S-(+)-Etodolac Prolonged-Release Tablets 300 mg

Each Prolonged-Release film coated tablet contains:

S-(+)-Etodolac 300 mg

Excipients q.s

Tablet, 300 mg

4.1 Therapeutic indication

For the relief of pain and inflammation in patients with rheumatoid arthritis and osteoarthritis.

4.2 Posology and method of administration

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms.

Adults: One tablet daily.

The safety of doses in excess of 300mg per day has not been established. No occurrence of tolerance or tachyphylaxis has been reported.

Elderly: No change in initial dosage is generally required in the elderly.

The elderly population are at increased risk of the serious consequences of adverse reactions. If an NSAID is considered necessary, the lowest effective dose should be used and for the shortest possible duration. The patient should be monitored regularly for GI bleeding during NSAID therapy.

Paediatric population: Not recommended.

Method of administration: For oral administration.

To be taken preferably with or after food. Swallow the tablet whole with a glass of water.

4.3 Contraindications

• Hypersensitivity to the active substance or to any of the excipients.
• Setolac 300 ER Tablets should not be used in patients with severe heart failure.
• Setolac 300 ER Tablets should not be used in patients with active or history of recurrent peptic ulceration or a history of peptic ulcer disease (with two or more distinct episodes of proven ulceration or bleeding).
• NSAIDs are contraindicated in patients who have previously shown hypersensitivity reactions (e.g. asthma, rhinitis angioedema or urticaria) during therapy with ibuprofen, aspirin or other non-steroidal anti-inflammatory drugs.
• Severe heart failure, hepatic failure and renal failure
• During the last trimester of pregnancy
• History of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy.

4.4 Special warnings and precautions for use

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms.

The use of Setolac 300 ER Tablets with concomitant NSAIDs including cyclooxygenase-2-selective inhibitors should be avoided.

Elderly:

The elderly people have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal.

Cardiovascular and cerebrovascular effects:

Appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy.

Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long term treatment) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). There are insufficient data to exclude such a risk for Setolac 300 ER Tablets.

Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with Setolac 300 ER Tablets after careful consideration. Similar consideration should be made before initiating longer-term treatment of patients with risk factors for cardiovascular disease (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking).

Respiratory disorders:

Caution is required if Setolac 300 ER Tablets is administered to patients suffering from, or with a previous history of, bronchial asthma since NSAIDs have been reported to precipitate bronchospasm in such patients.

Cardiovascular, Renal and Hepatic Impairment:

In patients with renal, cardiac or hepatic impairment especially those taking diuretics and the elderly, renal function should be monitored in these patients. Caution is required since the use of NSAIDs may result in a dose dependent reduction in prostaglandin formation and precipitate renal failure. The dose should be kept as low as possible. However, impairment of renal or hepatic functions due to other causes may alter drug metabolism; patients receiving concomitant long term therapy, especially the elderly, should be observed for potential side effects and their drug doses adjusted as needed, or the drug discontinued.

Gastrointestinal bleeding, ulceration and perforation:

Serious gastrointestinal adverse effects such as bleeding, ulceration and perforation, which can be fatal, has been reported and can occur at any time with or without warning symptoms in patients treated with NSAIDs or a previous history of serious GI events. If any sign of gastrointestinal bleeding occurs, Setolac 300 ER Tablets should be stopped immediately.

Platelets:

Although non-steroidal anti-inflammatory drugs do not have the same direct effects on platelets as does aspirin, all drugs which inhibit the biosynthesis of prostaglandins may interfere, to some extent, with platelet function. Patients receiving Setolac 300 ER Tablets who may be adversely affected by such actions should be carefully observed.

Patients on long-term treatment with Setolac 300 ER Tablets should be regularly reviewed as a precautionary measure e.g. for changes in, renal function, haematological parameters, or hepatic function.

The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation, and in the elderly. These patients should commence treatment on the lowest dose available. Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients, and also for patients requiring concomitant low dose aspirin, or other drugs likely to increase gastrointestinal risk.

Patients with a history of GI toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment.

Caution should be advised in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin-reuptake inhibitors or anti-platelet agents such as aspirin.

When GI bleeding or ulceration occurs in patients receiving Etodolac, the treatment should be withdrawn.

NSAIDs should be given with care to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn's disease) as these conditions may be exacerbated.

SLE and mixed connective tissue disease:

In patients with systemic lupus erythematous (SLE) and mixed connective tissue disorders there may be an increased risk of aseptic meningitis.

Dermatological:

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs (see section 4.8). Patients appear to be at highest risk for these reactions early in the course of therapy: the onset of the reaction occurring in the majority of cases within the first month of treatment. Setolac 300 ER Tablets should be discontinued at the first appearance of the skin rash, mucosal lesions, or any other sign of hypersensitivity.

4.5 Drug interactions

Since Setolac 300 ER Tablets is extensively protein-bound, it may be necessary to modify the dosage of other highly protein-bound drugs.

Other analgesics including cyclooxygenase-2 selective inhibitor: Avoid concomitant use of two or more NSAIDs (including aspirin) as this may increase the risk of adverse effects (see section 4.4)

Anti-hypertensives: Reduced anti-hypertensive effect

Diuretics: Reduced diuretic effect. Diuretics can increase the risk of nephrotoxicity of NSAIDs.

Cardiac glycosides: NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.

Lithium: Decreased elimination of lithium

Methotrexate: Decreased elimination of methotrexate

Ciclosporin: Increased risk of nephrotoxicity

Anti-coagulants: NSAIDs may enhance the effects of anti-coagulants, such as warfarin (see section 4.4)

Anti-platelet agents: and selective serotonin reuptake inhibitors (SSRIs): Increased risk of gastrointestinal bleeding (see section 4.4)

Tacrolimus: Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.

Zidovudine: Increased risk of haematological toxicity when NSAIDs are given with zidovudine. There is a evidence of an increased risk of haemarthroses and haemtoma in HIV(+) haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.

Bilirubin tests can give a false positive result due to the presence of phenolic metabolites of Setolac 300 ER Tablets in the urine.

Mifepristone: NSAIDs should not be used for 8-12 days after mifepristone administration as NSAIDs can reduce the effect of mifepristone.

Corticosteroids: increased risk of gastrointestinal ulceration or bleeding (see section 4.4)

Quinolone antibiotics: animal data indicate that NSAIDs can increase the risk of convulsions associated with quinolone antibiotics. Patients taking NSAIDs and quinolones may have an increased risk of developing convulsions.

4.6 Use in special populations (such as pregnant women, lactating women, paediatric patients, geriatric patients etc.)

Fertility:

The use of Setolac 300 ER Tablets may impair female fertility and is not recommended in woman attempting to conceive. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of Setolac 300 ER Tablets should be considered.

Pregnancy:

Drugs which inhibit prostaglandin biosynthesis may cause dystocia and delayed parturition as evidenced by studies in pregnant animals.

Congenital abnormalities have been reported in association with NSAID administration in man; however, these are low in frequency and do not appear to follow any discernible pattern. In view of the known effects of NSAIDs on the foetal cardiovascular system, some inhibitors of prostaglandin biosynthesis have been shown to interfere with the risk of closure of the ductus arteriosus, use in the last trimester of pregnancy is contraindicated. The onset of labour may be delayed and the duration increased with an increased bleeding tendency in both mother and child.

From the 20th week of pregnancy onward, etodolac use may cause oligohydramnios resulting from foetal renal dysfunction. This may occur shortly after treatment initiation and is usually reversible upon discontinuation. In addition, there have been reports of ductus arteriosus constriction following treatment in the second trimester, most of which resolved after treatment cessation. Therefore, during the first and second trimester of pregnancy, etodolac should not be given unless clearly necessary. If etodolac is used by a woman attempting to conceive, or during the first and second trimester of pregnancy, the dose should be kept as low and duration of treatment as short as possible. Antenatal monitoring for oligohydramnios and ductus arteriosus constriction should be considered after exposure to etodolac for several days from gestational week 20 onward. Etodolac should be discontinued if oligohydramnios or ductus arteriosus constriction are found.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the foetus to:

- cardiopulmonary toxicity (premature constriction/closure of the ductus arteriosus and pulmonary hypertension);

- renal dysfunction (see above);

the mother and the neonate, at the end of pregnancy, to:

- possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses.

- inhibition of uterine contractions resulting in delayed or prolonged labour.

Consequently, etodolac is contraindicated during the third trimester of pregnancy.

Lactation:

In limited studies so far available, NSAIDs can appear in breast milk in very low concentrations. NSAIDs should, if possible, be avoided when breastfeeding.

4.7 Effects on ability to drive and use machines

Setolac 300 ER can cause dizziness, drowsiness, fatigue or abnormal vision. Patients need to be aware of how they react to this medicine before driving or operating machines.

4.8 Undesirable effects

Oedema, hypertension and cardiac failure, have been reported in association with NSAID treatment. Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long term treatment) may be associated with an increased risk of arterial thrombotic events (for example myocardial infarction or stroke).

Gastrointestinal: Reported side effects include nausea, epigastric pain, diarrhoea, indigestion, heartburn, flatulence, abdominal pain, constipation, vomiting, ulcerative stomatitis, dyspepsia, haematemesis, melaena, rectal bleeding, exacerbation of colitis, vasculitis, headaches, dizziness, abnormal vision, pyrexia, drowsiness, tinnitus, rash, pruritus, fatigue, depression, insomnia, confusion, paraesthesia, tremor, weakness/malaise, dyspnoea, palpitations, bilirubinuria, hepatic function abnormalities and jaundice, urinary frequency, dysuria, angioedema, anaphylactoid reaction, photosensitivity, urticaria and Stevens-Johnson syndrome and Crohn's disease have been reported following administration. Less frequently, gastritis has been observed. Pancreatitis has been reported very rarely.

Hypersensitivity: Hypersensitivity reactions have been reported following treatment with NSAIDs. These may consist of (a) non-specific allergic reactions and anaphylaxis (b) respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm or dyspnoea, or (c) assorted skin disorders, including rashes of various types, pruritus, urticaria, purpura, angioedema and more rarely exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme).

Cardiovascular and cerebrovascular:

Oedema, hypertension and cardiac failure have been reported in association with NSAID treatment

Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long term treatment) may be associated with an increased risk of arterial thrombotic events (for example myocardial infarction or stroke).

Renal: Nephrotoxicity in various forms, including interstitial nephritis, nephrotic syndrome and renal failure.

Hepatic: abnormal liver function, hepatitis and jaundice

Neurological and special senses: Visual disturbances, optic neuritis, headaches, paraethesia, reports of aseptic meningitis (especially in patients with existing auto-immune disorders, such as systemic lupus erythematous, mixed connective tissue disease), with symptoms such as stiff neck, headache, nausea, vomiting, fever or disorientation (See section 4.4), depression, confusion, hallucinations, tinnitus, vertigo, dizziness, malaise, fatigue and drowsiness.

Haematological: Thrombocytopenia, neutropenia, agranulocytosis, aplastic anaemia and haemolytic anaemia.

Dermatological: Bullous reactions including Stevens Johnson Syndrome and Toxic Epidermal Necrolysis (very rare). Photosensitivity.

Reporting of side effects

• Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to: medico@zuventus.com
• Website: http://www.zuventus.co.in/safety.aspx

By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

(a) Symptoms

Symptoms include headache, nausea, vomiting, epigastric pain, gastrointaestinal bleeding, rarely diarrhoea, disorientation, excitation, coma, drowsiness, dizziness, tinnitus, fainting, occasionally convulsions. In cases of significant poisoning acute renal failure and liver damage are possible.

(b) Therapeutic measure

Patients should be treated symptomatically as required.

Within one hour of ingestion of a potentially toxic amount, activated charcoal should be considered. Alternatively, in adults, gastric lavage should be considered within one hour of indigestion of a potentially life-threatening overdose.

Good urine output should be ensured.

Renal and liver function should be closely monitored.

Patients should be observed for at least four hours after ingestion of potentially toxic amounts.

Frequent or prolonged convulsions should be treated with intravenous diazepam.

Other measures may be indicated by the patient's clinical condition.

The standard practices of gastric lavage, activated charcoal administration and general supportive therapy should be undertaken.

5.1 Mechanism of Action

Etodolac is a racemic mixture of [-] R- and [+] S-etodolac. As with other NSAIDs, it has been demonstrated in animals that the [+] S form is biologically active. S (+) Etodolac is the pharmacologically active component of racemate Etodolac. The anti-inflammatory, analgesic, and antipyretic activities of S (+) Etodolac have been observed to be due to inhibition of cyclooxygenase-2 (COX-2) resulting in inhibition of prostaglandin synthesis.

