Setolac Mr

Uses

Carefully consider the potential benefits and risks of etodolac capsules and other treatment options before deciding to use etodolac capsules. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals.Etodolac are used:1. For acute and long-term use in the management of signs and symptoms of the following:

• Osteoarthritis
• Rheumatoid arthritis

2. For the management of acute pain

Thiocolchicoside is a semi-synthetic colchicine derivative used as an analgesic and anti-inflammatory.

Thiocolchicoside is a skeletal muscle-relaxant drug used in the treatment of orthopedic, traumatic and rheumatologic disorders . It is indicated as an adjuvant drug in the treatment of painful muscle contractures and is indicated in acute spinal pathology, for adults and adolescents 16 years of age and older . Recent studies have examined its effect on muscle tone, stiffness, contractures, and soreness experienced by athletes during sporting competitions .

Setolac Mr is also used to associated treatment for these conditions: Chronic Back Pain, Extra-Articular Rheumatism, Juvenile Idiopathic Arthritis (JIA), Muscle Spasms, Nonspecific Pain Post Traumatic Injury, Osteoarthritis (OA), Pain, Acute, Postoperative pain, Rheumatoid Arthritis, Spinal DisordersBack Pain, Acute, Chronic Back Pain, Extra-Articular Rheumatism, Muscle Inflammation, Muscle Spasms, Musculoskeletal Pain, Nonspecific Pain Post Traumatic Injury, Osteoarthritis (OA), Pain, Post Surgical Pain, Post-traumatic pain, Postoperative pain, Rheumatoid Arthritis, Soreness, Muscle, Spasms, Spinal pain, Vertebral column pain, Inflammation localized, Localized pain, Mild to moderate pain, Musculoskeletal spasms

How Setolac Mr works

Similar to other NSAIDs, the anti-inflammatory effects of etodolac result from inhibition of the enzyme cycooxygenase (COX). This decreases the synthesis of peripheral prostaglandins involved in mediating inflammation. Etodolac binds to the upper portion of the COX enzyme active site and prevents its substrate, arachidonic acid, from entering the active site. Etodolac was previously thought to be a non-selective COX inhibitor, but it is now known to be 5 – 50 times more selective for COX-2 than COX-1. Antipyresis may occur by central action on the hypothalamus, resulting in peripheral dilation, increased cutaneous blood flow, and subsequent heat loss.

Thiocolchicoside, is a synthetic sulfur derivative of colchicoside, a naturally occurring glucoside contained in the Colchicum autumnale plant. Thiocolchicoside has a selective and potent affinity for g-aminobutyric acid A (GABA-A) receptors and acts on muscular contractures by activating the GABA inhibitory pathways thereby behaving as a potent muscle relaxant . Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the human cortex . GABAergic neurons are involved in myorelaxation, anxiolytic treatment, sedation, and anesthetics. GABA can also modulate heart rate and blood pressure.

It also has an affinity for the inhibitory glycine receptors (i.e., have glycomimetic and GABA mimetic activity), therefore acts as a muscle relaxant. Glycine is an inhibitory neurotransmitter and acts as an allosteric regulator of NMDA (N-methyl-D-aspartate) receptors. It is involved in the processing of motor and sensory data, thereby regulating movement, vision, and audition. Inhibitory neurotransmitter in spinal cord, allosteric regulator of NMDA receptors .

In one study, thiocolchicoside inhibited the function of recombinant human strychnine-sensitive glycine receptors composed of the alpha1 subunit with a potency (median inhibitory concentration of 47 microM) lower than that apparent with recombinant GABA(A) receptors. The drug also inhibited the function of human nicotinic acetylcholine receptors made of the alpha4 and beta2 subunits, however, this effect was partial and moreover only apparent at high concentrations. Thiocolchicoside demonstrated no effect on the function of 5-HT(3A) serotonin receptors .

Dosage

Setolac Mr dosage

Carefully consider the potential benefits and risks of Etodolac and other treatment options before deciding to use Etodolac capsules. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals.

After observing the response to initial therapy with Etodolac capsules, the dose and frequency should be adjusted to suit an individual patient's needs.

Dosage adjustment of Etodolac is generally not required in patients with mild to moderate renal impairment. Etodolac should be used with caution in such patients, because, as with otherNSAIDs, they may further decrease renal function in some patients with impaired renal function.

