Diclofenac + Misoprostol

Diclofenac + Misoprostol is an anti-inflammatory agent belonging to pharmacological class of NSAIDS and Prostaglandin Analogue

Diclofenac:

Diclofenac is completely absorbed from the GI tract after oral administration; bioavailability is only about 50% due to extensive first-pass metabolism. Diclofenac appears to be widely distributed, with significant amounts in synovial fluid. Protein binding is roughly 99%, primarily to albumin. The Vd of diclofenac is approximately 0.55 L/kg. Extensive and rapid hydroxylation and conjugation occur in the liver via cytochrome P450 (CYP) CYP2C9 and CYP3A4; UGT2B7 and CYP2C8 may also play a role. The major metabolite, 4-hydroxy-diclofenac, has very weak pharmacologic activity. The formation of 4-hydroxy diclofenac is primarily mediated by CYP2C9. About 65% of a dose is excreted in the urine and about 35% in the bile. Little to no unchanged diclofenac is excreted in the urine, with the remainder as metabolites or conjugates of the drug. The elimination half-life is approximately 2 hours.

Misoprostol:

Misoprostol is absorbed rapidly after oral administration. The plasma protein binding of misoprostol acid, the active metabolite of misoprostol, is less than 90% and is concentration-independent in the therapeutic range. Misoprostol is rapidly and extensively metabolized to misoprostol acid. After administration of a radio-labeled dosage, approximately 70% of detected radioactivity appears in the urine. The elimination half-life of misoprostol acid is approximately 30 minutes.

The common side effects associated with Molecule (name) include Abdominal pain, diarrhea, dyspepsia, nausea, and flatulence. etc.

Diclofenac + Misoprostol is available in the form of tablets

The molecule is available in USA, India, Japan, Australia.

Diclofenac + Misoprostol, belonging to the NSAIDS acts a anti-inflammatory agent.

Diclofenac:

Diclofenac is a potent inhibitor of prostaglandin (PG) synthesis in vitro. Diclofenac concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Diclofenac is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues.

Misoprostol:

Misoprostol has a protective impact on the mucosa, which helps explain why it works so well to cure ulcers. According to some theories, the cytoprotective effect is due to the secretion of mucus and bicarbonate, the avoidance of the breakdown of the mucus bilayer, the decrease of hydrogen ion backflow, the regulation of mucosal blood flow, and the preservation of the mucosal ability to create cells. Under baseline settings, misoprostol lowers pepsin concentrations; however, histamine-stimulated secretion is unaffected. Misoprostol has other effects that have been discovered since prostaglandins can impact a variety of tissues. By directly affecting the parietal cell, misoprostol also prevents the production of stomach acid throughout the day and at night. The receptors in parietal cells show a strong affinity for prostaglandins of the E series. With increasing doses, misoprostol appears to have a more potent impact on suppressing stomach acid secretion that is stimulated by food, histamine, pentagastrin, and coffee. However, H2-antagonists have a stronger suppressive effect on stomach acid output than misoprostol, particularly at night. Last but not least, misoprostol has a tendency to induce miscarriages since it makes uterine contractions occur more frequently.

Diclofenac + Misoprostol is available in Tablet

Tablet to be swallowed whole with water/liquid.

Diclofenac + Misoprostol can be used in the treatment of rheumatoid arthritis, osteoarthritis.

Misoprostol is a synthetic prostaglandin of the E family that suppresses stomach acid secretion and increases mucus secretion in the digestive system. Diclofenac is a nonsteroidal anti-inflammatory medication (NSAID). However, all NSAIDs, including diclofenac, increase the risk of serious gastrointestinal side effects such as bleeding, ulceration, and perforation of the stomach or intestines. They also may increase the risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke. Misoprostol has been shown to reduce the risk of NSAID-induced gastric ulcers.

Diclofenac + Misoprostol is approved for use in the following clinical indications

• Rheumatoid arthritis
• Osteoarthritis

For the treatment of the signs and symptoms of osteoarthritis in patients at high risk of developing NSAID-induced gastric and duodenal ulcers and their complications

Oral dosage

Adults:

Usual starting dose is diclofenac sodium 50 mg in combination with misoprostol 0.2 mg (1 Diclofenac + Misoprostol 50/0.2 mg tablet) taken orally 3 times daily. Adjust according to patient response. For patients who experience intolerance, diclofenac sodium 75 mg in combination with misoprostol 0.2 mg (1 Diclofenac + Misoprostol 75/0.2 mg tablet) PO twice daily or diclofenac sodium 50 mg in combination with misoprostol 0.2 mg (1 Diclofenac + Misoprostol 50/0.2 mg tablet) taken orally twice daily can be used but are less effective in preventing ulcers. The lowest effective dose of diclofenac; misoprostol should be sought for each patient.