5.2 Pharmacodynamic properties

Inhibition of prostaglandin synthesis and COX-2 selectivity: All non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to inhibit the formation of prostaglandins. It is this action which is responsible both for their therapeutic effects and some of their side-effects. The inhibition of prostaglandin synthesis observed with etodolac differs from that of other NSAIDs. In an animal model at an established anti-inflammatory dose, cytoprotective PGE concentration in the gastric mucosa have been shown to be reduced to a lesser degree and for a shorter period than other NSAIDs. This finding is consistent with subsequent in-vitro studies which have found etodolac to be selective for induced cyclo-oxygenase 2 (COX-2, associated with inflammation) over COX-1 (cytoprotective).

Furthermore, studies in human cell models have confirmed that etodolac is selective for the inhibition of COX-2.

The clinical benefit of preferential COX-2 inhibition over COX-1 has yet to be proven.

Anti-inflammatory effects: Experiments have shown etodolac to have marked anti-inflammatory activity, being more potent than several clinically established NSAIDs.

5.3 Pharmacokinetic properties

The systemic availability of etodolac from etodolac extended-release tablets is generally greater than 80%.

Etodolac does not undergo significant first-pass metabolism following oral administration. After oral administration of etodolac 300 mg extended-release tablets the Mean peak plasma concentration (C_max) was 3.943mcg/ml. The Mean T_max was 2.89 h.

The mean apparent volume of distribution (Vd/F) of etodolac following administration of etodolac extended-release tablets is 566 mL/kg.

Etodolac is more than 99% bound to plasma proteins, primarily to albumin, and is independent of etodolac concentration over the dose range studied.

The mean oral clearance of etodolac following oral etodolac extended-release tablets dosing is 47 (±17) mL/h/kg. The primary route of excretion is through urine, mostly in the form of metabolites.

The elimination half-life (T1/2) averages 7 hours in man.

6.1 Animal Toxicology or Pharmacology

Not Available

(S)-etodolac is the S-enantiomer of etodolac. It is a preferential inhibitor of cyclo-oxygenase 2 and a non-steroidal anti-inflammatory, whereas the enantiomer, (R)-etodolac, is inactive. The racemate is commonly used for the treatment of rheumatoid arthritis and osteoarthritis, and for the alleviation of postoperative pain. It has a role as a cyclooxygenase 2 inhibitor and a non-narcotic analgesic. It is an enantiomer of a (R)-etodolac.

Chemical Name: 2-[(1S)-1,8-diethyl-4,9-dihydro-3H-pyrano[3,4-b]indol-1-yl]acetic acid

Molecular Formula: C₁₇H₂₁NO₃

Molecular Weight: 287.35 g/mol

Structure:

8.1 List of excipients

Lactose Monohydrate, Hypromellose, Dibasic Calcium Phosphate Dihydrate, Povidone, Polyethylene Glycol 6000, Talc, Colloidal Silicon Dioxide, Magnesium Stearate, Hypromellose, Titanium Dioxide, Propylene Glycol Sodium Lauryl Sulfate, Colour Lake Indigo Carmine

8.2 Incompatibilities

None

8.3 Shelf life

24 Months

8.4 Special precautions for storage

Store in a cool, dry & dark place.

Keep out of reach of children.

8.5 Nature and contents of container

Setolac 300ER: 1x10T, ALU-ALU Blister

8.6 Special precautions for disposal and other handling

Any unused product or waste material should be disposed of in accordance with local requirements.

Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.

1. Setolac 300 ER Tablets, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up.

2. Setolac 300 ER Tablets, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up.

3. Setolac 300 ER Tablets, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible.

4. Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians.

5. Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy.

6. Patients should be informed of the signs of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help.

7. In late pregnancy, the third trimester, as with other NSAIDs, Setolac 300 ER Tablets should be avoided because it may cause premature closure of the ductus arteriosus

S (+) Etodolac & Thiocolchicoside Tablets [200 mg + 4 mg]

Each Film-coated tablet contains:

S (+) Etodolac 200 mg

Thiocolchicoside IP 4 mg

Excipients q.s.

Colours: Yellow Oxide of Iron & Titanium Dioxide IP

Tablet

200 mg of S (+) Etodolac and 4 mg of Thiocolchicoside

4.1 Therapeutic indication

For the treatment of patients with acute painful musculoskeletal conditions.

4.2 Posology and method of administration

Adults: One tablet two times daily orally.

Paediatric population: Not recommended.

Method of administration: For oral administration.

To be taken preferably with or after food. Swallow the tablet whole with a glass of water.

4.3 Contraindications

• Patients with known hypersensitivity to S (+) Etodolac and/or Thiocolchicoside.
• Pregnancy and lactation.
• Women of childbearing potential who are not using effective contraception.
• Patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs.
• Setolac®-MR Tablets should not be used in patients with active or history of recurrent peptic ulceration or a history of peptic ulcer disease.
• Setolac®-MR tablet is not recommended for pediatric use.

4.4 Special warnings and precautions for use

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms.

The use of Setolac®-MR Tablets with concomitant NSAIDs including cyclooxygenase-2-selective inhibitors should be avoided.

Seizures

Thiocolchicoside may precipitate seizures, especially in patients with epilepsy or those at risk for seizures. Thiocolchicoside should not be administered to individuals prone to seizures.

Cardiovascular and Cerebrovascular Effects

COX-2 selective and non-selective NSAIDs have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for adverse CV events in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. NSAIDs, including Etodolac, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout therapy. Fluid retention and edema have been observed in some patients taking NSAIDs. Setolac®-MR tablets should be used with caution in patients with fluid retention or heart failure.

Pre-existing Asthma

Patients with asthma may have Aspirin-sensitive asthma. Since cross reactivity, including bronchospasm, between Aspirin and other NSAIDs has been reported in such Aspirin-sensitive patients, Setolac®-MR tablets should not be administered to patients with this form of Aspirin sensitivity and should be used with caution in patients with pre-existing asthma.

Renal Effects

Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. In these patients, administration of a NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the elderly. No information is available from controlled clinical studies regarding the use of S (+) Etodolac in patients with advanced renal disease. Therefore, treatment with Setolac®-MR tablets is not recommended in these patients with advanced renal disease.

Hepatic Effects

Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including S (+) Etodolac. Setolac®-MR tablets should be used with caution in patients with hepatocellular insufficiency or non-cirrhotic alcoholic liver disease. Impairment of renal or hepatic functions due to other causes may alter drug metabolism; patients receiving concomitant long-term therapy, especially the elderly, should be observed for potential side effects and their drug doses adjusted as needed, or the drug discontinued.

Post-marketing cases of cytolytic and cholestatic hepatitis have been reported with Thiocolchicoside. Severe cases (i.e. fulminant hepatitis) have been reported in patients concomitantly taking NSAIDs or paracetamol. Patients should be advised to report any sign of liver toxicity.

Gastrointestinal Effects

NSAIDs, including Etodolac, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. Setolac®-MR tablets should be prescribed with extreme caution to those with a prior history of ulcer disease or gastrointestinal bleeding. To minimize the potential risk for an adverse GI event in patients, the lowest effective dose should be used for the shortest possible duration. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population.

Hematological Effects

Anemia is sometimes seen in patients receiving NSAIDs, including Etodolac, due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including Etodolac, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia. NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Patients receiving Setolac®-MR tablets who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.

SLE and mixed connective tissue disease:

In patients with systemic lupus erythematosus (SLE) and mixed connective tissue disorders, there may be an increased risk of aseptic meningitis.

Dermatological:

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs (see section 4.8). Patients appear to be at the highest risk for these reactions early in the course of therapy: the onset of the reaction occurs in the majority of cases within the first month of treatment. Tablets should be discontinued at the first appearance of the skin rash, mucosal lesions, or any other sign of hypersensitivity.

Anaphylactoid Reactions

As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to Etodolac. Setolac®-MR tablets should not be given to patients with the aspirin triad.

Teratogenicity/Embryofoetotoxicity

In preclinical studies, one of the thiocolchicoside metabolites (SL59.0955) induced aneuploidy (i.e. unequal number of chromosomes in dividing cells) at concentrations close to human exposure observed at doses 8 mg twice daily per os. Aneuploidy is reported as a risk factor for teratogenicity, embryo-fetotoxicity/spontaneous abortion, cancer, and impaired male fertility. As a precautionary measure, use of this product at doses exceeding the recommended dose or long-term use should be avoided.

Other Precautions

• S (+) Etodolac cannot be expected to substitute corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation.
• The pharmacological activity of Setolac®-MR in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed non-infectious, painful conditions.
• Setolac®-MR tablets should be used with caution in patients with severe renal insufficiency (creatinine clearance 30 mL/min), Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency, chronic alcoholism, excessive alcohol intake (3 or more alcoholic drinks every day), anorexia, bulimia or cachexia; chronic malnutrition (low reserves of hepatic glutathione), dehydration, and hypovolemia.
• In case of diarrhea, the treatment with Thiocolchicoside should be stopped.

4.5 Drug interactions

ACE inhibitors: Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors.

Aspirin: When Etodolac is administered with Aspirin, its protein binding is reduced, although the clearance of free Etodolac is not altered.

Other analgesics including cyclooxygenase-2 selective inhibitor: Avoid concomitant use of two or more NSAIDs (including aspirin) as this may increase the risk of adverse effects (see section 4.4)

Anti-hypertensives: Reduced anti-hypertensive effect

Diuretics: Etodolac can reduce the natriuretic effect of furosemide and thiazides in some patients with possible loss of blood pressure control. Caution should be paid to the concomitant intake of enzyme-inducing agents.

Cardiac glycosides: NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.

Lithium: NSAIDs have produced an elevation of plasma Lithium levels and a reduction in renal Lithium clearance. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and Lithium are administered concurrently, subjects should be observed, carefully for signs of Lithium toxicity.

Cyclosporin, Digoxin, Methotrexate: Etodolac, like other NSAIDs, through effects on renal prostaglandins, may cause changes in the elimination of these drugs leading to elevated serum levels of Cyclosporine, Digoxin, Methotrexate, and increased toxicity. Nephrotoxicity associated with Cyclosporine may also be enhanced.

Anti-coagulants: NSAIDs may enhance the effects of anti-coagulants, such as warfarin.

Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs): Increased risk of gastrointestinal bleeding.

Tacrolimus: Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.

Zidovudine: Increased risk of haematological toxicity when NSAIDs are given with zidovudine. There is an evidence of an increased risk of haemarthroses and haemtoma in HIV (+) haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.

Bilirubin tests can give a false positive result due to the presence of phenolic metabolites of Setolac®-MR Tablets in the urine.

Mifepristone: NSAIDs should not be used for 8-12 days after mifepristone administration as NSAIDs can reduce the effect of mifepristone.

Corticosteroids: increased risk of gastrointestinal ulceration or bleeding.

Quinolone antibiotics: animal data indicate that NSAIDs can increase the risk of convulsions associated with quinolone antibiotics. Patients taking NSAIDs and quinolones may have an increased risk of developing convulsions.

Phenylbutazone: Phenylbutazone causes an increase (by about 80%) in the free fraction of Etodolac though the clinical implication of the same is not known.

Chloramphenicol: Increased plasma concentration of chloramphenicol.

4.6 Use in special populations

Fertility:

The use of Setolac®-MR Tablets may impair female fertility and is not recommended in women attempting to conceive. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of Setolac®-MR Tablets should be considered.

Pregnancy:

In teratology studies, isolated occurrences of alterations in limb development were found and included polydactyly, oligodactyly, syndactyly, and unossified phalanges in rats and oligodactyly and synostosis of metatarsals in rabbits.

Drugs which inhibit prostaglandin biosynthesis may cause dystocia and delayed parturition as evidenced by studies in pregnant animals.

Congenital abnormalities have been reported in association with NSAID administration in man; however, these are low in frequency and do not appear to follow any discernible pattern. In view of the known effects of NSAIDs on the foetal cardiovascular system, some inhibitors of prostaglandin biosynthesis have been shown to interfere with the risk of closure of the ductus arteriosus, use in the last trimester of pregnancy is contraindicated. The onset of labour may be delayed and the duration increased with an increased bleeding tendency in both mother and child.

From the 20th week of pregnancy onward, etodolac use may cause oligohydramnios resulting from foetal renal dysfunction. This may occur shortly after treatment initiation and is usually reversible upon discontinuation. In addition, there have been reports of ductus arteriosus constriction following treatment in the second trimester, most of which resolved after treatment cessation. Therefore, during the first and second trimester of pregnancy, etodolac should not be given unless clearly necessary. If etodolac is used by a woman attempting to conceive, or during the first and second trimester of pregnancy, the dose should be kept as low and duration of treatment as short as possible. Antenatal monitoring for oligohydramnios and ductus arteriosus constriction should be considered after exposure to etodolac for several days from gestational week 20 onward. Etodolac should be discontinued if oligohydramnios or ductus arteriosus constriction are found.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the fetus to:

- cardiopulmonary toxicity (premature constriction/closure of the ductus arteriosus and pulmonary hypertension);

- renal dysfunction (see above);

the mother and the neonate, at the end of pregnancy, to:

- possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses.

