if unable to vomit, perform gastric lavage. May give activated charcoal after stomach emptying and/or osmotic cathartic in symptomatic patients with known ingestion within 4 hours or in case of large over dosage. Consider correction of severe electrolyte abnormalities. Administer antacids as necessary. Monitor renal and liver function. In case of frequent or prolonged convulsions, administer IV diazepam.

• Pharmacodynamics

Indomethacin is a strong analgesic and antipyretic with spasmolytic properties. It has weak anti-inflammatory or antithrombotic properties and does not follow the same mechanism of action as conventional non-steroidal anti-inflammatory drugs (NSAIDs). Indomethacin can lead to agranulocytosis, a life-threatening side effect where a patient’s neutrophil count falls below 500 cells per microliter.

• Pharmacokinetics

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1364710/
• https://reference.medscape.com/drug/colestid-Indomethacin -342452
• https://go.drugbank.com/drugs/DB00375
• https://www.sciencedirect.com/topics/medicine-and-dentistry/Indomethacin
• https://europepmc.org/article/med/6988203