PRECAUTIONS: Hematological Effects: Anemia is sometimes seen in patientsreceiving NSAIDs, including FDC of Misoprostol / Diclofenac Sodium. This maybe due to fluid retention, occult or gross GI blood loss, or an incompletelydescribed effect upon erythropoiesis. Patients on long-term treatment withNSAIDs, including FDC of Misoprostol / Diclofenac Sodium, should have theirhemoglobin or hematocrit checked if they exhibit any signs or symptoms ofanemia. NSAIDs inhibit platelet aggregation and have been shown to prolongbleeding time in some patients. Preexisting Asthma Patients with asthma mayhave aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitiveasthma has been associated with severe bronchospasm which can be fatal.Since cross reactivity, including bronchospasm, between aspirin and othernonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitivepatients, FDC of Misoprostol / Diclofenac Sodium should not be administered topatients with this form of aspirin.

Pregnancy: Pregnancy category X: Misoprostol may endanger pregnancy (may cause abortion) and thereby cause harm to the fetus when administered to a pregnant woman. Misoprostol may produce uterine contractions, uterine bleeding, and expulsion of the products of conception.

Aseptic meningitis: As with other NSAIDs, aseptic meningitis with fever andcoma has been observed on rare occasions in patients on diclofenac therapyrelated to diclofenac should be considered.Porphyria: The use of FDC of Misoprostol / Diclofenac Sodium in patients withhepatic porphyria should be avoided. To date, one patient has been describedin whom diclofenac sodium probably triggered a clinical attack of porphyria.The postulated mechanism, demonstrated in rats, for causing such attacks bydiclofenac sodium, as well as some other NSAIDs, is through stimulationof the porphyrin precursor delta-aminolevulinic acid (ALA).

DRUG INTERACTIONS: ACE-Inhibitors: Reports suggest that NSAIDs maydiminish the antihypertensive effect of ACE-inhibitors. This interaction shouldbe given consideration in patients taking NSAIDs concomitantly with ACEinhibitors.Aspirin: When FDC of Misoprostol / Diclofenac Sodium is administered withaspirin, the protein binding of diclofenac Sodium is reduced, although theclearance of the free FDC of Misoprostol / Diclofenac Sodium is not altered.The clinical significance of this interaction is not known; however, as withother NSAIDs, concomitant administration of diclofenac sodium and aspirinis not generally recommended because of the potential risk of increasedadverse effects.Digoxin: Elevated digoxin levels have been reported in patients receivingdigoxin and diclofenac sodium. Patients receiving digoxin and FDC ofMisoprostol / Diclofenac should be monitored for possible digoxin toxicity.Warfarin: The effects of warfarin and NSAIDs on GI bleeding are synergistic,such that users of both drugs together have a risk of serious bleeding greaterthan users of either drug alone.Oral hypoglycemics: Diclofenac sodium does not alter glucose metabolismin healthy people nor does it alter the effects of oral hypoglycemic agents.There are rare reports, however, from marketing experience, of changes ineffects of insulin or oral hypoglycemic agents in the presence of diclofenacsodium that necessitated change in the doses of such agents. Both hypo- andhyperglycemic effects have been reported. A direct causal relationship hasnot been established, but physicians should consider the possibility thatdiclofenac sodium may alter a diabetic patient‘s response to insulin or oralhypoglycemic agents.Methotrexate: NSAIDs have been reported to competitively inhibitmethotrexate accumulation in rabbit kidney slices. This may indicate thatthey could enhance the toxicity of methotrexate. Caution should be usedwhen NSAIDs are administered concomitantly with methotrexate.Cyclosporine: FDC of Misoprostol / Diclofenac, like other NSAID containingproducts, may affect renal prostaglandins and increase the toxicity of certaindrugs. Ingestion of FDC of Misoprostol / Diclofenac may increase cyclosporinenephrotoxicity. Patients who begin taking FDC of Misoprostol / Diclofenac or whoincrease their dose of FDC of Misoprostol / Diclofenac while taking cyclosporinemay develop toxicity characteristic for clyclosporine. They should beobserved closely, particularly if renal function is impaired.Lithium: NSAIDs have produced an elevation of plasma lithium levels and areduction in renal lithium clearance. The mean minimum lithium concentrationincreased 15% and the renal clearance was decreased by approximately 20%.These effects have been attributed to inhibition of renal prostaglandinsynthesis by the NSAID. Thus, when INSADs and lithium are administeredconcurrently, subjects should be observed carefully for signs of lithium toxicity.Antacids: Antacids reduce the bioavailability of misoprostol acid. Antacids mayalso delay absorption of diclofenac sodium. Magnesium-containing antacidsexacerbate misoprostol-associated diarrhea. Thus, it is not recommended thatFDC of Misoprostol / Diclofenac be coadministered with magnesium-containing antacids.Diuretics: Clinical studies, as well as post marketing observations, have shownthat FDC of Misoprostol / Diclofenac Sodium can reduce the natriuretic effect offurosemide and thiazides in some patients. This response has beenattributed to inhibition of renal prostaglandin synthesis. During concomitanttherapy with NSAIDs, the patient should be observed closely for signs of

renal failure, as well as to assure diuretic efficacy. Concomitant therapy withpotassium-sparing diuretics may be associated with increased serumpotassium levels.