- inhibition of uterine contractions resulting in delayed or prolonged labor. Consequently, etodolac is contraindicated during the pregnancy.

Studies of Thiocolchicoside conducted in animals have shown reproductive toxicity including teratogenic effects. There are insufficient clinical data to evaluate the safety of use in pregnancy. Thus, the potential hazards for the embryo and fetus are unknown. In consequence, Thiocolchicoside is contraindicated in pregnancy and women of childbearing potential who are not using effective contraception.

Lactation:

Since it passes into the mother's milk, the use of Thiocolchicoside is contraindicated during breast feeding. Many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from S (+) Etodolac, 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.

Setolac®-MR Tablets are contraindicated in lactating mothers.

Pediatric use:

Safety and effectiveness in pediatric patients below the age of 18 years have not been established.

Geriatric use:

As with any NSAID, caution should be exercised in treating the elderly (65 years and older) and when increasing the dose. Elderly patients may be more sensitive to the anti-prostaglandin effects of NSAIDs (on the gastrointestinal tract and kidneys) than younger patients. In particular, elderly or debilitated patients who receive NSAID therapy seem to have a lower tolerance for gastrointestinal ulceration or bleeding as compared to other individuals, and most spontaneous reports of fatal GI events are in this population. S (+) Etodolac is eliminated primarily by the kidney. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

4.7 Effects on the ability to drive and use machines

There is no data available regarding the effect of Setolac®-MR on driving vehicles and using machines. It may cause dizziness or somnolence. So, you should not drive or operate heavy machinery if you feel dizzy or not fully alert.

4.8 Undesirable effects

Most frequently reported adverse reactions (approx. 1 - 10%):

Gastrointestinal experiences including abdominal pain, constipation, diarrhea, dyspepsia, flatulence, gross bleeding / perforation, heartburn, nausea, GI ulcers (gastric / duodenal), vomiting.

Other events including: abnormal renal function, anemia, dizziness, edema, elevated liver enzymes, headaches, increased bleeding time, pruritis, rashes, tinnitus.

Additional NSAID Adverse Experiences Reported Occasionally with

Body as a whole: Allergic skin reactions, anaphylactic / anaphylactoid reactions (including shock), chills, fever, sepsis.

Digestive system: diarrhea, nausea, vomiting, anorexia, cholestatic hepatitis / jaundice, dry mouth, duodenitis, esophagitis, gastritis, gastric peptic ulcers, glossitis, hepatic failure, hepatitis, hematemesis, intestinal ulceration, jaundice, liver necrosis, melena, pancreatitis, rectal bleeding, stomatitis. Less frequently, gastritis has been observed. Pancreatitis has been reported very rarely.

Hypersensitivity: Hypersensitivity reactions have been reported following treatment with NSAIDs. These may consist of (a)non-specific allergic reactions and anaphylaxis (b)respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm or dyspnoea, or (c)assorted skin disorders, including rashes of various types, pruritus, urticaria, purpura, angioedema and more rarely exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme).

Cardiovascular and cerebrovascular:

Congestive heart failure, flushing, palpitations, tachycardia, syncope, vasculitis (including necrotizing and allergic). Oedema, hypertension and cardiac failure have been reported in association with NSAID treatment Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long term treatment) may be associated with an increased risk of arterial thrombotic events (for example myocardial infarction or stroke).

Hepatic: Abnormal liver function, cytolytic and cholestatic hepatitis and jaundice

Metabolic and nutritional: hyperglycaemia in previously controlled diabetic patients.

Neurological and special senses: Visual disturbances, somnolence, photophobia, blurred vision, optic neuritis, headaches, paraesthesia, reports of aseptic meningitis (especially in patients with existing auto-immune disorders, such as systemic lupus erythematous, mixed connective tissue disease), with symptoms such as stiff neck, headache, nausea, vomiting, fever or disorientation, depression, confusion, hallucinations, tinnitus, vertigo, dizziness, malaise, fatigue, and drowsiness. Anxiety, confusion, depression, dream abnormalities, insomnia, nervousness, paresthesia, somnolence, tremors, vertigo. Syncope vasovagal, convulsions may be seen with Thiocolchicoside.

Blood and lymphatic system: Agranulocytosis, ecchymosis, eosinophilia, hemolytic anemia, leukopenia, neutropenia, pancytopenia, purpura, thrombocytopenia and aplastic anaemia.

There have been reports of blood dyscrasias including methaemoglobenaemia and agranulocytosis, but these were not necessarily causality related to paracetamol.

Respiratory system: Asthma, dyspnea, pulmonary infiltration with eosinophilia.

Dermatological: Bullous reactions including Stevens Johnson Syndrome and Toxic Epidermal Necrolysis (very rare). Photosensitivity. Angioedema, cutaneous vasculitis with purpura, erythema multiforme, hyperpigmentation, sweating, urticaria, vesiculobullous rash.

Urogenital system: Dysuria, elevated BUN, oliguria / polyuria, proteinuria, renal failure, renal insufficiency, renal papillary necrosis, serum creatinine increase, urinary frequency, Nephrotoxicity in various forms, including interstitial nephritis, nephrotic syndrome.

Anaphylactic reactions: Uncommon: pruritus, Rare: urticaria, Unknown: angioneurotic edema,

Reporting of side effects

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via

email to: medico@zuventus.com

Website: http://www.zuventus.co.in/safety.aspx

By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

Etodolac

Symptoms include headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding, rarely diarrhea, disorientation, excitation, coma, drowsiness, dizziness, tinnitus, fainting, and occasionally convulsions. In cases of significant poisoning acute renal failure and liver damage are possible.

Management: Patients should be treated symptomatically as required. Within one hour of ingestion of a potentially toxic amount, activated charcoal should be considered. Alternatively, in adults, gastric lavage should be considered within one hour of indigestion of a potentially life-threatening overdose. Good urine output should be ensured. Renal and liver function should be closely monitored. Patients should be observed for at least four hours after ingestion of potentially toxic amounts. Frequent or prolonged convulsions should be treated with intravenous diazepam. Other measures may be indicated by the patient's clinical condition. The standard practices of gastric lavage, activated charcoal administration, and general supportive therapy should be undertaken.

Thiocolchicoside

No specific symptoms of overdose have been reported in patients treated with Thiocolchicoside. Management Should overdosage occur, medical supervision and symptomatic measures are recommended.

5.1 Mechanism of Action

S (+) Etodolac is the pharmacologically active component of racemate Etodolac. The anti-inflammatory, analgesic, and antipyretic activities of S (+) Etodolac have been observed to be due to the inhibition of cyclooxygenase-2 (COX-2) resulting in the inhibition of prostaglandin synthesis.

Thiocolchicoside is a sulfur-containing, semi-synthetic analog of colchicine, a natural colchicum glucoside found in “meadow-saffron” which behaves pharmacologically as a muscle relaxant, both in humans and in animals. It is a muscle relaxant with anti-inflammatory and analgesic effects. It eliminates or substantially decreases centrally originating muscle contracture: in spastic hypertonia, it reduces the muscle’s passive resistance to stretching and decreases, or removes, the residual contracture. Its muscle-relaxing effect can also be observed in the visceral muscles: it has, in particular, been demonstrated in the uterus. However, Thiocolchicoside has no curariform effect, since it acts through the central nervous system rather than paralyzing the muscle’s motor plaque.

5.2 Pharmacodynamic properties

Etodolac

Inhibition of prostaglandin synthesis and COX-2 selectivity: All non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to inhibit the formation of prostaglandins. It is this action which is responsible both for their therapeutic effects and some of their side-effects. The inhibition of prostaglandin synthesis observed with etodolac differs from that of other NSAIDs. In an animal model at an established anti-inflammatory dose, cytoprotective PGE concentration in the gastric mucosa have been shown to be reduced to a lesser degree and for a shorter period than other NSAIDs. This finding is consistent with subsequent in-vitro studies which have found etodolac to be selective for induced cyclo-oxygenase 2 (COX-2, associated with inflammation) over COX-1 (cytoprotective).

Furthermore, studies in human cell models have confirmed that etodolac is selective for the inhibition of COX-2.

The clinical benefit of preferential COX-2 inhibition over COX-1 has yet to be proven.

Anti-inflammatory effects: Experiments have shown etodolac to have marked anti-inflammatory activity, being more potent than several clinically established NSAIDs.

Thiocolchicoside

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. GABA is the main inhibitory neurotransmitter in the human cortex. GABAergic neurons are involved in myorelaxation, anxiolytic treatment, sedation, and anesthetics. It also has an affinity for the inhibitory glycine receptors (i.e., has glycomimetic and GABA mimetic activity) and, 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 micron) 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 only apparent at high concentrations.

5.3 Pharmacokinetic properties

S (+) Etodolac is well absorbed and does not undergo significant first-pass metabolism following oral administration. The extent of absorption of S (+) Etodolac is not affected after a meal. Food intake, however, reduces the peak concentration reached by approximately one-half and increases the time to peak concentration.

Thiocolchicoside: 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.

6.1 Animal Toxicology or Pharmacology

Etodolac: Not Available

Thiocolchicoside

Thiocolchicoside safety profile has been assessed in vitro and in vivo following parenteral and oral administration. Acute Toxicity- At higher doses, thiocolchicoside induced emesis in dog, diarrhea in rat and convulsions in both rodents and non-rodents after acute administration by oral route. Chronic Toxicity-Thiocolchicoside was well tolerated following oral administration for periods of up to 6 months in both the rat and the non-human primate when administered at repeated doses of less than or equal to 2mg/kg/day in the rat and less or equal to 2.5mg/kg/day in non-human primate, and by the intramuscular route in the primate at repeated doses upto 0.5mg/kg/day for 4 weeks. After repeated administration, thiocolchicoside induced gastrointestinal disorders (enteritis, emesis) by oral route and emesis by i.m. route. Carcinogenicity-The carcinogenic potential was not evaluated Genotoxicity Thiocolchicoside itself did not induce gene mutation in bacteria (Ames test), in vitro chromosomal damage (chromosome aberration test in human lymphocytes) and in vivo chromosomal damage (in vivo intraperitoneal micronucleus in mouse bone marrow) The major glucuro-conjugated metabolite SL18.0740 did not induce gene mutation in bacteria (Ames test); however it induced in vitro chromosomal damage (in vitro micronucleus test on human lymphocytes) and in vivo chromosomal damage (in vivo oral micronucleus test in mouse bone marrow). The micronuclei predominantly resulted from chromosome loss (centromere positive micronuclei after FISH centromere staining), suggesting aneugenic properties. The aneugenic effect of SL18.0740 was observed at concentrations in the in vitro test and at AUC plasma exposures in the in vivo test higher (> 10 times based on AUC) than those observed in human plasma at therapeutic doses. The aglycon metabolite (3-demethylthiocolchicine-SL59.0955) induced in vitro chromosomal damage (in vitro micronucleus test on human lymphocytes) and in vivo chromosomal damage (in vivo oral micronucleus test in rat bone marrow). The micronuclei predominantly resulted from chromosome loss (centromere positive micronuclei after FISH or CREST centromere staining), suggesting aneugenic properties. The aneugenic effect of SL59.0955 was observed at concentrations in the in vitro test and at exposures in the in vivo test close to those observed in human plasma at therapeutic doses of 8 mg twice daily per os.

Aneugenic effect in dividing cells may result in aneuploid cells. Aneuploidy is a modification in the number of chromosomes and loss of heterozygosity, which is recognized as a risk factor for teratogenicity, embryo-toxicity/spontaneous abortion, impaired male fertility, when impacting germ cells and cancer when impacting somatic cells

Teratogenicity.

In the rat, a dose of 12 mg/kg of thiocolchicoside caused major malformations along with foetotoxicity (retarded growth, embryo death, impairment of sex distribution rate). The dose without toxic effect was 3 mg/kg. In the rabbit, thiocolchicoside showed maternotoxicity starting from 24 mg/kg. Furthermore, minor abnormalities have been observed (supernumerary ribs, retarded ossification).

Impairment of Fertility

In a fertility study performed in rats, no impairment of fertility was seen at doses up to 12 mg/kg, i.e. at dose levels inducing no clinical effect. Thiocolchicoside and its metabolites exert aneugenic activity at different concentration levels, which is recognized as a risk factor for impairment of human male fertility.

(S)-etodolac is the S-enantiomer of etodolac. It is a preferential inhibitor of cyclo-oxygenase 2 and a non-steroidal anti-inflammatory, whereas the enantiomer, (R)-etodolac, is inactive. The racemate is commonly used for the treatment of rheumatoid arthritis and osteoarthritis, and for the alleviation of postoperative pain.

