Indometacinum

Uses

Indometacinum is used for the treatment of rheumatoid arthritis, ankylosing spondylitis, osteoarthritis (degenerative joint disease), gout, acute non-articular rheumatism (bursitis, synovitis, tendinitis).

Indometacinum is also used to associated treatment for these conditions: Acute Gouty Arthritis, Joint Pain, Moderate to Severe Osteoarthritis, Moderate to Severe Rheumatoid Arthritis, Moderate to severe ankylosing spondylitis, Patent Ductus Arteriosus (PDA), Soreness, Muscle, Acute Shoulder Pain

How Indometacinum works

Indometacin is a nonspecific and reversible inhibitor of the cyclo-oxygenase (COX) enzyme or prostaglandin G/H synthase. There are two identified isoforms of COX: COX-1 is universally present in most body tissues and is involved in the synthesis of the prostaglandins and thromboxane A2, while COX-2 is expressed in response to injury or inflammation. Constitutively expressed, the COX-1 enzyme is involved in gastric mucosal protection, platelet, and kidney function by catalyzing the conversion of arachidonic acid to prostaglandin (PG) G2 and PGG2 to PGH2. COX-2 is constitutively expressed and highly inducible by inflammatory stimuli. It is found in the central nervous system, kidneys, uterus, and other organs. COX-2 also catalyzes the conversion of arachidonic acid to PGG2 and PGG2 to PGH2. In the COX-2-mediated pathway, PGH2 is further converted to PGE2 and PGI2 (also known as prostacyclin). PGE2 is involved in mediating inflammation, pain, and fever. Decreasing levels of PGE2 leads to reduced inflammatory reactions. Indometacin is known to inhibit both isoforms of COX, however, with greater selectivity for COX-1, which accounts for its increased adverse gastric effects relative to other NSAIDs. It binds to the enzyme's active site and prevents the interaction between the enzyme and its substrate, arachidonic acid. Indometacin, unlike other NSAIDs, also inhibits phospholipase A2, the enzyme responsible for releasing arachidonic acid from phospholipids. The analgesic, antipyretic and anti-inflammatory effects of indomethacin as well as adverse reactions associated with the drug occur as a result of decreased prostaglandin synthesis. Its antipyretic effects may be due to action on the hypothalamus, resulting in increased peripheral blood flow, vasodilation, and subsequent heat dissipation.

The exact mechanism of action of indometacin in inducing closure of a patent ductus arteriosus is not fully understood; however, it is thought to be through inhibition of prostaglandin synthesis. At birth, the ductus arteriosus is normally closed as the tension of the oxygen increases significantly after birth. Patent ductus arteriosus in premature infants is associated with congenital heart malformations where PGE1 mediates an opposite effect to that of oxygen. PGE1 dilates the ductus arteriosus through smooth muscle relaxation and prevents the closure of the ductus arteriosus. By inhibiting the synthesis of prostaglandins, indometacin promotes the closure of ductus arteriosus.

Indometacin has been described as possessing anticancer and antiviral properties through activation of protein kinase R (PKR) and downstream phosphorylation of eIF2α, inhibiting protein synthesis.

Dosage

Indometacinum dosage

Indometacinum is available for oral administration as a 25 mg capsule and as a rectal suppository containing 100 mg of indomethacin.

The recommended dosage of Indometacinum is 50 mg to 200 mg daily in divided doses and should be individually adjusted to the patient's response and tolerance. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals.

Unlike some other potent antirheumatic agents, an initial high "loading" dose of Indometacinum is not necessary. In chronic rheumatic disorders, initiating therapy with low doses, increasing gradually when necessary, and continuing for an adequate period (up to one month is recommended) will produce maximum benefit and minimise adverse reactions.

In patients with persistent night pain and/or morning stiffness, a dose of up to 100 mg at bedtime may be helpful in affording relief. It is rarely necessary to exceed a dosage of 200 mg per day.

In the treatment of acute gouty arthritis, the recommended daily dosage is 150 mg to 200 mg until all symptoms and signs subside.

In primary dysmenorrhoea, the recommended dosage is 25 mg three times a day starting with onset of cramps or bleeding and continuing for as long as the symptoms usually last.

To minimise the possibility of gastrointestinal disturbances, it is recommended that oral Indometacinum be taken with food, milk, or an antacid.

Side Effects

Headache, usually in the morning and mild vertigo may occur during the early weeks of therapy. These symptoms are transient and usually disappear with continued use or by reduction of the dose. Gastrointestinal reactions such as nausea, vomiting, diarrhea, epigastric and abdominal pain are often due to large doses of the drug and disappear when the dose is reduced.

Toxicity

Acute oral LD50 is 2.42 mg/kg in rats and 13 mg/kg in mice. The oral LD50 of indomethacin in mice and rats (based on 14-day mortality response) was 50 and 12 mg/kg, respectively.

Symptoms of overdose may be characterized by nausea, vomiting, intense headache, dizziness, mental confusion, disorientation, or lethargy. In addition, there have been reports of paresthesias, numbness, and convulsions. In case of an overdose, the patient should receive symptomatic and supportive treatment with stomach emptying through induced vomiting or gastric lavage. The patient should then be closely monitored for any signs of gastrointestinal ulceration and hemorrhage. Antacids may be useful.

Interaction

It may interact with anticoagulants, lithium, diuretics, ß-blockers, diflunisal, aspirin, probenecid and sulfonylureas.