Other drugs: In small groups of patients (7–10 patients/interaction study), theconcomitant administration of azathioprine, gold, chloroquine, D-penicillamine,prednisolone, doxycycline or digitoxin did not significantly affect the peak levelsand AUC levels of diclofenac sodium. Phenobarbital toxicity has been reportedto have occurred in a patient on chronic phenobarbital treatment following theinitiation of diclofenac sodium therapy. In vitro, diclofenac sodium interferesminimally with the protein binding of prednisolone (10% decrease in binding).Benzylpenicillin, ampicillin, oxacillin, chlortetracycline, doxycycline, cephalot-hin, erythromycin, and sulfamethoxazole have no influence, in vitro, on theprotein binding of diclofenac in human serum.Misoprostol has been used to ripen the cervix, to induce labor, and to treatpostpartum hemorrhage, outside of its approved indication. Additionally,because of the known effects of nonsteroidal anti-inflammatory drugsincluding the diclofenac sodium component of FDC of Misoprostol / Diclofenac Sodium, on the fetal cardiovascular system (closure of ductusarteriosus), use during pregnancy (particularly late pregnancy) should beavoided.

Nursing mothers: Diclofenac Sodium has been found in the milk of nursingmothers. Misoprostol is rapidly metabolized in the mother to misoprostol acid,which is biologically active and is excreted in breast milk. There are nopublished reports of adverse effects of misoprostol in breast-feeding infants ofmothers taking misoprostol. Caution should be exercised when FDC ofMisoprostol / Diclofenac Sodium is administered to a nursing woman.Pediatric use: Safety and effectiveness of FDC of Misoprostol / DiclofenacSodium in pediatric patients have not been established.

Geriatric use: As with any NSAIDs, caution should be exercised in treating theelderly (65 years and older).

OVERDOSAGE: The toxic dose of FDC of Misoprostol / Diclofenac Sodiumhas not been determined. However, signs of overdosage from thecomponents of the product have been described. Diclofenac sodium Clinicalsigns that may suggest diclofenac sodium overdose include GI complaints,confusion, drowsiness or general hypotonia. Misoprostol The toxic dose ofmisoprostol in humans has not been determined. Cumulative total daily dosesof 1600 mcg have been tolerated, with only symptoms of GI discomfort beingreported. Symptoms of overdosage with FDC of Misoprostol / DiclofenacSodium should be treated with supportive therapy. In case of acuteoverdosage, gastric lavage is recommended. Induced diuresis may bebeneficial because diclofenac sodium and misoprostol metabolites areexcreted in the urine.

DOSAGE AND ADMINISTRATION:Osteoarthritis: The recommended dosage for maximal GI mucosalprotection is FDC of Misoprostol / Diclofenac Sodium 50 tid. For patients whoexperience intolerance, FDC of Misoprostol / Diclofenac Sodium 75 bid or FDC ofMisoprostol / Diclofenac Sodium 50 bid can be used.

Rheumatoid Arthritis: The recommended dosage is FDC of Misoprostol /Diclofenac Sodium 50 tid or qid. For patients who experience intolerance, FDC ofMisoprostol / Diclofenac Sodium 75 bid or FDC of Misoprostol / Diclofenac Sodium 50 bidcan be used, but are less effective in preventing ulcers.

This fixed combination product, ESMA RT (Misoprstol / Diclofenac Sodium), isnot appropriate for patients who would not receive the appropriate dose ofboth ingredients.

HOW SUPPLIED:Esmart 50 : A Blister pack of 20’s film coated bi-layered tablets.Esmart 75 : A Blister pack of 20’s film coated bi-layered tablets.

STORAGE:Store below 30ºC.Keep all the medicines out of the reach of ChildrenProtect from heat, light and moisture.

stan

Manufactured by:

PharmEvo (Pvt.) Ltd. Plot # A-29, North Western Industrial Zone,Port Qasim, Karachi-75020, PakiWebsite: www.pharmevo.biz

Gastrointestinal Effects: Risk of Ulceration, Bleeding and PerforationNSAIDs, including FDC of Misoprstol / Diclofenac Sodium, can cause seriousgastrointest inal (GI) adverse events including inf lammation, bleeding,ulceration, and perforation of the stomach, small intestine, or large intestine,which can be fatal. These serious adverse events can occur at any time, withor without warning symptoms, in patients treated with NSAIDs. NSAIDs shouldbe prescribed with extreme caution in those with a prior history of ulcer diseaseor gastrointestinal bleeding. For high risk patients, alternate therapies that donot involve NSAIDs should be considered.