Chemical Name: 2-[(1S)-1,8-diethyl-4,9-dihydro-3H-pyrano[3,4-b]indol-1-yl]acetic acid

Molecular Formula: C₁₇H₂₁NO₃

Molecular Weight: 287.35 g/mol

Structure:

Thiocolchicoside is a semi-synthetic derivative of the colchicine, a natural anti-inflammatory glycoside. It is a muscle relaxant with anti-inflammatory and analgesic effects.

Chemical Name: N-[(7S)-1,2-dimethoxy-10-(methylthio)-9-oxo-3-[[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)-2-oxanyl]oxy]-6,7-dihydro-5H-benzo[a]heptalen-7-yl]acetamide is a glycoside.

Molecular Formula: C₂₇H₃₃NO₁₀S

Molecular Weight: 563.6 g/mol

Structure:

8.1 Incompatibilities

None

8.2 Shelf life

Refer on the pack.

8.3 Packaging Information

10 Blister strips of 10 tablets each

8.4 Storage and handling instructions

Store below 30ºC. Protect from light and moisture. Keep out of reach of children. Tablets should be swallowed whole & not to be broken, chewed, or crushed. Any unused product or waste material should be disposed of in accordance with local requirements.

• Take it with food to avoid getting an upset stomach.
• The drug should be taken precisely as it has been prescribed. Meant for oral consumption, Setolac®-MR Tablet should be taken whole. Do not chew or crush it as it may reduce its effect on the body.
• It is best that you do not stop the medication mid-course as the pain may reoccur. Complete the entire treatment course for the best results.
• Avoid consuming alcohol when taking Setolac®-MR Tablet as it may cause excessive drowsiness and increase the risk of liver damage.
• Do not take it with any other medicine containing acetaminophen (drugs for pain/fever or cough and cold) without asking your doctor first.

Polmacoxib Capsules 2 mg

Each hard gelatin capsule contains :

Polmacoxib 2 mg

Excipients q.s

Approved colours used in capsule shell

Polmacoxib 2 mg capsules for oral use.

4.1 Therapeutic indications

Polmacoxib capsules is indicated for the treatment of idiopathic (primary) osteoarthritis of hip / knee.

4.2 Posology and method of administration

Adults

The recommended dose of Polmacoxib is 2 mg once daily after a meal, should not exceed 2 mg/day. If there is no therapeutic benefit at the recommended dose, administration of this drug should be discontinued and appropriate alternative treatment methods should be considered.

Patients with hepatic and renal impairment

This drug should not be administered because there is no administration experience.

Recommendations for use in cardiovascular disorders

The potential risks and benefits of Polamcoxib and other alternative therapies should be considered before administering Polmacoxib.

As the dose and duration of exposure increases, the risk of cardiovascular disease increases.

The efficacy of this drug for more than 6 weeks and the safety of long-term administration of more than 6 months have not been established, and adverse reactions such as hypertension, angina pectoris, and edema may occur when administering this drug.

Therefore, when administering this drug, the patient's symptom relief and response to treatment should be reevaluated regularly at least monthly.

4.3 Contraindications

• Patients who have a history of hypersensitivity reactions or a history of this drug and its components.
• Patients with allergic reactions to Sulfonamide.
• Patients with a history of asthma, acute rhinitis, nasal polyps, angioedema, urticaria or allergic reactions to Aspirin or other non-steroidal anti-inammatory drugs (including COX-2 inhibitors).
• Patients with uncontrolled hypertension (systolic blood pressure above 140 mmHg or higher and/or diastolic blood pressure above 90 mmHg or higher).
• Patients with edema or fluid retention.
• Patients with renal and hepatic impairment.
• Patients with active peptic ulcer or gastrointestinal bleeding.
• Patients with inflammatory bowel disease such as Crohn's disease or ulcerative colitis.
• Patients with congestive heart failure (NYHA II - IV).
• Established ischemic heart disease, peripheral arterial disease and/or cerebrovascular disease.
• Pregnant women or women who may be pregnant.
• Nursing mother.
• Treatment of pain before and after coronary artery bypass graft (CABG).
• Patients with hyperkalemia.
• Patients with a blood clotting disorder or receiving anticoagulants.

Carefully administer to the following patients

• Patients with bronchial asthma.
• Heart failure patients or patients with such a history of it.
• High blood pressure (hypertension) patients or patients with such a history of it.
• Patients with a history of edema.
• Patients taking diuretics or ACE inhibitors.
• Patients at risk of hypovolemia
• Dehydration patients.
• Elderly.
• Patients with a history of peptic ulcer or gastrointestinal bleeding.
• Patients with high risk factors for adverse cardiovascular events (such as heart attack, stroke, etc.) (e.g. high blood pressure, hyperlipidemia, diabetes, smoking, etc.) patients with cardiovascular system or a history.
• Patients with difficult metabolism by CYP3A4.
• Women planning pregnancy (taking this drug may impair female fertility).
• Diabetics.

4.4 Warnings and precautions

Warning

If a person who regularly drinks three or more drinks daily who needs to take this medicine or other antipyretic analgesics, they must consult a doctor or pharmacist. When these people take this drug, gastrointestinal bleeding can occur.

Cardiovascular risk

Non-steroidal anti-inflammatory analgesic drugs including Polmacoxib, may increase the risk of severe cardiovascular thrombosis, myocardial infarction and stroke which can be fatal. Depending on the duration of administration, dosage and underlying cardiovascular risk factors, these risks may be increased and may be more risky in patients with cardiovascular disease. To minimize the potential risk of adverse cardiovascular events in patients treated with Polmacoxib, it should be used for the shortest possible time at the minimum effective dose. Doctors and patients should carefully monitor the onset of these cardiovascular symptoms, even if there is no history of cardiovascular disease. Patients have signs and/or symptoms of significant cardiovascular toxicity and these symptoms (chest pain, shortness of breath, weakness, obscured pronunciation) it is important to know in advance what measures to take if this occurs. As a result of clinical trials of this drug, adverse reactions of prothrombin time prolongation have been reported, but this drug has not been studied for its action on platelets, so it cannot be used as a substitute for aspirin as a prophylactic treatment for the cardiovascular system.

Gastrointestinal risk

Non-steroidal anti-inflammatory drugs, including Polmacoxib, may increase the risk of serious gastrointestinal adverse events including gastric or intestinal bleeding, ulcers and perforation, which can be fatal. These adverse reactions can occur without warning symptoms during the administration period. Older people may be at greater risk of serious gastrointestinal adverse events. As the duration of administration increases, the likelihood of serious gastrointestinal adverse events may increase, but short-term administration does not completely exclude these risks. While taking Polmacoxib, you should carefully monitor for symptoms and signs of gastrointestinal ulcer or bleeding, and immediately if you suspect any suggestive symptoms or severe gastrointestinal adverse reactions, including pain, indigestion, black stools, and hematomes. Additional evaluation and treatment should be performed. In high-risk patients, alternative treatments not related to non-steroidal anti-inflammatory drugs should be considered.

Effect on clinical test values

• If symptoms or signs of anemia or blood loss appear due to long-term administration of this drug, hemoglobin or hematocrit test should be performed.
• Patients who take non-steroidal anti-inflammatory drugs, including this drug, for a long time should have regular complete blood count (CBC) and physical and chemical tests.
• Clinical examinations (urinalysis, blood tests, kidney function tests, liver function tests, electrocardiogram tests, fecal occult blood tests, etc.) should be performed regularly or as necessary, and if any abnormalities are confirmed, appropriate treatment such as withdrawal or suspension of administration should be performed.
• If clinical symptoms or systemic signs (e.g. eosinophilia, rash) associated with liver disease or renal disease are present, or abnormal liver function tests or renal function test results persist or worsen, administration of this drug should be discontinued.

Gastrointestinal adverse reactions

Extreme caution should be exercised when prescribing NSAIDs, including this drug, to patients with a history of ulcerative disease or gastrointestinal bleeding.

In patients with a history of peptic ulcer disease and/or gastrointestinal bleeding, the risk of gastrointestinal bleeding increased by more than 10-fold with NSAIDs compared to patients without these risk factors.

Other risk factors for increased gastrointestinal bleeding include concomitant use of oral corticosteroids or anticoagulants, concomitant use of non-steroidal anti-inflammatory drugs or aspirin, alcohol consumption, smoking, advanced age, and poor health.

Since most of the spontaneous reports of fatal gastrointestinal adverse events are in the elderly and infirm, special care should be taken when administering this drug to these patients.

Hypertension

Non-steroidal anti-inammatory drugs, including this drug, may cause hypertension or worsen existing hypertension, which may increase the incidence of adverse cardiovascular events, so patients with uncontrolled hypertension should not be administered.

Patients taking thiazide diuretics or loop diuretics may have a reduced response to these therapies when taking NSAIDs.

Non-steroidal anti-inflammatory drugs, including this drug, should be administered with caution in patients with high blood pressure. Blood pressure should be closely monitored at the beginning of administration and during the administration of this drug. If there is a significant increase in blood pressure during the administration of this drug, alternative treatment should be considered.

Congestive heart failure and edema

Fluid retention and edema have been observed in some patients taking NSAIDs, including this drug. This drug should not be given to patients with edema or fluid retention.

Inhibition of prostaglandin synthesis can cause deterioration of renal function and fluid retention, so this drug should be administered with caution in patients with a history of heart failure, left ventricular dysfunction, or hypertension.

In addition, patients who are taking diuretics or who are at risk of hypovolemia for other reasons should also be careful when administering this drug.

Long-term use of non-steroidal anti-inflammatory drugs including this drug may cause renal papillary necrosis or other kidney damage.

In addition, since the role of prostaglandins in maintaining renal blood flow is important, special care should be taken in patients with heart failure, patients with renal failure, patients with liver failure, patients receiving diuretic ACE inhibitors or angiotensin II receptor antagonists, and the elderly. When the medication is discontinued, most people return to their pre-treatment state.

Advanced renal disease

No controlled clinical trials have been conducted on the use of this drug in patients with advanced renal disease. Therefore, administration of this drug is not recommended for patients with advanced renal disease. If administration of this drug is to be initiated, the patient's renal function should be closely monitored.

Administration of NSAIDs, including this drug, may cause an increase in liver function levels. These abnormal test values may worsen, change or be temporary as treatment continues.

In addition, severe liver-related adverse reactions, including jaundice, fatal fulminant hepatitis, hepatic necrosis, and liver failure (some of which are fatal), have been reported infrequently with NSAIDs, including this drug.

In patients with symptoms and/or signs suggestive of abnormal liver function or abnormal liver function test results, continue to carefully observe whether liver function deteriorates during the administration period, and if abnormal liver function test results (more than 3 times the upper limit of normal) are continuously observed, or clinical symptoms or systemic signs related to liver disease (e.g. eosinophilia, rash) are observed, the administration of this drug is stopped.

Anaphylactic reactions

As with other NSAIDs, pseudo-anaphylactic reactions can occur in patients who have never been exposed to the drug.

This combination of symptoms typically occurs in asthma patients with or without nasal polyps or presenting with potentially fatal severe bronchospasm after administration of aspirin or other NSAIDs. In the event of such a similar anaphylactic reaction, first aid should be administered.

Skin reactions

• This drug is a Sulfonamide class of drugs, which can cause serious adverse skin reactions such as exfoliative dermatitis, mucosal eye syndrome (Stevens-Johnson syndrome) and toxic epidermal necrosis (Riell's syndrome), which can be fatal.
• These serious adverse reactions can occur without warning symptoms and may occur in patients with no history of sulfa allergy. In most cases, these adverse reactions occur within the first month of administration.
• Patients should be aware of the symptoms and symptoms of serious skin manifestations and should stop taking the drug at the first symptoms and signs of hypersensitivity reactions such as skin rashes, mucosal lesions or blisters, fever, and itching.

Some people with asthma may be sensitive to aspirin. The use of aspirin in patients with aspirin-sensitive asthma may be associated with severe bronchospasm, which can be fatal.

Cross-reactivity involving bronchospasm between Aspirin and other NSAIDs has been repor ted in these aspirin-sensitive patients. Therefore, this drug should not be administered to these aspirin-sensitive patients and should be used with caution in asthma patients.

This drug cannot be used as a substitute for corticoid preparations or as a drug to treat corticoid deciency. Abrupt discontinuation of corticosteroids may result in worsening of corticosteroid-responsive disease. If this drug is to be administered to patients who have been taking corticosteroids for a long time, the dose should be reduced gradually.

Due to the pharmacological properties of this drug, it is possible to indiscriminate other symptoms and signs of fever and inflammation, thereby delaying the diagnosis of infectious complications under painful and non-infectious conditions.