Food Interaction

• Avoid alcohol. Ingestion of alcohol can increase the risk of GI bleeding.
• Take with or without food. Food has no effect on drug absorption. However, food may decrease the extent of gastrointestinal irritation caused by indomethacin.

Indometacinum Alcohol interaction

[Moderate] GENERALLY AVOID:

The concurrent use of aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) and ethanol may lead to gastrointestinal (GI) blood loss.

The mechanism may be due to a combined local effect as well as inhibition of prostaglandins leading to decreased integrity of the GI lining.

Patients should be counseled on this potential interaction and advised to refrain from alcohol consumption while taking aspirin or NSAIDs.

Indometacinum Hypertension interaction

[Major] Fluid retention and edema have been reported in association with the use of nonsteroidal anti-inflammatory drugs (NSAIDs).

Therapy with NSAIDs should be administered cautiously in patients with preexisting fluid retention, hypertension, or a history of heart failure.

Blood pressure and cardiovascular status should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy.

[Moderate] Nonsteroidal anti-inflammatory drugs (NSAIDs), including topicals, can lead to new onset of hypertension or worsening of preexisting hypertension, either of which can contribute to the increased incidence of cardiovascular events.

NSAIDs should be used with caution in patients with hypertension.

Blood pressure should be monitored closely during the initiation of NSAID therapy and throughout the course of therapy.

Indometacinum Drug Interaction

Moderate: aspirin, aspirin, duloxetine, duloxetine, omega-3 polyunsaturated fatty acids, omega-3 polyunsaturated fatty acidsUnknown: diphenhydramine, diphenhydramine, cyclobenzaprine, cyclobenzaprine, pregabalin, pregabalin, acetaminophen, acetaminophen, cyanocobalamin, cyanocobalamin, ascorbic acid, ascorbic acid, cholecalciferol, cholecalciferol

Indometacinum Disease Interaction

Major: asthma, fluid retention, GI toxicity, rash, renal toxicities, thrombosisModerate: CNS effects, anemia, heart failure, hepatotoxicity, hyperkalemia, hypertension, platelet aggregation inhibition

Volume of Distribution

The volume of distribution ranged from 0.34 to 1.57 L/kg following oral, intravenous, or rectal administration of single and multiple doses of indometacin in healthy individuals. Indometacin is distributed into the synovial fluid and is extensively bound to tissues . It has been detected in human breast milk and placenta. Although indometacin has been shown to cross the blood-brain barrier (BBB), its extensive plasma protein binding allows only the small fraction of free or unbound indometacin to diffuse across the BBB.

Elimination Route

Indometacin displays a linear pharmacokinetics profile where the plasma concentrations and area under the curve (AUC) are dose-proportional, whereas half-life (T1/2) and plasma and renal clearance are dose-dependent. Indometacin is readily and rapidly absorbed from the gastrointestinal tract. The bioavailability is virtually 100% following oral administration and about 90% of the dose is absorbed within 4 hours. The bioavailability is about 80-90% following rectal administration.

The peak plasma concentrations following a single oral dose were achieved between 0.9 ± 0.4 and 1.5 ± 0.8 hours in a fasting state. Despite large intersubject variation as well using the same preparation, peak plasma concentrations are dose-proportional and averaged 1.54 ± 0.76 μg/mL, 2.65 ± 1.03 μg/mL, and 4.92 ± 1.88 μg/mL following 25 mg, 50 mg, and 75 mg single doses in fasting subjects, respectively. With a typical therapeutic regimen of 25 or 50 mg t.i.d., the steady-state plasma concentrations of indomethacin are an average 1.4 times those following the first dose.

Half Life

Indometacin disposition from the plasma is reported to be biphasic, with a half-life of 1 hour during the initial phase and 2.6–11.2 hours during the second phase. Interindividual and intraindividual variations are possible due to the extensive and sporadic nature of the enterohepatic recycling and biliary discharge of the drug.

The mean half-life of oral indomethacin is estimated to be about 4.5 hours. The disposition of intravenous indometacin in preterm neonates was shown to vary across premature infants. In neonates older than 7 days, the mean plasma half-life of intravenous indometacin was approximately 20 hours, ranging from 15 hours in infants weighing more than 1000 g and 21 hours in infants weighing less than 1000 g.

Clearance

In a clinical pharmacokinetic study, the plasma clearance of indometacin was reported to range from 1 to 2.5 mL/kg/min following oral administration.

Elimination Route

Indometacin is eliminated via renal excretion, metabolism, and biliary excretion. It is also subject to enter the enterohepatic circulation through excretion of its glucuronide metabolites into bile followed by resorption of indometacin after hydrolysis . The extent of involvement in the enterohepatic circulation ranges from 27 to 115%.

About 60 percent of an oral dosage is recovered in urine as drug and metabolites (26 percent as indomethacin and its glucuronide), and 33 percent in the feces (1.5 percent as indomethacin).

Pregnancy & Breastfeeding use

Use in pregnancy: Not recommended for pregnant women, because at the present time clinical studies are insufficient.

Use in children: Not recommended for children.

Contraindication

Indometacinum is contraindicated in patients with ulcer, gastritis, active ulcerative colitis, and should be used with caution in patients with a history of these disorders. It is also contraindicated in previously hypersensitive patient.

Storage Condition

Should be stored in cool and dry place

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