Analgesia: The recommended total daily dose of Etodolac for acute pain is up to 1000 mg, given as 200 to 400 mg every 6 to 8 hours. Doses of Etodolac greater than 1000 mg/day have not been adequately evaluated in well-controlled clinical trials.

Osteoarthritis and Rheumatoid Arthritis: The recommended starting dose is 300 mg b.i.d., t.i.d., or 400 mg b.i.d., or 500 mgb.i.d.A lower dose of 600 mg/day may suffice for long-term administration. Physicians should be aware that doses above 1000 mg/day have not been adequately evaluated in well-controlled clinical trials.

In chronic conditions, a therapeutic response to therapy with Etodolac is sometimes seen within one week of therapy, but most often is observed by two weeks. After a satisfactory response has been achieved, the patient's dose should be reviewed and adjusted as required.

Side Effects

The common side effects of Etodolac involve the gastrointestinal system. It can cause abdominal pain, constipation, diarrhea, dyspepsia, flatulence, heartburn, nausea, GI ulcers, vomiting. Other events including abnormal renal function, anemia, dizziness, edema, elevated liver enzymes, headaches, increased bleeding time, pruritis, rashes, tinnitus etc.

Toxicity

Selective COX-2 inhibitors have been associated with increased risk of serious cardiovascular events (e.g. myocardial infarction, stroke) in some patients. Current data is insufficient to assess the cardiovascular risk of etodolac. Etodolac may increase blood pressure and/or cause fluid retention and edema. Risk of GI toxicity including bleeding, ulceration and perforation. Risk of direct renal injury, including renal papillary necrosis. Anaphylactoid and serious skin reactions (e.g. exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis) have been reported. Common adverse events include abdominal pain, constipation, diarrhea, dyspepsia, flatulence, GI bleeding, GI perforation, nausea, peptic ulcer, vomiting, renal function abnormalities, anemia, dizziness, edema, liver function test abnormalities, headache, prolonged bleeding time, pruritus, rash, tinnitus. Symptoms of overdose include lethargy, drowsiness, nausea, vomiting, and epigastric pain.

Has been shown to cause chromosomal aneuploidy and male infertility. Should be avoided during all stages of pregnancy, lactation and puberty. Is a potential risk factor for cancer.

In 2013, The European Medical Association (EMA) mandated that the use of thiocolchicoside-containing medicines by mouth or injection should be restricted across the European Union (EU). These drugs are now recommended only as an add-on treatment for painful muscle contractures resulting from spinal conditions in adults and adolescents 16 years old and older. Additionally, the dose of thiocolchicoside by mouth or injection should be limited. This is due to experimental evidence suggesting that thiocolchicoside was metabolized into M2 or SL59.0955, that has the propensity to damage dividing cells, resulting in aneuploidy (an abnormal number or arrangement of chromosomes). As a result, the CHMP (committee for medicinal products for human use) examined the safety profile of this medicine and consider what regulatory action might be appropriate .

The CHMP reviewed the evidence, with consideration of opinions from experts in medicines safety, and concluded that aneuploidy may occur with M2 at levels not significantly greater than those measured after recommended doses of thiocolchicoside ingested orally. Aneuploidy is a strong risk factor for fetal harm, decreased fertility in men, and could theoretically increase the risk of developing cancer .

The maximum recommended oral dose is 8 mg every 12 hours; treatment length should not exceed 7 consecutive days. When given intramuscularly (IM), the maximum dose is 4 mg every 12 hours, for a maximum of 5 days .

In addition to the above toxicity, a study was done on the hepatotoxic potential of thiocolchicoside. It was observed that serum AST and ALT levels increased following of the administration oral thiocolchicoside at 8 mg/day. Two weeks after discontinuing thiocolchicoside therapy, liver enzymes had decreased to levels within the normal range. Although infrequent, thiocolchicoside should be considered a rare hepatotoxic agent in clinical practice .

Precaution

Etodolac should be given with caution in patients with severe hepatic reactions, pre-existing asthma, fluid retention, hypertension or heart failure. If clinical sings and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g. eosinophilia, rash etc.), it should be discontinued.