Patients with severe dehydration should be carefully monitored after hydration.

This drug is not administered because its safety and efficacy in acute pain relief (postoperative or post-tooth extraction) have not been established.

This drug should be avoided in combination with non-steroidal anti-inflammatory drugs other than low-dose aspirin (less than 1 mg per day), regardless of the dose administered.

Patients who are receiving antiplatelet therapy should not stop the treatment, so this drug is not administered. Patients with autoimmune diseases [e.g. patients with systemic erythematosus lupus (SLE) and mixed connective tissue disease (MCTD)] may have an increased risk of developing aseptic meningitis when taking NSAIDs, including this drug.

In the case of non-steroidal anti-inflammatory drugs, including this drug, hyperkalemia may occur in diabetic patients or when co-administered with drugs that increase bloodpotassium levels, so regular monitoring of potassium levels is necessary in such cases.

Transient infertility has been reported in women taking NSAIDs for a long time.

4.5 Drug interactions

Since this drug is mainly metabolized by CYP3A4 in the liver, caution should be exercised when co-administered with drugs that inhibit CYP3A4.

Ketoconazole

Concurrent administration of Ketoconazole 400 mg with Polmacoxib inhibits the metabolism of CYP3A4, AUC is 1.3 fold higher when given the drug in combination, lower dosage than the typical dosage amount is worth considering. In addition, the drugs when administered in combination of Ketoconazole Tmax median was 71.9 hours, when administered alone was 9 hours, because the extended portion of the time, note that administration of the ketoconazole in combination, the therapeutic response time may be delayed. Concurrent administration with the antifungal agent Ketoconazole, which also interferes with many CYP isoforms, led to a 29% increase of Polmacoxib plasma concentration.

CYP enzymes

Drug-drug interactions with diuretics Acetazolamide, Furosemide, Hydrochlorothiazide or Antiepileptic drugs as it inhibits the metabolism of cytochrome P450 (CYP) 2D6 substrates, affects the metabolism of cytochrome P450, with the isoform CYP3A being involved.

The main exposure in the blood concentration of the clinical dose of these drugs in the study CYP enzymes (CYP1A2, 2C9, 2C19, 2D6, etc.) showed that it does not inhibit the action. In vivo because the bar exam studies, should consult with your doctor when administered in combination with other drugs.

ACE inhibitors or angiotensin Ⅱ receptor antagonists

NSAIDs including about ACE inhibitor or angiotensin Ⅱ receptor antagonist, where in it may be reduced in hypertensive effect of the drug and ACE inhibitor or angiotensin Ⅱ because of administering the antagonist in combination. If so, you should keep these interactions in mind. In patients with impaired renal function (e.g. dehydrated patients or the elderly), co-administration of non-steroidal anti-inflammatory drugs, including Polmacoxib, in combination with an ACE inhibitor or angiotensin II receptor antagonist may generally increase the risk of reversible acute renal failure. Therefore, care should be taken when administering such a combination, especially to the elderly. Shall be supplied to the patient adequate water, it should be regularly monitored for renal function after starting this combination therapy.

Diuretics

In the case of non-steroidal anti-inflammatory analgesics including this drug, it was confirmed that the natriuretic effect of Furosemide and Thiazide diuretics may be reduced in some patients by inhibition of prostaglandin synthesis in the kidney. Therefore, during co-administration of these drugs and non-steroidal anti-inflammatory drugs including Polmacoxib, signs of kidney failure should be closely monitored.

NSAIDS and Aspirin

There is no consistent evidence that combination with Aspirin may reduce the risk of serious cardiovascular thrombotic reactions associated with the use of non-steroidal anti-inflammatory drugs, including Polmacoxib. Selective COX-2 inhibitors of low-dose Aspirin (325 mg or less), can be administered together, about a monotherapy gastrointestinal adverse events than (gastrointestinal ulcer) reported that the increased incidence of other gastrointestinal complications. Since this drug has not been studied for its action on platelets, it cannot be a substitute for aspirin as a prophylactic treatment for the cardiovascular system.

Lithium

Non-steroidal anti-inflammatory drugs can increase the concentration of serum Lithium and decrease the application rate of Lithium by inhibiting the synthesis of prostaglandins in the kidney. Therefore, when a combination of non-steroidal anti-inflammatory analgesics and Lithium is administered, the signs of toxicity of Lithium should be carefully observed.

Methotrexate

NSAIDs delay the excretion of Methotrexate when administered in the combination, haematological toxicity of fatal Methotrexate can be increased in anti-cancer therapy (15 mg/week or more), Methotrexate is not administered in combination, when used in combination low-dose Methotrexate dose should be administered carefully, and consider the appropriate monitoring for toxicity associated with Methotrexate.

Coumarin-based anticoagulants

Warfarin and non-steroidal anti-inflammatory analgesics may exhibit synergistic effects on gastrointestinal bleeding. It can increase your risk of bleeding.

As a result of clinical trials of Polmacoxib, adverse reactions of prothrombin time prolongation were reported, and serious bleeding related to prothrombin time prolongation, which may be fatal, was reported in patients who co-administered selective COX-2 inhibitors and Warfarin. Should not be administered in combination. Especially, it was reported more in the elderly.

Cyclosporine or Tacrolimus

The nephrotoxicity of Cyclosporine or Tacrolimus may be increased by co-administration of non-steroidal anti-inflammatory analgesics with Cyclosporine or Tacrolimus, so renal function should be monitored when co-administered with these drugs.

Aspirin

In addition to low-dose Aspirin (less than 325 mg per day), co-administration with other non-steroidal anti-inflammatory drugs may increase the risk of adverse reactions and should not be administered in combination.

Corticosteroids

There is a risk of increased gastrointestinal adverse events (e.g. Ulcers, bleeding). It is especially dangerous for the elderly (65 years or older).

4.6 Use in special populations

Pregnancy

It has been reported that this drug does not delay delivery in rats. However, the effect of this drug on delivery and childbirth in pregnant women is unknown.

Risk summary

There is no clinical data for administering this drug to pregnant women. In animal studies (rabbits and rats), administration of Polmacoxib has shown reproductive toxicity, including teratogenicity, but the potential risk of human pregnancy is unknown. Also, this drug, like other drugs that inhibit prostaglandin synthesis, may cause uterine asthenia or premature obstruction of the foetal arterial duct when administered at the end of pregnancy. If pregnancy is conrmed while taking Polmacoxib, stop taking Polmacoxib.

Maternal and/or embryo / fetal risk

In rabbit embryo / foetal development tests, the incidence of foetal abnormalities such as rib fusion and sternal segment fusion and ventricular septal defects rarely increased when administered orally over 3 mg/kg/day dose. In the embryo / foetal development test of rats, when 3 mg/kg/day dose was administered orally, the 13th rib length in the foetus was shorter than that of the control group or the low dose group, which is statistically significant that can be observed in the foetus. It was a phenomenon. In addition, there were no changes in mean number of luteal bodies, mean number of implants, and number of survival times in all administration groups. The use of non-steroidal anti-inflammatory analgesic drugs may interfere or delay follicular rupture due to its mechanism of action, which may cause reversible infertility in some women. Therefore, in the case of women having difficulty conceiving or undergoing infertility testing, discontinuation of non-steroidal anti-inflammatory analgesic drugs, including this drug, should be considered.

The inhibitory action of prostaglandin synthesis may adversely affect pregnancy. Epidemiologic studies have shown that the risk of natural abortion increases after taking drugs that inhibit prostaglandin synthesis in early pregnancy. Animal studies have shown that implantation failure increases when drugs that inhibit prostaglandin synthesis are administered. Polmacoxib was found to significantly reduce the average number of luteal bodies, implantation and surviving embryos when administered at a dose of 1 mg/kg/day or more in rats.

Lactation

It has been confirmed that Polmacoxib can be transferred to the breast milk of rats at a concentration similar to or slightly higher than that of plasma and transmitted to the foetus. Many drugs not only transfer into breast milk, but if they do, serious adverse reactions may occur in infants. Therefore, taking into account the importance of drug administration to nursing mothers, lactation should be stopped or drug administration should be discontinued.

Paediatric use

Safety and effectiveness of Polmacoxib in paediatric patients under 18 years of age have not been established.

Geriatric use

Elderly people are likely to have decreased renal function, liver function, and especially heart function, so appropriate observation is required when administering Polmacoxib to the elderly.

In patients with arthritis age 70 or older, the blood drug concentration of is 1.4 times higher than that in ar thritis patients aged 40 to 69 years, so it should be administered carefully.

4.7 Effects on ability to drive and use machines

Patients who experience dizziness, drowsiness, etc. after taking this drug should avoid driving or handling machinery

4.8 Undesirable effects

The safety of this drug was evaluated in 601 patients with osteoarthritis. In osteoarthritis patients, the maximum duration of administration of this drug was 24 weeks, and the most common patients were 2 to 3 weeks. According to the clinical trials of placebo or the active and reference formulations, the most frequent of which at least stop the medication due to adverse reactions was indigestion and epigastric pain. The most commonly reported TEAEs with the treatment of Polmacoxib were associated with GI and general disorders. All adverse reactions reported in the clinical trial of Polmacoxib in osteoarthritis patients, regardless of the causal relationship with this drug are as follows:-

Infection

Common : Nasopharyngitis. Uncommon : Pneumonia, ringworm, bronchitis, cellulitis, boil, shingles, influenza, syphilis, urinary tract infection, nail fungus.

Gastrointestinal disorders

Common : Epigastric pain, diarrhoea, indigestion, nausea, abdominal pain. Uncommon : Vomiting, bowel movement disorder, irritable bowel syndrome, stool discoloration, food poisoning, gastric ulcer, gingivitis, tooth disorder, dry mouth, enteritis, upper abdominal discomfort, gastritis, abdominal discomfort, lower abdominal pain, aphthous stomatitis, constipation, gastroesophageal reflux disease, colon polyps, esophagitis.

General disorders and administration site conditions

Common : Chest discomfort, facial swelling, oedema, peripheral swelling. Uncommon : Fatigue, systemic oedema, influenza-like disease, weight gain, asthenia, thirst, bruise, abrasion, laceration, traffic accident, spinal cord compression fracture, chills, fever, insect bite, concussion, ligament rupture, ligament sprain, wound, wrist fracture.

Skin and subcutaneous tissue disorders

Uncommon : Swelling of the face, hives, erythema, neuro dermatitis, itching, general itching, dry eczema.

Musculoskeletal and connective tissue disorders

Uncommon : Arthralgia, back pain, flat feet, joint swelling, neck pain, limb pain, musculoskeletal pain, muscle spasms

Investigation

Uncommon : Heat sensation, drug overdose, increased neutrophils, decreased unsaturated iron binding capacity, prothrombin time, haemoglobin decreased, increased alanine aminotransferase (ALT), Increased blood creatinine, increased aspartate aminotransferase, increased creatine phosphate activator.

increased aspartate aminotransferase, increased creatine phosphate activator.

Nervous system disorders

Common : Headache.

Uncommon : Insomnia, paraesthesia, conscious depression, dizziness, drowsiness, dullness, Alzheimer's type dementia.

Benign and malignant neoplasms

Uncommon : Colon adenoma.

Blood and lymphatic system disorders

Common : Anaemia.

Uncommon : Skin papilloma.

Immune system disorder

Uncommon : Eosinophilia, hypersensitivity reaction.

Metabolic and nutritional system

Uncommon : Chemical allergy, diabetes, hypercholesterolemia, hyperkalaemia.

Mental disorder

Uncommon : Depressed mood, major depression.

Visual impairment

Uncommon : Eye edema, swelling of the eyelids, blepharitis, eyelid cramps, dry eyes, keratitis, macular hole.

Ear and maze disorders

Uncommon : Ear discomfort, positional dizziness.

Heart disorder

Uncommon : Palpitations, angina, right leg block, myocardial ischemia.

Vascular disorder

Common : Increase in blood pressure.

Uncommon : Arrhythmia, high blood pressure, facial flushing, abnormal blood pressure.

Respiratory, thoracic and mediastinal disorders

Common : Coughing, difficulty breathing Uncommon : Asthma, runny nose, oropharyngeal pain, wet cough, rhinitis, allergic rhinitis

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to : medico@zuventus.com

Website : http://www.zuventus.co.in/safety.aspx

By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

Symptoms caused by excessive administration of NSAIDs is usually lethargy, drowsiness, nausea, vomiting and upper abdominal pain etc., can be recovered as a co-therapy. Gastrointestinal bleeding can also occur, and in rare cases, high blood pressure, acute renal failure, respiratory depression and coma can occur.

Usually symptomatic and adjuvant treatment is performed, and there is no specific antidote.

Vomiting, activated carbon (60 to 100 g for adults, 1 to 2 g per kg of children), and osmotic diarrhea can be used if symptoms appear within 4 hours of taking the drug or are taken in very large amounts.