Renal Effects: Long-term administration of NSAIDs has resulted in renal papillarynecrosis and other renal injury.Advanced Renal Disease: Diclofenac metabolites are eliminated primarily bythe kidneys. The extent to which the metabolites may accumulate in patientswith renal failure has not been studied. Therefore, treatment with FDC ofMisoprostol / Diclofenac Sodium is not recommended in these patients withadvanced renal disease. If FDC of Misoprostol / Diclofenac Sodium therapy mustbe initiated, close monitoring of the patient’s renal function is advisable. Hepatic effects: Physicians should measure transaminases periodically inpatients receiving long-term therapy with diclofenac, because severe hepatotox-icity may develop without a prodrome of distinguishing symptoms. Transami-nases should be monitored within 4 to 8 weeks after initiating treatment withdiclofenac. However, severe hepatic reactions can occur at any time duringtreatment with diclofenac. If abnormal liver tests persist or worsen, if clinical signsand/or symptoms consistent with liver disease develop, or if systemic manifesta-tions occur (e.g., eosinophilia, rash, abdominal pain, diarrhea, dark urine, etc.), FDC of Misoprostol / Diclofenac Sodium should be discontinued immediatelyAnaphylactic reactions: As with other NSAIDs, anaphylactic reactions mayoccur in patients without known prior exposure to FDC of Misoprostol / Diclofenac Sodium. FDC of Misoprostol / Diclofenac Sodium should not be given to patientswith the aspirin triad. Anaphylactic reactions may also occur to the misoprostolcomponent of FDC of Misoprostol / Diclofenac Sodium.Skin Reactions: NSAIDs, including FDC of Misoprostol / Diclofenac Sodium, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can befatal. These serious events may occur without warning.

ADVERSE REACTIONSThe most common adverse reaction encountered with NSAIDs are gastrointes- tinal, of which peptic ulcer, with or without bleeding is the most severe. Thefollowing adverse reactions occur:

Gastrointestinal: Abdominal pain, Diarrhea, Dyspepsia, Nausea, Flatulence,hiccup and melena.Body as a whole: Asthenia, death, fatigue, fever, infection, malaise, sepsis,chills.Cardiovascular system: Arrhythmia, atrial fibrillation, congestive heart failure,hypertension, hypotension, increased CPK, increased LDH, myocardialinfarction, palpitations, phlebitis, premature ventricular contractions, syncope,tachycardia, vasculitis.Central and peripheral nervous system: Coma, convulsions, dizziness,drowsiness, headache, hyperesthesia, hypertonia, hypoesthesia, insomnia,meningitis, migraine, neuralgia, paresthesia, somnolence, tremor, vertigo.Digestive: Anorexia, appetite changes, constipation, dry mouth, dysphagia,enteritis, esophageal ulceration, esophagitis, eructation, gastritis, gastroesophageal reflux, GI bleeding, GI neoplasm benign, glossitis,heartburn, hematemesis, hemorrhoids, intestinal perforation, peptic ulcer,stomatitis and ulcerative stomatitis, tenesmus, vomiting.Female reproductive disorders: Breast pain, dysmenorrhea, intermenstrualbleeding, leukorrhea, menstrual disorder, menorrhagia, vaginal hemorrhage.Hypersensitivity: Angioedema, laryngeal/pharyngeal edema, urticaria.Liver and biliary system: Abnormal hepatic function, bilirubinemia, hepatitis,jaundice, liver failure, pancreatitis.Male reproductive disorders: Impotence, perineal pain.Metabolic and nutritional: Alkaline phosphatase increased, BUN increased,dehydration, glycosuria, gout, hypercholesterolemia, hyperglycemia,hyperuricemia, hypoglycemia, hyponatremia, periorbital edema, porphyria,weight changes.Musculoskeletal system: Arthralgia, myalgia.Psychiatric: Anxiety, concentration impaired, confusion, depression,disorientation, dream abnormalities, hallucinations, irritability, nervousness,paranoia, psychotic reaction.Respiratory system: Asthma, coughing, dyspnea, hyperventilation,pneumonia, respiratory depression.Skin and appendages: Acne, alopecia, bruising, eczema, erythemamultiforme, exfoliative dermatitis, pemphigoid reaction, photosensitivity,pruritus, pruritus ani, rash, skin ulceration, Stevens-Johnson syndrome,sweating increased, toxic epidermal necrolysis.Special senses: Hearing impairment, taste loss, taste perversion, tinnitus.Urinary system: Cystitis, dysuria, hematuria, interstitial nephritis, micturitionfrequency, nocturia, nephrotic syndrome, oliguria/polyuria, papillary necrosis,proteinuria, renal failure, urinary tract infection.Vision: Amblyopia, blurred vision, conjunctivitis, diplopia, glaucoma, iritis,lacrimation abnormal,night blindness, vision abnormal.

DESCRIPTION: Esmart is a fixed dose combination containing Enteric Coated Diclofenac Sodium and Misoprostol.