Interaction

Since Etodolac is extensively protein-bound, it may be necessary to modify the dosage of other highly protein-bound drugs. The concomitant administration of Warfarin and Etodolac should not require a dosage adjustment of either drug, however it has rarely led to prolonged prothrombin times, therefore caution should be exercised when Etodolac is administered with Warfarin. Concomitant use of Ciclosporin, Methotrexate, Digoxin, or Lithium with NSAIDs may cause an increase in serum levels of these compounds and associated toxicities. Care should also be taken in patients treated with any of the following drugs as interactions have been reported in some patients: Anti-hypertensives, Mifepristone, other Analgesics, Corticosteroids and Quinolone Antibiotics.

Volume of Distribution

• 390 mL/kg

The apparent volume of distribution of thiocolchicoside is estimated to be approximately 42.7 L after an intramuscular injection of 8 mg .

Elimination Route

Based on mass balance studies, the systemic bioavailability of etodolac from either the tablet or capsule formulation is at least 80%.

Oral bioavailability is ~25% After intramuscular administration, thiocolchicoside Cmax occur in 30 min and .reach values of 113 ng/mL after a 4 mg dose and 175 ng/mL after a 8 mg dose. The corresponding values of AUC are respectively 283 and 417 ng.h/mL. The pharmacologically active metabolite SL18.0740 is found at lower concentrations with a Cmax of 11.7 ng/mL occurring 5 h post administration and an AUC of 83 ng.h/mL .

After oral administration, no thiocolchicoside is detected in plasma. Only two metabolites are observed: The pharmacologically active metabolite SL18.0740 and an inactive metabolite SL59.0955. For both metabolites, maximum plasma concentrations occur 1hour after thiocolchicoside administration. After a single oral dose of 8 mg of thiocolchicoside the Cmax and AUC of SL18.0740 are about 60 ng/mL and 130 ng.h/mL respectively. For SL59.0955 these values are much lower: Cmax around 13 ng/mL and AUC ranging from 15.5 ng.h/mL (until 3h) to 39.7 ng.h/mL (until 24h) .

Half Life

Terminal t_1/2, 7.3 ± 4.0 hours. Distribution t_1/2, 0.71 ± 0.50 hours

Approximately 7.7h .

Clearance

• Oral cl=49.1 mL/h/kg [Normal healthy adults]
• Oral cl=49.4 mL/h/kg [Healthy males (18-65 years)]
• Oral cl=35.7 mL/h/kg [Healthy females (27-65 years)]
• Oral cl=45.7 mL/h/kg [Eldery (>65 years)]
• Oral cl=58.3 mL/h/kg [Renal impairement (46-73 years)]
• Oral cl=42.0 mL/h/kg [Hepatic impairement (34-60 years)]

Primarily extrarenal elimination (75% of the total body clearance) .

Elimination Route

It is not known whether etodolac is excreted in human milk; however, based on its physical-chemical properties, excretion into breast milk is expected. Etodolac is extensively metabolized in the liver. The hydroxylated-etodolac metabolites undergo further glucuronidation followed by renal excretion and partial elimination in the feces (16% of dose). Approximately 1% of a etodolac dose is excreted unchanged in the urine with 72% of the dose excreted into urine as parent drug plus metabolite.

Thiocolchicoside is not eliminated unchanged, rather as one of three metabolites found in either feces (~79 %) or in urine 20%. 3- demethylcolchicine (M2) and 3-O-glucurono-demethylcolchicine (M1) are found in both urine and feces, where as di-demethylcolchicine is found only in feces .

Pregnancy & Breastfeeding use

Pregnancy: There are no adequate and well-controlled studies in pregnant women. It should be use in pregnancy only if the potential benefit justifies the potential risk to the fetus.

Lactation: It is not known whether Etodolac is excreted in human milk. A decision should be made whether to discontinue nursing or to discontinue the drug taking into account the importance of the drug to the mother.

Contraindication

Etodolac is contraindicated in patients with known hypersensitivity to Etodolac. Etodolac should not be given to patients who have experienced asthma, urticaria or other allergic-type reactions after taking Aspirin or other NSAIDs.

Acute Overdose

Symptoms following acute NSAID overdose are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain which are generally reversible with supportive care.

Storage Condition

Store at a cool and dry place protected from light & moisture. Keep out of reach of children.

Innovators Monograph

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