Hemodialysis, forced diuresis, alkalized of urine, the treatment such as blood perfusion is not useful because of the high protein bonding ratio of the drug.

5.1 Mechanism of action / pharmacodynamic properties

Polmacoxib is not only a selective COX-2 inhibitor but also a potent inhibitor of carbonic anhydrases (CAs). Both CA I and CA II are highly expressed in the GI tract and kidneys, organs that are also thought to be the sites at which selective COX-2 inhibitors show their side effects. By inhibition assays, we show that both CA I and CA II are strongly inhibited by Polmacoxib, while CA II also demonstrates direct competition with COX-2. To understand, at the molecular level, how Polmacoxib interacts with CA I and II, we solved the first crystal structures of CA I and CA II in complex with Polmacoxib, at 2.0 Å and 1.8 Å, respectively. Interestingly, three Polmacoxib molecules bind to the active site of CA I, whereas only one molecule binds CA II. In the active site, the three molecules of Polmacoxib organize itself along hydrophobic interaction as “stack-on-formation”, and fully occupy a cone-shaped active pocket in CA I. The binding mode of Polmacoxib to CA II was found different than its binding to Celecoxib and Valdecoxib. Our results provide structural insight into inhibition of CA I and CA II by Polmacoxib, to assess its potential clinical efficacy.

5.2 Pharmacokinetic properties

In non-clinical pharmacokinetic studies, this drug showed a high distribution in whole blood compared to plasma, and in clinical studies, drug exposure in whole blood was observed to be 80 to 100 times higher than in plasma.

Absorption

In a single oral dose clinical trial for healthy adults, the blood exposure C_max of this drug increased in proportion to the dose increase, but the AUC (ng h/mL) increased more than the dose increase rate. The maximum plasma t concentration (C_max) observed in the same clinical trial reached a median value of about 5.5 to 72 hours after administration, and the blood concentration was expected to reach a steady state about 20 days after the start of administration. The half-life of a single 5 mg dose of this drug was approximately 5 days.

Distribution

In vitro tests, the binding rate of human plasma protein of this drug was observed to be about 92% and the distribution rate to whole blood was about 98%. In a clinical trial of a single dose of 8 mg loading dose followed by a 2-day repeat dose of 6 mg in healthy adults, the drug exposure (AUC ) of whole blood was about 50 ~ 70 times higher than that of plasma. At this time, the average t C_max in the steady state was 2,054 ng / mL in whole blood and 40 ~ 51 ng/mL in plasma.

Metabolism

This drug is mainly metabolized by CYP3A4. When a single oral administration of this dr ug was administered to healthy adults, Phase I and Phase II metabolites were identied in the plasma and urine of the subjects. Phase I metabolites were detected in both plasma and urine of the subjects, and glucuronic acid conjugates were detected only in urine. No other reactive metabolites were detected.

Excretion

Af 14 ter a single oral administration of [ C]-radiolabelled this drug to male and female monkeys, the total radioactivity detected in the excretions collected up to 168 hours was about 70.4% of the dose, and the radioactivity recovered by intravenous administration was 54.5 ~67.7% higher than the highest 13%. In addition, when administered orally, the cumulative radioactivity in feces was 38.5 ~ 49.4%, and the cumulative radioactivity in urine was 20.8 ~ 32.1%, and radioactivity was detected in both feces and urine of monkeys. The ratio of metabolites in the radioactivity recovered from monkey feces was more than 99%, and the parent drug detected in the feces was less than 0.9% of the dose. In a clinical trial of repeated administration of 2 mg for 6 days after 8 mg loading dose in healthy adults, the half-reduction period was about 6 to 7 days in whole blood and about 5 to 6 days in plasma.

(1) Safety pharmacological test

In rats to evaluate the effect on the central nervous system and respiratory system, and in monkeys to evaluate the effect on the circulatory system, up to 30 mg/kg of this drug was orally administered, and no effect of this drug administration was observed.

(2) Repeated administration toxicity test

As a result of toxicity tests performed in rats and monkeys by repeated oral administration, which is the clinical route of administration, the non-toxic dose (NOAEL) was observed to be less than 26.1 mg/kg/day in males, 25.0 mg/kg/day in females, and 3.39 mg/kg/day in monkeys at 1 weeks in the rat 25-week trial. Digestive tract disorders with inflammation and ulceration were mainly observed as common toxicity symptoms in rats and monkeys.

(3) Genotoxicity test

In the reversion mutation test using bacteria and the mouse micronucleus test, this drug did not show mutagenicity, but in the chromosomal abnormality test using CHO cells at 200 μg/mL, an increase in the frequency of cells with chromosomal abnormalities was observed in the presence of a metabolic active system.

(4) Carcinogenicity test

Tumors were not induced when this drug was orally administered to rats at doses of 1 mg/kg for males and 0.3 mg/kg for females for 102 weeks and 91 weeks, respectively. It represents a safety margin of 2.8 times and 3.0 times, respectively, compared to the recommended dose of 2 mg exposure. Tumors were not induced when this drug was orally administered to mice at a dose of up to 6mg/kg for 78 weeks, and the exposure at week 26 (AUC0-24h) at the highest dose used in the study was compared to the exposure at the clinically recommended dose of 2mg for males and females, respectively. 2.7-fold and 3.4-fold margins of safety.

Polmacoxib, an orally-active tissue-selective COX-2 inhibitor and binds to enzyme arbonic anhydrase. It is chemically described as Benzenesulfonamide, 4-[3-(3-fluorophenyl)-4,5-dihydro-5,5-dimethyl-4-oxo-2-furanyl] with a molecular formula of C₁₈H₁₆FNO₄S and a molecular weight of 361.40 g/mol.

8.1 Incompatibilities

None

8.2 Shelf-life

Refer on the pack.

8.3 Packing information

Alu-Alu blister strip of 10 capsules.

8.4 Storage and handling instructions

Store at a temperature not exceeding 30^oC. Protect from moisture.

Keep out of reach of children. Capsule should be swallowed whole and not to be opened, chewed or crushed.

Advise the patient to read the approved patient labeling. Before administering this drug, the potential risks and benefits of this drug and other alternative therapies should be considered. As the dose and duration of exposure increases, the cardiovascular risk increases. Therefore, administer the lowest effective dose for the shortest period possible. The efficacy of this drug for more than 6 weeks and the safety of long-term administration of more than 6 months have not been established, and adverse reactions such as hypertension, angina pectoris, and edema may occur when administering this drug. Therefore, when administering this drug, the efficacy of this drug for more than 6 weeks and the safety of long-term administration for more than6 months have not been established. Therefore, at least monthly, whether to continue administration according to the patient's symptom relief and response to treatment should be re-evaluated. In patients with significant risk factors for cardiovascular events (e.g. hypertension, hyperlipidemia, diabetes mellitus, smoking), it should be administered after careful consideration.

Elderly

When administering this drug to the elderly or patients with cardiac dysfunction, medically appropriate management should be continued. If symptoms worsen during treatment, appropriate measures such as discontinuation of treatment should be taken.

When administering this drug to the elderly or patients with cardiac dysfunction, medically appropriate management should be continued. If symptoms worsen during treatment, appropriate measures such as discontinuation of treatment should be taken.

Gastrointestinal adverse reactions

Extreme caution should be exercised when prescribing NSAIDs, including this drug, to patients with a history of ulcerative disease or gastrointestinal bleeding.

In patients with a history of peptic ulcer disease and/or gastrointestinal bleeding, the risk of gastrointestinal bleeding increased more than 10-fold when treated with NSAIDs compared to patients without these risk factors. Other risk factors for increased gastrointestinal bleeding include concomitant use of oral corticosteroids or anticoagulants, non-steroidal anti-inflammatory drugs or aspirin, alcohol consumption, smoking, old age, and poor health.

Since most of the spontaneous reports of fatal gastrointestinal adverse reactions are in the elderly and infirm, special care should be taken when administering this drug to these patients.

Hypertension

NSAIDs, including this drug, can cause hypertension or aggravate pre-existing hypertension, which may increase the incidence of adverse cardiovascular events. Therefore, this drug should not be administered to patients with uncontrolled hypertension. do.

Patients taking Thiazide diuretics or loop diuretics may have a reduced response to these therapies when taking NSAIDs.

NSAIDs, including this drug, should be administered with caution in hypertensive patients. Blood pressure should be closely monitored at the beginning and during treatment with this drug. Alternative treatment should be considered if blood pressure rises significantly during treatment with this drug.

Congestive heart failure and edema

Fluid retention and edema have been observed in some patients taking non-steroidal anti-inflammatory drugs including this drug. This drug should not be administered to patients with edema or fluid retention. Because inhibition of prostaglandin synthesis can lead to deterioration of renal function and fluid retention, this drug should be administered with caution in patients with a history of heart failure, left ventricular dysfunction, or hypertension.

n addition, caution should be exercised when administering this drug in patients taking diuretics or at risk of hypovolemia for other reasons.

NSAID’s

When taking non-steroidal anti-inflammatory drugs including this drug for a long time, renal papillary necrosis or other kidney damage may occur. In addition, since the role of prostaglandin in maintaining renal blood flow is important, special attention is required in patients with heart failure, renal failure, liver failure, patients receiving diuretic ACE inhibitors or angiotensin II receptor antagonists, and the elderly. When the drug is discontinued, most patients return to their pre-treatment state.

Advanced renal disease

No controlled clinical trials have been conducted on the use of this drug in patients with advance adrenal disease. Therefore, administration of this drug is not recommended for patients with advanced renal disease. If treatment with this drug is to be initiated, the patient's renal function should be closely monitored.

Liver function

Administration of non-steroidal anti-inflammatory drugs including this drug may cause an increase in liver function levels. These abnormal laboratory values may worsen, remain unchanged, or be transient as treatment continues. In addition, there have been rare reports of severe liver-related adverse reactions, including jaundice, fatal fulminant hepatitis, hepatic necrosis, and hepatic failure (some fatal), with NSAIDs including this drug. Patients with symptoms and/or signs suggestive of liver function abnormalities, or patients with abnormal liver function test results, should be continuously and carefully monitored for deterioration of liver function during the administration period, and abnormal liver function test results (up to 3 upper limit of normal) Dosage should be discontinued if liver disease-related clinical symptoms or systemic signs (e.g. eosinophilia, rash) are observed.

Hematology

If symptoms or signs of anemia or blood loss appear due to long-term administration of this drug, hemoglobin or hematocrit should be tested. Selective COX-2 inhibitors do not generally affect platelet count, prothrombin time (PT), or partial thromboplastin time (PTT), and do not inhibit platelet aggregation at recommended doses. Adverse reactions have been reported, so caution should be exercised. 10) Patients taking NSAIDs, including this drug, for a long period of time should have a complete blood count (CBC) and physicochemical tests performed regularly. If clinical symptoms or systemic signs (e.g. eosinophilia, rash) associated with liver or renal disease develop, or if abnormal liver or renal function test results persist or worsen, the drug should be discontinued.

Anaphylactic reactions

Similar to other non-steroidal anti-inflammatory analgesics, similar anaphylactic reactions can occur in patients who have never been exposed to drugs. These complex symptoms typically occur in asthma patients with or without nasal polyps or with potentially fatal severe bronchospasm after administration of Aspirin or other non-steroidal anti-inflammatory drugs. First aid measures should be taken in the event of such an anaphylactic reaction.

Skin reactions

This medicine as a sulfonamide-based drugs, deprived dermatitis, skin, mucous membranes should syndrome (Stevens - Johnson syndrome) and toxic epidermal bars with (Riel's syndrome) can cause serious skin adverse events such as, which can be fatal there is. These serious adverse reactions can occur without warning symptoms and can also occur in patients with no history of sulfa drug allergy. In most cases, these adverse reactions occur within the first month of administration. Patients should be aware of the signs and symptoms of significant skin manifestations and should be discontinued at the first symptoms and signs of hypersensitivity reactions such as skin rash, mucosal lesions or blisters, fever and itching.

Asthma patients

Some people with asthma may be sensitive to aspirin. Aspirin Sensitization The use of Aspirin in patients with asthma may be associated with severe bronchospasm, which can be fatal. Cross-reactions involving bronchospasm between Aspirin and other non-steroidal anti-inflammatory drugs have been reported in these Aspirin-sensitive patients. Therefore, this drug is administered and do not have such Aspirin-sensitive patients, should be with caution for patients with asthma.

Corticosteroids

This drug cannot be used as a substitute for corticosteroids or as a drug to treat corticoid deficiency. Sudden discontinuation of corticosteroids can lead to exacerbation of corticosteroid - reactive disorders. If you are taking this drug to patients who have been taking corticosteroids for a long time, you should gradually decrease the dose.