CLINICAL PHARMACOLOGY: Diclofenac sodium is a nonsteroidalanti-inflammatory drug (NSAID). In pharmacologic studies, diclofenac sodiumhas shown anti-inflammatory, analgesic and antipyretic properties. The mechanism of action of diclofenac sodium, like other NSAIDs, is not completelyunderstood but may be related to prostaglandin synthetase inhibition. Diclofenacsodium is completely absorbed from the GI tract after fasting, oral administration.The dic lofenac sodium in FDC of Misoprostol / Diclofenac Sodium is in apharmaceutical formulation that resists dissolution in the low pH of gastric fluidbut allows a rapid release of drug in the higher pH environment of theduodenum. Peak plasma levels are achieved in 2 hours (range 1–4 hours), andthe area under the plasma concentration curve (AUC) is dose proportionalwithin the range of 25 mg to 150 mg. More than 99% of diclofenac sodium isreversibly bound to human plasma albumin. Diclofenac sodium is eliminatedthrough metabolism and subsequent urinary and biliary excretion of theglucuronide and the sulfate conjugates of the metabolites. Approximately65% of the dose is excreted in the urine and 35% in the bile.

Misoprostol is a synthetic prostaglandin E1 analog with gastric antisecretory and(in animals) mucosal protective properties. NSAIDs inhibit prostaglandin synthesis. A deficiency of prostaglandins within the gastric and duodenal mucosamay lead to diminishing bicarbonate and mucus secretion and may contribute tothe mucosal damage caused by NSAIDs. Misoprostol can increase bicarbonateand mucus production, but in humans this has been shown at doses 200 mcg andabove that are also antisecretory It is therefore not possible to tell whether theability of misoprostol to reduce the risk of gastric and duodenal ulcers is the resultof its antisecretory effect, its mucosal protective effect, or both.Orallyadministered misoprostol is rapidly and extensively absorbed, and itundergoes rapid metabolism to its biologically active metabolite, misoprostolacid. Misoprostol acid in FDC of Misoprostol / Diclofenac Sodium reaches amaximum plasma concentration in about 20 minutes and is, thereafter, quicklyeliminated with an elimination t1/2 of about 30 minutes. The serum protein bindingof misoprostol acid is less than 90% and is concentration independent in thetherapeutic range. After oral administration of radio-labeled misoprostol, about70% of detected radioactivity appears in the urine. Maximum plasma concentra-tions of misoprostol acid are diminished when the dose is taken with food, andtotal availability of misoprostol acid is reduced by use of concomitant antacid.PHARMACOKINETICS: The pharmacokinetics following oral administrationof a single dose or multiple doses of FDC of Misoprostol / Diclofenac Sodiumto healthy subjects under fasted conditions are similar to the pharmacokinetics ofthe two individual components. INDICATIONS AND USAGE:Misoprostol / Diclofenac Sodium is indicated for treatment of the signs andsymptoms of osteoarthritis or rheumatoid arthritis in patients at high risk ofdeveloping NSAID-induced gastric and duodenal ulcers and their complications.CONTRAINDICATIONS:It is contraindicated in patients with hypersensitivity to diclofenac or tomisoprostol or other prostaglandins. Misoprostol / Diclofenac Sodium should notbe g iven to pat ients who have exper ienced asthma, ur t icar ia, or otherallergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal,anaphylactic like reactions to diclofenac sodium have been reported in suchpatients Misoprostol / Diclofenac Sodium is contraindicated for the treatment ofperi-operative pain in the setting of coronary artery bypass graft (CABG)surgery. CARDIOVASCULAR EFFECTS:Cardiovascular Thrombotic Events: Clinical trials of several COX-2 selectiveand nonselective NSAIDs of up to three years duration have shown anincreased risk of serious cardiovascular (CV) thrombotic events, myocardialinfarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective andnonselective, may have a similar risk.Hypertension: NSAIDs including FDC of Misoprostol / Diclofenac Sodium, canlead to onset of new hypertension or worsening of preexisting hypertension,either of which may contribute to the increased incidence of CV events. Patientstaking thiazides or loop diuret ics may have impaired response to thesetherapies when taking NSAIDs. NSAIDs, including FDC of Misoprostol /Diclofenac Sodium, should be used with caution in patients with hypertension. Blood pressure (BP): should be monitored closely during the initiation ofNSAID treatment and throughout the course of therapy.Congestive Heart Failure and Edema: Fluid retention and edema have beenobserved in some patients taking NSAIDs. FDC of Misoprostol / Diclofenac Sodium,should be used with caution in patients with fluid retention or heart failure.