Diagnosis of infectious complications Due to the pharmacological nature of this drug, it may delay the diagnosis of infectious complications under painful and non-infectious conditions by making other symptoms and signs of fever and inflammation invisible.

Dehydration

In patients with severe dehydration symptoms, the drug should be administered after hydration and carefully observed.

Pain relief

Do not administer this drug as the safety and efficacy for acute pain relief (pain relief after surgery or tooth extraction) have not been established.

Myocardial infarction and stroke

The incidence of myocardial infarction and stroke was found in two large-scale controlled clinical trials for the treatment of pain from the first 10 to 14 days immediately after coronary artery bypass grafting (CABG) with other selective COX-2 inhibitors used for postoperative pain.

Clinical test

Conduct clinical tests [urinalysis, blood tests, renal function tests, liver function tests, electrocardiogram (EKG) and the fecal occult blood test, etc.] regularly or as needed, and if abnormalities are found, take appropriate measures such as withdrawal or discontinuation of the drug.

Combination with NSAIDS

This drug should be avoided in combination with non-steroidal anti-inflammatory drugs other than low-dose Aspirin (less than 325 mg per day), regardless of the dose administered.

Driving or handling machinery

Patients who experience dizziness, drowsiness, etc. after taking this drug should avoid driving or handling machinery.

Aspirin

Results of clinical trials have been reported about the adverse reactions prothrombin time extension, the drug is not because the bar acts conducted research on platelets as a preventative therapy for cardiovascular drugs can be a substitute for aspirin. Patients receiving anti-platelet therapy, so should not stop the treatment, do not administer this medicine.

Symptomatic treatment

Note that treatment with anti-inflammatory analgesics is symptomatic, not causative therapy.

Cross-sensitivity

Patients who are susceptible to one non-steroidal anti-inflammatory analgesic can likewise show sensitivity to other non-steroidal anti-inflammatory analgesics.

Autoimmune diseases

Autoimmune diseases (e.g. systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD) patients) may have a risk of aseptic meningitis when taking NSAIDs, including Polmacoxib. In the case of non-steroidal anti-inflammatory analgesics including this drug, hyperkalemia may occur in diabetic patients or when coadministered with drugs that increase blood potassium levels, so in such cases, regular observation of potassium levels is necessary

Infertility

Temporary infertility has been reported in women who take non-steroidal anti-inammatory drugs for a long time.

Diet

This drug has not been carried out clinical trials on dietary inuences, authorized usage, by complying with the capacity to be administered after a meal.

Cefditoren Pivoxil Dispersible Tablets

Each uncoated dispersible tablet contains :

Cefditoren Pivoxil

equivalent to Cefditoren 50 mg

Excipients q.s.

Dispersible Tablet 50 mg

4.1 Therapeutic indications

Cefditoren Pivoxil is indicated for the treatment of mild to moderate infections in children (2 months to 12 years of age) which are caused by susceptible strains of the designated microorganisms in the conditions listed below:

• Acute bacterial exacerbation of chronic bronchitis.
• Community-acquired pneumonia.
• Pharyngitis / tonsillitis.
• Acute sinusitis.
• Uncomplicated skin and skin-structure infections.

4.2 Posology and method of administration

Recommended doses in children (2 months to 12 years of age)

For children with pneumonia, otitis media or sinusitis

In general, 3 mg/kg/dose, 3 times a day, after meals. The dosage may be increased up to 6 mg/kg/dose as needed, but should not exceed 200 mg, 3 times a day (600 mg/day).

For children with diseases other than above diseases

In general, 3 mg/kg/dose, 3 times a day, after meals. The dosage may be adjusted according to the disease or the patient's age and symptoms, but should not exceed 200 mg, 3 times a day (600 mg /day).

Method of administration

Disperse the tablet in one teaspoonful of previously boiled and cooled water before administration.

4.3 Contraindications

Patients with known allergy to the cephalosporin class of antibiotics or any of its components. Patients with carnitine deficiency or inborn errors of metabolism that may result in clinically significant carnitine deficiency, because use of Cefditoren Pivoxil causes renal excretion of carnitine.

4.4 Special warnings and precautions for use

• Before therapy with Cefditoren Pivoxil is instituted, careful inquiry should be made to determine whether the patient has had previous hypersensitivity reactions to Cefditoren Pivoxil, other cephalosporins, penicillins, or other drugs.
• If Cefditoren Pivoxil is to be given to penicillin-sensitive patients, caution should be exercised because cross-hypersensitivity among β-lactam antibiotics has been clearly documented and may occur in up to 10% of patients with a history of penicillin allergy.
• If an allergic reaction to Cefditoren Pivoxil occurs, the drug should be discontinued. Serious acute hypersensitivity reactions may require treatment with epinephrine and other emergency measures, including oxygen, intravenous fluids, intravenous antihistamines, corticosteroids, pressor amines, and airway management, as clinically indicated.
• Pseudomembranous colitis has been reported with nearly all antibacterial agents, including Cefditoren Pivoxil, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.
• Treatment with antibacterial agents alters normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is a primary cause of antibiotic-associated colitis.
• After the diagnosis of pseudomembranous colitis has been established, appropriate therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against C. difficile colitis.
• Prescribing Cefditoren Pivoxil in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
• Cefditoren Pivoxil is not recommended when prolonged antibiotic treatment is necessary. since other pivalate-containing compounds have caused clinical manifestations of carnitine deficiency when used over a period of months. No clinical effects of carnitine decrease have been associated with short-term treatment.
• Community-acquired pneumonia clinical trials demonstrated no adverse events attributable to decreases in serum carnitine concentrations. However, some sub-populations (e.g., patients with renal impairment, patients with decreased muscle mass) may be at increased risk for reductions in serum carnitine concentrations during Cefditoren Pivoxil therapy.
• As with other antibiotics, prolonged treatment may result in the possible emergence and overgrowth of resistant organisms. Careful observation of the patient is essential. If superinfection occurs during therapy, appropriate alternative therapy should be administered.
• Prothrombin time should be monitored in patients at risk and exogenous Vitamin K should be administered as indicated.

4.5 Interaction with other medicinal products and other forms of interaction

Antacids reduces the oral absorption of a single 400 mg dose of Cefditoren Pivoxil administered following a meal, by a 14% decrease in mean Cmax and an 11% decrease in mean AUC.

H2-Receptor Antagonists like Famotidine reduce the oral absorption of a single 400 mg dose of Cefditoren Pivoxil administered following a meal, by a 27% decrease in mean Cmax and a 22% decrease in mean AUC. Probenecid increases the plasma concentration of Cefditoren Pivoxil, with a 49% increase in mean Cmax, a 122% increase in mean AUC, and a 53% increase in t1/2.

4.6 Use in special populations

Pregnancy

The safety of Cefditoren Pivoxil has not been established. Cefditoren Pivoxil should not be used in pregnant women unless the potential benefits to the mother outweigh the risk to the fetus.

benefits to the mother outweigh the risk to the fetus.

Nursing mothers

Many drugs are excreted in human breast milk so caution should be exercised when Cefditoren Pivoxil is administered to nursing women.

Geriatric use

No clinically significant differences in effectiveness or safety were observed between older and younger patients. No dose adjustments are necessary in geriatric patients with normal (for their age) renal function.

4.7 Effects on ability to drive and use machines

Cefditoren Pivoxil has no or negligible influence on the ability to drive or use machines. However, Cefditoren Pivoxil may cause side effects influencing the capacity of reaction and the ability to drive and use machines.

4.8 Undesirable effects

As a result of post-marketing survey of Cefditoren Pivoxil granules, total 5,821 clinical cases were reported from 875 facilities in Japan. The number of side effects was 136 cases (2.34%), and the number of adverse reactions occurred was 146 cases. The main adverse reactions were 121 cases (2.08%) of digestive tract disorders (diarrhea, loose stools, etc.), skin and skin structure disorders (rash, urticaria) 10 cases (0.17%).

Post-marketing case study reports shows that Cephalosporin class drugs are associated with Fixed Drug Eruption (FDE).

Serious side effects (< 0.1%)

• Shock and anaphylaxis, Severe colitis (as pseudomembranous colitis), Toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, Interstitial pneumonia, Liver function disorder, Severe kidney injury, Agranulocytosis, Haemolytic anemia if any of these disorders are recognized, stop administration immediately and take appropriate measures.
• Since hypoglycemia (frequency unknown) associated with hypo-carnitineemia may be seen in cases in which antibiotics having Pivoxil groups are administered to children (especially infants), hypoglycemic symptoms such as convulsions and disturbances of consciousness are observed If so, discontinue administration and take appropriate measures.

other side effects

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to: medico@zuventus.com

Website: https://www.zuventus.com/drug-safety-reporting

By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

Treat over-dosage symptomatically and institute supportive measures as required. In animals diarrhea and soft stool lasting for few days were observed. Gastric Lavage may be done to remove the excess drug from the stomach.

5.1 Mechanism of action

Cefditoren Pivoxil is bactericidal in nature and its activity results from the inhibition of cell wall synthesis via affinity for penicillin-binding proteins (PBPs). It has high affinity for penicillin binding protein (PBP) of various bacteria.

5.2 Pharmacodynamic properties

Antibacterial activity Cefditoren Pivoxil is metabolized into cefditoren on absorption in the intestinal wall and shows its antibacterial activity. Cefditoren Pivoxil exerts broad spectrum antibacterial activity in vitro against gram-positive and gram-negative bacteria. Especially it showed strong antibacterial activity against gram-positive bacteria such as Staphylococcus sp., Streptococcus sp. and Streptococcus pneumoniae, and gram-negative bacteria such as Escherichia coli, Moraxella (Branhamella) catarrhalis, Klebsiella sp., Proteus sp. and Haemophilus influenzae, and against anaerobic bacteria such as Peptostreptococcus sp., Propionibacterium acnes, Bacteroides sp. and Prevotella sp. Cefditoren Pivoxil also showed antibacterial activity against β-lactamase-non producing ampicillin resistant Haemophilus influenzae (BLNAR). In vitro, Cefditoren Pivoxil was stable against β-lactamases producing strains.

5.3 Pharmacokinetic Properties

Absorption and distribution

Following oral administration, Cefditoren Pivoxil is absorbed from the gastrointestinal tract and hydrolyzed to Cefditoren by esterases. Serum concentration and pharmacokinetic parameters of Cefditoren Pivoxil were as shown in Table 1 when doses of 3 mg - 6 mg/kg were orally administered to pediatric patients with normal renal function.

Table 1: Pharmacokinetic parameters of normal pediatric patients with renal function

After absorption Cefditoren Pivoxil is distributed to different body fluids and tissues e.g. sputum, tonsil tissue, maxillary sinus mucosa, skin tissue, tooth extraction wound etc.

Protein binding

The binding rate with human serum protein measured by ultrafiltration was 91.5% at a concentration of 25 μg/mL (in vitro).

Metabolism / excretion

Cefditoren Pivoxil undergoes metabolism upon absorption and becomes Cefditoren and pivalic acid with antimicrobial activity. Pivalic acid undergoes carnitine conjugation and is excreted in the urine as pivaloylcarnitine. Cefditoren Pivoxil is excreted largely in urine and bile without much metabolism. Urinary excretion rate (0 to 8 hours) as Cefditoren Pivoxil was about 20% and 17%, respectively, when orally administered 3 mg/kg, 6 mg/kg once or twice to pediatric patients with normal renal function.

Urinary excretion rate decreased as the extent of impairment of renal function increased, and a delay of excretion was observed.

6.1 Animal toxicology or pharmacology

No known animal toxicology data.

Zostum O 50 DT Tablet contains Cefditoren Pivoxil, a semi-synthetic cephalosporin antibiotic for oral administration. It is a prodrug which is hydrolyzed by esterases during absorption, and the drug is distributed in the circulating blood as active Cefditoren.

Chemical name: 2, 2-Dimethylpropanoyloxymethyl (6R, 7R)-7-[(Z)-2- (2-aminothiazol-4-yl)-2-(methoxyimino) acetylamino]-3-[(1Z)- 2-(4-methylthiazol-5-yl) ethenyl]-8-oxo-5-thia-1-azabicyclo[4.2.0] oct-2-ene -2-carboxylate.

Molecular formula: C₂₅H₂₈N₆O₇S₃

Molecular weight: 620.72 g/mol

8.1 Incompatibilities

Not applicable

8.2 Shelf-life

Refer on the pack.

8.3 Packaging information

A strip of 10 tablets.

8.4 Storage and handing instructions

Store below 25°C. Protect from light & moisture.

Keep away from the reach of children.