COMPOSITION:Esmart 50Each film coated bi-layered tablet contains: Diclofenac Sodium USP…………50mg (as enteric coated)Misoprostol B.P. ………………200 mcg(PharmEvo Specs)

Esmart 75Each film coated bi-layered tablet contains: Diclofenac Sodium USP…………75mg (as enteric coated)Misoprostol B.P. ………………200 mcg(PharmEvo Specs)

(Diclofenac Sodium + Misoprostol)

PRECAUTIONS: Hematological Effects: Anemia is sometimes seen in patientsreceiving NSAIDs, including FDC of Misoprostol / Diclofenac Sodium. This maybe due to fluid retention, occult or gross GI blood loss, or an incompletelydescribed effect upon erythropoiesis. Patients on long-term treatment withNSAIDs, including FDC of Misoprostol / Diclofenac Sodium, should have theirhemoglobin or hematocrit checked if they exhibit any signs or symptoms ofanemia. NSAIDs inhibit platelet aggregation and have been shown to prolongbleeding time in some patients. Preexisting Asthma Patients with asthma mayhave aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitiveasthma has been associated with severe bronchospasm which can be fatal.Since cross reactivity, including bronchospasm, between aspirin and othernonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitivepatients, FDC of Misoprostol / Diclofenac Sodium should not be administered topatients with this form of aspirin.

Pregnancy: Pregnancy category X: Misoprostol may endanger pregnancy (may cause abortion) and thereby cause harm to the fetus when administered to a pregnant woman. Misoprostol may produce uterine contractions, uterine bleeding, and expulsion of the products of conception.

Aseptic meningitis: As with other NSAIDs, aseptic meningitis with fever andcoma has been observed on rare occasions in patients on diclofenac therapyrelated to diclofenac should be considered.Porphyria: The use of FDC of Misoprostol / Diclofenac Sodium in patients withhepatic porphyria should be avoided. To date, one patient has been describedin whom diclofenac sodium probably triggered a clinical attack of porphyria.The postulated mechanism, demonstrated in rats, for causing such attacks bydiclofenac sodium, as well as some other NSAIDs, is through stimulationof the porphyrin precursor delta-aminolevulinic acid (ALA).

DRUG INTERACTIONS: ACE-Inhibitors: Reports suggest that NSAIDs maydiminish the antihypertensive effect of ACE-inhibitors. This interaction shouldbe given consideration in patients taking NSAIDs concomitantly with ACEinhibitors.Aspirin: When FDC of Misoprostol / Diclofenac Sodium is administered withaspirin, the protein binding of diclofenac Sodium is reduced, although theclearance of the free FDC of Misoprostol / Diclofenac Sodium is not altered.The clinical significance of this interaction is not known; however, as withother NSAIDs, concomitant administration of diclofenac sodium and aspirinis not generally recommended because of the potential risk of increasedadverse effects.Digoxin: Elevated digoxin levels have been reported in patients receivingdigoxin and diclofenac sodium. Patients receiving digoxin and FDC ofMisoprostol / Diclofenac should be monitored for possible digoxin toxicity.Warfarin: The effects of warfarin and NSAIDs on GI bleeding are synergistic,such that users of both drugs together have a risk of serious bleeding greaterthan users of either drug alone.Oral hypoglycemics: Diclofenac sodium does not alter glucose metabolismin healthy people nor does it alter the effects of oral hypoglycemic agents.There are rare reports, however, from marketing experience, of changes ineffects of insulin or oral hypoglycemic agents in the presence of diclofenacsodium that necessitated change in the doses of such agents. Both hypo- andhyperglycemic effects have been reported. A direct causal relationship hasnot been established, but physicians should consider the possibility thatdiclofenac sodium may alter a diabetic patient‘s response to insulin or oralhypoglycemic agents.Methotrexate: NSAIDs have been reported to competitively inhibitmethotrexate accumulation in rabbit kidney slices. This may indicate thatthey could enhance the toxicity of methotrexate. Caution should be usedwhen NSAIDs are administered concomitantly with methotrexate.Cyclosporine: FDC of Misoprostol / Diclofenac, like other NSAID containingproducts, may affect renal prostaglandins and increase the toxicity of certaindrugs. Ingestion of FDC of Misoprostol / Diclofenac may increase cyclosporinenephrotoxicity. Patients who begin taking FDC of Misoprostol / Diclofenac or whoincrease their dose of FDC of Misoprostol / Diclofenac while taking cyclosporinemay develop toxicity characteristic for clyclosporine. They should beobserved closely, particularly if renal function is impaired.Lithium: NSAIDs have produced an elevation of plasma lithium levels and areduction in renal lithium clearance. The mean minimum lithium concentrationincreased 15% and the renal clearance was decreased by approximately 20%.These effects have been attributed to inhibition of renal prostaglandinsynthesis by the NSAID. Thus, when INSADs and lithium are administeredconcurrently, subjects should be observed carefully for signs of lithium toxicity.Antacids: Antacids reduce the bioavailability of misoprostol acid. Antacids mayalso delay absorption of diclofenac sodium. Magnesium-containing antacidsexacerbate misoprostol-associated diarrhea. Thus, it is not recommended thatFDC of Misoprostol / Diclofenac be coadministered with magnesium-containing antacids.Diuretics: Clinical studies, as well as post marketing observations, have shownthat FDC of Misoprostol / Diclofenac Sodium can reduce the natriuretic effect offurosemide and thiazides in some patients. This response has beenattributed to inhibition of renal prostaglandin synthesis. During concomitanttherapy with NSAIDs, the patient should be observed closely for signs of

renal failure, as well as to assure diuretic efficacy. Concomitant therapy withpotassium-sparing diuretics may be associated with increased serumpotassium levels.