• Parents or caregivers should be counselled that antibacterial drugs including Zostum O 50 DT should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold).
• When Zostum O 50 DT is prescribed to treat a bacterial infection, patients/ parents or caregivers should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Zostum O 50 DT or other antibacterial drugs in the future.
• Zostum O 50 DT (cefditoren pivoxil) should be taken with meals to enhance absorption.
• It is not recommended that Zostum O 50 DT be taken concomitantly with antacids or other drugs taken to reduce stomach acids.

06 April 2023

Cefditoren Pivoxil Tablets 200 mg

Each film coated tablet contains :

Cefditoren Pivoxil equivalent to Cefditoren 200 mg

Excipients q.s. Colours : Lake of Quinoline Yellow & Titanium Dioxide IP

Tablet 200 mg

4.1 Therapeutic indications

Cefditoren pivoxil tablet is indicated for the treatment of mild to moderate infections in adults and adolescents (12 years of age or older) which are caused by susceptible strains of the designated microorganisms in the conditions listed below.

• Acute bacterial exacerbation of chronic bronchitis
• Pharyngitis /tonsillitis
• Uncomplicated skin and skin-structure infections

4.2 Posology and method of administration

Acute Bacterial Exacerbation of Chronic Bronchitis: 400 mg b.i.d. for 10 days

In Pharyngitis/Tonsillitis and Skin and Skin Structure infections: 200 mg b.i.d. for 10 days.

It is recommended to take dose with the meal.

Patients with Renal Insufficiency

No dose adjustment is necessary for patients with mild renal impairment (CLcr: 50-80 mL/min/1.73 m2). It is recommended that not more than 200 mg BID be administered to patients with moderate renal impairment (CLcr: 30-49 mL/min/1.73 m2) and 200 mg QD be administered to patients with severe renal impairment (CLcr: <30 mL/min/1.73 m2). The appropriate dose in patients with end-stage renal disease has not been determined.

Patients with Hepatic Disease

No dose adjustments are necessary for patients with mild or moderate hepatic impairment

4.3 Contraindications

Cefditoren is contraindicated in patients with known allergy to the Beta-lactam class of antibiotics or any of the components of the formulations.

4.4 Special warnings and precautions for use

Before therapy with cefditoren pivoxil is instituted, careful inquiry should be made to determine whether the patient has had previous hypersensitivity reactions to cefditoren pivoxil, other cephalosporins, penicillins, or other drugs. If cefditoren pivoxil is to be given to penicillin- sensitive patients, caution should be exercised because cross- hypersensitivity among beta-lactam antibiotics has been clearly documented and may occur in up to 10% of patients with a history of penicillin allergy.

If an allergic reaction to cefditoren pivoxil occurs, the drug should be discontinued. Serious acute hypersensitivity reactions may require treatment with epinephrine and other emergency measures, including oxygen, intravenous fluids, intravenous antihistamines, corticosteroids, pressor amines, and airway management, as clinically indicated.

Cefditoren pivoxil is not recommended when prolonged antibiotic treatment is necessary, since other pivalate-containing compounds have caused clinical manifestations of carnitine deficiency when used over a period of months. With other antibiotics prolonged treatment may result in the possible emergence and overgrowth of resistant organisms. It should be taken with meals to enhance absorption. It may be taken concomitantly with oral contraceptives. It is not recommended when taken concomitantly with antacids or other drugs taken to reduce stomach acids

4.5 Interaction with other medicinal products and other forms of interaction

Antacids – Antacids reduces the oral absorption of a single 400 mg dose of Cefditoren pivoxil administered following a meal, by a 14% decrease in mean Cmax and an 11% decrease in mean AUC. H2-Receptor Antagonists like Famotidine reduce the oral absorption of a single 400 mg dose of Cefditoren pivoxil administered following a meal, by a 27% decrease in mean Cmax and a 22% decrease in mean AUC. Probenecid increases the plasma concentration of cefditoren pivoxil, with a 49% increase in mean Cmax, a 122% increase in mean AUC, and a 53% increase in t1/2

4.6 Use in special populations

Pregnancy

The safety of Cefditoren has not been established. Cefditoren should not be used in pregnant women unless the potential benefits to the mother outweigh the risk to the fetus.

Nursing mothers:

Many drugs are excreted in human breast milk so caution should be exercised when cefditoren pivoxil is administered to nursing women. Geriatric use:

No clinically significant differences in effectiveness or safety were observed between older and younger patients. No dose adjustments are necessary in geriatric patients with normal (for their age) renal function.

4.7 Effects on ability to drive and use machines

Cefditoren has no or negligible influence on the ability to drive or use machines. However, cefditoren may cause side effects influencing the capacity of reaction and the ability to drive and use machines.

4.8 Undesirable effects

Fixed Drug Eruption (FDE) has been associated with Cefditoren pivoxil use

In clinical trials, 4834 adult and adolescent patients have been treated with the recommended doses of cefditoren pivoxil tablets (200 mg or 400 mg BID). Most adverse events were mild and self-limiting. No deaths or permanent disabilities have been attributed to cefditoren. The following adverse events were thought by the investigators to be possibly, probably, or definitely related to cefditoren tablets in multiple-dose clinical trials:

 

The overall incidence of adverse events, and in particular diarrhea, increased with the higher recommended dose of Cefditoren Pivoxil. Treatment related adverse events experienced by <1% but >0.1% of patients who received 200 mg or 400 mg BID of cefditoren pivoxil were abnormal dreams, allergic reaction, anorexia, asthenia, asthma, coagulation time increased, constipation, dizziness, dry mouth, eructation, face edema, fever, flatulence, fungal infection, gastrointestinal disorder, hyperglycemia, increased appetite, insomnia, leukopenia, leukorrhea, liver function test abnormal, myalgia, nervousness, oral moniliasis, pain, peripheral edema, pharyngitis, pseudomembranous colitis, pruritus, rash, rhinitis, sinusitis, somnolence, stomatitis, sweating, taste perversion, thirst, thrombocythemia, urticaria, and vaginitis. Pseudomembranous colitis symptoms may begin during or after antibiotic treatment.

Sixty-one of 2675 (2%) patients who received 200 mg BID and 69 of 2159 (3%) patients who received 400 mg BID of cefditoren pivoxil discontinued medication due to adverse events thought by the investigators to be possibly, probably, or definitely associated with cefditoren therapy. The discontinuations were primarily for gastrointestinal disturbances, usually diarrhea or nausea. Diarrhea was the reason for discontinuation in 19 of 2675 (0.7%) patients who received 200 mg BID and in 31 of 2159 (1.4%) patients who received 400 mg BID of cefditoren pivoxil.

Changes in laboratory parameters of possible clinical significance, without regard to drug relationship and which occurred in ≥1% of patients who received cefditoren pivoxil 200 mg or 400 mg BID, were hematuria (3.0% and 3.1%), increased urine white blood cells (2.3% and 2.3%), decreased hematocrit (2.1% and 2.2%), and increased glucose (1.8% and 1.1%). Those events which occurred in <1% but >0.1% of patients included the following: increased/decreased white blood cells, increased eosinophils, decreased neutrophils, increased lymphocytes, increased platelet count, decreased hemoglobin, decreased sodium, increased potassium, decreased chloride, decreased inorganic phosphorus, decreased calcium, increased SGPT/ALT, increased SGOT/AST, increased cholesterol, decreased albumin, proteinuria, and increased BUN. It is not known if these abnormalities were caused by the drug or the underlying condition being treated.

Cephalosporin Class Adverse Reactions

In addition to the adverse reactions listed above which have been observed in patients treated with cefditoren pivoxil, the following adverse reactions and altered laboratory test results have been reported for cephalosporin class antibiotics: Adverse Reactions: Allergic reactions, anaphylaxis, drug fever, Stevens-Johnson syndrome, serum sickness-like reaction, erythema multiforme, toxic epidermal necrolysis, colitis, renal dysfunction, toxic nephropathy, reversible hyperactivity, hypertonia, hepatic dysfunction including cholestasis, aplastic anemia, hemolytic anemia, hemorrhage, and superinfection. Altered Laboratory Tests: Prolonged prothrombin time, positive direct Coombs’ test, false-positive test for urinary glucose, elevated alkaline phosphatase, elevated bilirubin, levated LDH, increased creatinine, pancytopenia, neutropenia, and agranulocytosis. Several cephalosporins have been implicated in triggering seizures, particularly in patients with renal impairment when the dosage was not reduced. If seizures associated with drug therapy occur, the drug should be discontinued. Anticonvulsant therapy can be given if clinically indicated

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to: medico@zuventus.com

Website: https://www.zuventus.com/drug-safety-reporting

By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

Treat over-dosage symptomatically and institute supportive measures as required. In animals diarrhea and soft stool lasting for few days were observed. Gastric Lavage may be done to remove the excess drug from the stomach.

5.1 Mechanism of action

Cefditoren is bactericidal in nature and its activity results from the inhibition of cell wall synthesis via affinity for penicillin-binding proteins (PBPs). It has high affinity for penicillin binding protein (PBP) of various bacteria.

5.2 Pharmacodynamic properties

Antibacterial activity Cefditoren pivoxil is metabolized into cefditoren on absorption in the intestinal wall and shows its antibacterial activity. Cefditoren exerts broad spectrum antibacterial activity in vitro against gram-positive and gram-negative bacteria. Especially it showed strong antibacterial activity against gram-positive bacteria such as Staphylococcus sp., Streptococcus sp. and Streptococcus pneumoniae, and gram-negative bacteria such as Escherichia coli, Moraxella (Branhamella) catarrhalis, Klebsiella sp., Proteus sp. and Haemophilus influenzae, and against anaerobic bacteria such as Peptostreptococcus sp., Propionibacterium acnes, Bacteroides sp. and Prevotella sp. Cefditoren also showed antibacterial activity against -lactamase-non producing ampicillin resistant Haemophilus influenzae (BLNAR). In vitro, cefditoren was stable against -lactamases producing strains.

5.3 Pharmacokinetic Properties

Absorption

Following oral administration, cefditoren pivoxil is absorbed from the gastrointestinal tract and hydrolyzed to cefditoren by esterases. Maximal plasma concentrations (Cmax) of cefditoren under fasting conditions average 1.8 ± 0.6 µg/mL following a single 200 mg dose and occur 1.5 to 3 hours following dosing. Less than dose-proportional increases in Cmax and area under the concentration-time curve (AUC) were observed at doses of 400 mg and above. Cefditoren does not accumulate in plasma following twice daily administration to subjects with normal renal function. Under fasting conditions, the estimated absolute bioavailability of cefditoren pivoxil is approximately 14%. Administration of cefditoren pivoxil following a high fat meal resulted in a 70% increase in mean AUC and a 50% increase in mean Cmax compared to administration of cefditoren pivoxil in the fasted state.

Distribution

The mean volume of distribution at steady state (Vss) of cefditoren is 9.3 ± 1.6 L. Binding of cefditoren to plasma proteins averages 88% from in vitro determinations, and is concentration-independent at cefditoren concentrations ranging from 0.05 to 10 µg/mL.

Metabolism and Excretion

Cefditoren is eliminated from the plasma, with a mean terminal elimination half-life (t1/2) of 1.6 ± 0.4 hours in young healthy adults. Cefditoren is not appreciably metabolized. After absorption, cefditoren is mainly eliminated by excretion into the urine, with a renal clearance of approximately 4-5 L/h. Cefditoren renal clearance is reduced in patients with renal insufficiency.

6.1 Animal Toxicology or Pharmacology

No known animal toxicology data.

Zostum-O contains cefditoren pivoxil, a semi-synthetic cephalosporin antibiotic for oral administration. It is a prodrug which is hydrolyzed by esterases during absorption, and the drug is distributed in the circulating blood as active cefditoren.

Chemical name: 2, 2-Dimethylpropanoyloxymethyl (6R, 7R)-7-[(Z)-2- (2-aminothiazol-4-yl)-2-(methoxyimino) acetylamino]-3-[(1Z)- 2-(4-methylthiazol-5-yl) ethenyl]-8-oxo-5-thia-1-azabicyclo[4.2.0] oct-2-ene -2-carboxylate.

Molecular formula: C₂₅H₂₈N₆O₇S₃

Molecular weight: 620.72

 

8.1 Incompatibilities

Not applicable.

8.2 Shelf Life

Refer on the pack.

8.3 Packaging Information

A strip of 6 tablets / A strip of 10 tablets.

8.4 Storage and handing Instructions

Store below 25°C. Protect from light & moisture.

Keep out of reach of children.

• Patients should be counseled that antibacterial drugs including Cefditoren Pivoxil should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold).
• When Cefditoren Pivoxil is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Cefditoren Pivoxil or other antibacterial drugs in the future.
• Cefditoren Pivoxil should be taken with meals to enhance absorption.
• Cefditoren Pivoxil may be taken concomitantly with oral contraceptives.
• It is not recommended that Cefditoren Pivoxil be taken concomitantly with antacids or other drugs taken to reduce stomach acids

07 April 2023