Other drugs: In small groups of patients (7–10 patients/interaction study), theconcomitant administration of azathioprine, gold, chloroquine, D-penicillamine,prednisolone, doxycycline or digitoxin did not significantly affect the peak levelsand AUC levels of diclofenac sodium. Phenobarbital toxicity has been reportedto have occurred in a patient on chronic phenobarbital treatment following theinitiation of diclofenac sodium therapy. In vitro, diclofenac sodium interferesminimally with the protein binding of prednisolone (10% decrease in binding).Benzylpenicillin, ampicillin, oxacillin, chlortetracycline, doxycycline, cephalot-hin, erythromycin, and sulfamethoxazole have no influence, in vitro, on theprotein binding of diclofenac in human serum.Misoprostol has been used to ripen the cervix, to induce labor, and to treatpostpartum hemorrhage, outside of its approved indication. Additionally,because of the known effects of nonsteroidal anti-inflammatory drugsincluding the diclofenac sodium component of FDC of Misoprostol / Diclofenac Sodium, on the fetal cardiovascular system (closure of ductusarteriosus), use during pregnancy (particularly late pregnancy) should beavoided.

Nursing mothers: Diclofenac Sodium has been found in the milk of nursingmothers. Misoprostol is rapidly metabolized in the mother to misoprostol acid,which is biologically active and is excreted in breast milk. There are nopublished reports of adverse effects of misoprostol in breast-feeding infants ofmothers taking misoprostol. Caution should be exercised when FDC ofMisoprostol / Diclofenac Sodium is administered to a nursing woman.Pediatric use: Safety and effectiveness of FDC of Misoprostol / DiclofenacSodium in pediatric patients have not been established.

Geriatric use: As with any NSAIDs, caution should be exercised in treating theelderly (65 years and older).

OVERDOSAGE: The toxic dose of FDC of Misoprostol / Diclofenac Sodiumhas not been determined. However, signs of overdosage from thecomponents of the product have been described. Diclofenac sodium Clinicalsigns that may suggest diclofenac sodium overdose include GI complaints,confusion, drowsiness or general hypotonia. Misoprostol The toxic dose ofmisoprostol in humans has not been determined. Cumulative total daily dosesof 1600 mcg have been tolerated, with only symptoms of GI discomfort beingreported. Symptoms of overdosage with FDC of Misoprostol / DiclofenacSodium should be treated with supportive therapy. In case of acuteoverdosage, gastric lavage is recommended. Induced diuresis may bebeneficial because diclofenac sodium and misoprostol metabolites areexcreted in the urine.

DOSAGE AND ADMINISTRATION:Osteoarthritis: The recommended dosage for maximal GI mucosalprotection is FDC of Misoprostol / Diclofenac Sodium 50 tid. For patients whoexperience intolerance, FDC of Misoprostol / Diclofenac Sodium 75 bid or FDC ofMisoprostol / Diclofenac Sodium 50 bid can be used.

Rheumatoid Arthritis: The recommended dosage is FDC of Misoprostol /Diclofenac Sodium 50 tid or qid. For patients who experience intolerance, FDC ofMisoprostol / Diclofenac Sodium 75 bid or FDC of Misoprostol / Diclofenac Sodium 50 bidcan be used, but are less effective in preventing ulcers.

This fixed combination product, ESMA RT (Misoprstol / Diclofenac Sodium), isnot appropriate for patients who would not receive the appropriate dose ofboth ingredients.

HOW SUPPLIED:Esmart 50 : A Blister pack of 20’s film coated bi-layered tablets.Esmart 75 : A Blister pack of 20’s film coated bi-layered tablets.

STORAGE:Store below 30ºC.Keep all the medicines out of the reach of ChildrenProtect from heat, light and moisture.

stan

Manufactured by:

PharmEvo (Pvt.) Ltd. Plot # A-29, North Western Industrial Zone,Port Qasim, Karachi-75020, PakiWebsite: www.pharmevo.biz

Gastrointestinal Effects: Risk of Ulceration, Bleeding and PerforationNSAIDs, including FDC of Misoprstol / Diclofenac Sodium, can cause seriousgastrointest inal (GI) adverse events including inf lammation, bleeding,ulceration, and perforation of the stomach, small intestine, or large intestine,which can be fatal. These serious adverse events can occur at any time, withor without warning symptoms, in patients treated with NSAIDs. NSAIDs shouldbe prescribed with extreme caution in those with a prior history of ulcer diseaseor gastrointestinal bleeding. For high risk patients, alternate therapies that donot involve NSAIDs should be considered.

Renal Effects: Long-term administration of NSAIDs has resulted in renal papillarynecrosis and other renal injury.Advanced Renal Disease: Diclofenac metabolites are eliminated primarily bythe kidneys. The extent to which the metabolites may accumulate in patientswith renal failure has not been studied. Therefore, treatment with FDC ofMisoprostol / Diclofenac Sodium is not recommended in these patients withadvanced renal disease. If FDC of Misoprostol / Diclofenac Sodium therapy mustbe initiated, close monitoring of the patient’s renal function is advisable. Hepatic effects: Physicians should measure transaminases periodically inpatients receiving long-term therapy with diclofenac, because severe hepatotox-icity may develop without a prodrome of distinguishing symptoms. Transami-nases should be monitored within 4 to 8 weeks after initiating treatment withdiclofenac. However, severe hepatic reactions can occur at any time duringtreatment with diclofenac. If abnormal liver tests persist or worsen, if clinical signsand/or symptoms consistent with liver disease develop, or if systemic manifesta-tions occur (e.g., eosinophilia, rash, abdominal pain, diarrhea, dark urine, etc.), FDC of Misoprostol / Diclofenac Sodium should be discontinued immediatelyAnaphylactic reactions: As with other NSAIDs, anaphylactic reactions mayoccur in patients without known prior exposure to FDC of Misoprostol / Diclofenac Sodium. FDC of Misoprostol / Diclofenac Sodium should not be given to patientswith the aspirin triad. Anaphylactic reactions may also occur to the misoprostolcomponent of FDC of Misoprostol / Diclofenac Sodium.Skin Reactions: NSAIDs, including FDC of Misoprostol / Diclofenac Sodium, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can befatal. These serious events may occur without warning.

ADVERSE REACTIONSThe most common adverse reaction encountered with NSAIDs are gastrointes- tinal, of which peptic ulcer, with or without bleeding is the most severe. Thefollowing adverse reactions occur:

Gastrointestinal: Abdominal pain, Diarrhea, Dyspepsia, Nausea, Flatulence,hiccup and melena.Body as a whole: Asthenia, death, fatigue, fever, infection, malaise, sepsis,chills.Cardiovascular system: Arrhythmia, atrial fibrillation, congestive heart failure,hypertension, hypotension, increased CPK, increased LDH, myocardialinfarction, palpitations, phlebitis, premature ventricular contractions, syncope,tachycardia, vasculitis.Central and peripheral nervous system: Coma, convulsions, dizziness,drowsiness, headache, hyperesthesia, hypertonia, hypoesthesia, insomnia,meningitis, migraine, neuralgia, paresthesia, somnolence, tremor, vertigo.Digestive: Anorexia, appetite changes, constipation, dry mouth, dysphagia,enteritis, esophageal ulceration, esophagitis, eructation, gastritis, gastroesophageal reflux, GI bleeding, GI neoplasm benign, glossitis,heartburn, hematemesis, hemorrhoids, intestinal perforation, peptic ulcer,stomatitis and ulcerative stomatitis, tenesmus, vomiting.Female reproductive disorders: Breast pain, dysmenorrhea, intermenstrualbleeding, leukorrhea, menstrual disorder, menorrhagia, vaginal hemorrhage.Hypersensitivity: Angioedema, laryngeal/pharyngeal edema, urticaria.Liver and biliary system: Abnormal hepatic function, bilirubinemia, hepatitis,jaundice, liver failure, pancreatitis.Male reproductive disorders: Impotence, perineal pain.Metabolic and nutritional: Alkaline phosphatase increased, BUN increased,dehydration, glycosuria, gout, hypercholesterolemia, hyperglycemia,hyperuricemia, hypoglycemia, hyponatremia, periorbital edema, porphyria,weight changes.Musculoskeletal system: Arthralgia, myalgia.Psychiatric: Anxiety, concentration impaired, confusion, depression,disorientation, dream abnormalities, hallucinations, irritability, nervousness,paranoia, psychotic reaction.Respiratory system: Asthma, coughing, dyspnea, hyperventilation,pneumonia, respiratory depression.Skin and appendages: Acne, alopecia, bruising, eczema, erythemamultiforme, exfoliative dermatitis, pemphigoid reaction, photosensitivity,pruritus, pruritus ani, rash, skin ulceration, Stevens-Johnson syndrome,sweating increased, toxic epidermal necrolysis.Special senses: Hearing impairment, taste loss, taste perversion, tinnitus.Urinary system: Cystitis, dysuria, hematuria, interstitial nephritis, micturitionfrequency, nocturia, nephrotic syndrome, oliguria/polyuria, papillary necrosis,proteinuria, renal failure, urinary tract infection.Vision: Amblyopia, blurred vision, conjunctivitis, diplopia, glaucoma, iritis,lacrimation abnormal,night blindness, vision abnormal.

DESCRIPTION: Esmart is a fixed dose combination containing Enteric Coated Diclofenac Sodium and Misoprostol.

CLINICAL PHARMACOLOGY: Diclofenac sodium is a nonsteroidalanti-inflammatory drug (NSAID). In pharmacologic studies, diclofenac sodiumhas shown anti-inflammatory, analgesic and antipyretic properties. The mechanism of action of diclofenac sodium, like other NSAIDs, is not completelyunderstood but may be related to prostaglandin synthetase inhibition. Diclofenacsodium is completely absorbed from the GI tract after fasting, oral administration.The dic lofenac sodium in FDC of Misoprostol / Diclofenac Sodium is in apharmaceutical formulation that resists dissolution in the low pH of gastric fluidbut allows a rapid release of drug in the higher pH environment of theduodenum. Peak plasma levels are achieved in 2 hours (range 1–4 hours), andthe area under the plasma concentration curve (AUC) is dose proportionalwithin the range of 25 mg to 150 mg. More than 99% of diclofenac sodium isreversibly bound to human plasma albumin. Diclofenac sodium is eliminatedthrough metabolism and subsequent urinary and biliary excretion of theglucuronide and the sulfate conjugates of the metabolites. Approximately65% of the dose is excreted in the urine and 35% in the bile.

Misoprostol is a synthetic prostaglandin E1 analog with gastric antisecretory and(in animals) mucosal protective properties. NSAIDs inhibit prostaglandin synthesis. A deficiency of prostaglandins within the gastric and duodenal mucosamay lead to diminishing bicarbonate and mucus secretion and may contribute tothe mucosal damage caused by NSAIDs. Misoprostol can increase bicarbonateand mucus production, but in humans this has been shown at doses 200 mcg andabove that are also antisecretory It is therefore not possible to tell whether theability of misoprostol to reduce the risk of gastric and duodenal ulcers is the resultof its antisecretory effect, its mucosal protective effect, or both.Orallyadministered misoprostol is rapidly and extensively absorbed, and itundergoes rapid metabolism to its biologically active metabolite, misoprostolacid. Misoprostol acid in FDC of Misoprostol / Diclofenac Sodium reaches amaximum plasma concentration in about 20 minutes and is, thereafter, quicklyeliminated with an elimination t1/2 of about 30 minutes. The serum protein bindingof misoprostol acid is less than 90% and is concentration independent in thetherapeutic range. After oral administration of radio-labeled misoprostol, about70% of detected radioactivity appears in the urine. Maximum plasma concentra-tions of misoprostol acid are diminished when the dose is taken with food, andtotal availability of misoprostol acid is reduced by use of concomitant antacid.PHARMACOKINETICS: The pharmacokinetics following oral administrationof a single dose or multiple doses of FDC of Misoprostol / Diclofenac Sodiumto healthy subjects under fasted conditions are similar to the pharmacokinetics ofthe two individual components. INDICATIONS AND USAGE:Misoprostol / Diclofenac Sodium is indicated for treatment of the signs andsymptoms of osteoarthritis or rheumatoid arthritis in patients at high risk ofdeveloping NSAID-induced gastric and duodenal ulcers and their complications.CONTRAINDICATIONS:It is contraindicated in patients with hypersensitivity to diclofenac or tomisoprostol or other prostaglandins. Misoprostol / Diclofenac Sodium should notbe g iven to pat ients who have exper ienced asthma, ur t icar ia, or otherallergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal,anaphylactic like reactions to diclofenac sodium have been reported in suchpatients Misoprostol / Diclofenac Sodium is contraindicated for the treatment ofperi-operative pain in the setting of coronary artery bypass graft (CABG)surgery. CARDIOVASCULAR EFFECTS:Cardiovascular Thrombotic Events: Clinical trials of several COX-2 selectiveand nonselective NSAIDs of up to three years duration have shown anincreased risk of serious cardiovascular (CV) thrombotic events, myocardialinfarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective andnonselective, may have a similar risk.Hypertension: NSAIDs including FDC of Misoprostol / Diclofenac Sodium, canlead to onset of new hypertension or worsening of preexisting hypertension,either of which may contribute to the increased incidence of CV events. Patientstaking thiazides or loop diuret ics may have impaired response to thesetherapies when taking NSAIDs. NSAIDs, including FDC of Misoprostol /Diclofenac Sodium, should be used with caution in patients with hypertension. Blood pressure (BP): should be monitored closely during the initiation ofNSAID treatment and throughout the course of therapy.Congestive Heart Failure and Edema: Fluid retention and edema have beenobserved in some patients taking NSAIDs. FDC of Misoprostol / Diclofenac Sodium,should be used with caution in patients with fluid retention or heart failure.

COMPOSITION:Esmart 50Each film coated bi-layered tablet contains: Diclofenac Sodium USP…………50mg (as enteric coated)Misoprostol B.P. ………………200 mcg(PharmEvo Specs)

Esmart 75Each film coated bi-layered tablet contains: Diclofenac Sodium USP…………75mg (as enteric coated)Misoprostol B.P. ………………200 mcg(PharmEvo Specs)

(Diclofenac Sodium + Misoprostol)

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