For the treatment of the signs and symptoms of rheumatoid arthritis in patients at high risk of developing NSAID-induced gastric and duodenal ulcers and their complications

Oral dosage

Adults:

Usual starting dose is diclofenac sodium 50 mg in combination with misoprostol 0.2 mg (1 Diclofenac + Misoprostol 50/0.2 mg tablet) PO 3 to 4 times daily. Adjust according to patient response. For patients who experience intolerance, diclofenac sodium 75 mg in combination with misoprostol 0.2 mg (1 Diclofenac + Misoprostol 75/0.2 mg tablet) PO twice daily or diclofenac sodium 50 mg in combination with misoprostol 0.2 mg (1 Diclofenac + Misoprostol 50/0.2 mg tablet) PO twice daily can be used, but are less effective in preventing ulcers. The lowest effective dose of diclofenac; misoprostol should be sought for each patient.

Maximum Dosage Limits:

•Adults

Diclofenac 150 mg/day taken orally; misoprostol 0.6 mg/day taken orally for osteoarthritis or diclofenac 200 mg/day taken orally; misoprostol 0.8 mg/day taken orally for rheumatoid arthritis.

•Elderly

Diclofenac 150 mg/day taken orally; misoprostol 0.6 mg/day taken orally for osteoarthritis or diclofenac 200 mg/day taken orally; misoprostol 0.8 mg/day taken orally for rheumatoid arthritis.

•Adolescents

Safety and efficacy have not been established.

•Children

Safety and efficacy have not been established.

(The dosage and duration of treatment should be as per the clinical judgement of the treating physician)

50mg + 0.2 mg; 75 mg + 0.2 mg

Tablets

The dietary restriction should be individualized as per patient requirements.

Diclofenac + Misoprostol may be contraindicated in the following conditions:-

• Pregnancy Use of misoprostol, a component of diclofenac sodium and misoprostol delayed-release tablets, during pregnancy can result in maternal and fetal harm, including uterine rupture, abortion, premature birth, or birth defects

• In the setting of coronary artery bypass graft (CABG) surgery

• Active gastrointestinal bleeding

• History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients

• Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to diclofenac sodium and misoprostol, other prostaglandins, or any components of the drug product.

The treating physician must closely monitor the patient and keep pharmacovigilance as follows

Heart surgery warning: Patients who use this medicine and are scheduled for a coronary artery bypass transplant must cease using it prior to the procedure. Ask the doctor how long the patient must wait after the procedure to start taking it again and when the patient must stop taking it.

Heart problems warning: The risk of cardiac issues, including heart attacks and strokes, can rise when taking this medicine. People who have cardiac disease are more at risk. These ailments carry a risk of death. The danger of cardiac issues grows the longer the patient takes this medicine.

Gastrointestinal problems warning: This drug may raise the possibility of developing gastrointestinal issues like bleeding, ulcers, or holes in your stomach or intestines. These ailments carry a risk of death. These issues might arise at any time and occasionally with no prior notice. The risk of these issues is higher in people over the age of 65.

There is no sufficient scientific evidence traceable regarding use and safety of Diclofenac + Misoprostol in concurrent use with alcohol.

There is no sufficient scientific evidence traceable regarding use and safety of Diclofenac + Misoprostol in breast feeding.

There is no sufficient scientific evidence traceable regarding use and safety of Diclofenac + Misoprostol in pregnancy.

There is no sufficient scientific evidence traceable regarding use and safety of Diclofenac + Misoprostol in concurrent use with any particular food.

The adverse reactions related to Diclofenac + Misoprostol can be categorized as

• Common Adverse Effects: Abdominal pain, diarrhea, dyspepsia, nausea, and flatulence.

• Less Common Adverse Effects: abdominal pain, diarrhea, dyspepsia, nausea, and flatulence.

• Rare Adverse Effects: asthenia, death, fatigue, fever, infection, malaise, sepsis, chills, and edema

Post Marketing Experience

1. Gastrointestinal Effects: Diclofenac + Misoprostol is used to reduce the risk of NSAID-induced gastric ulcers, but it can still cause gastrointestinal side effects, such as abdominal pain, nausea, diarrhea, and indigestion.
2. Cardiovascular Effects: NSAIDs, including diclofenac, have been associated with an increased risk of cardiovascular events such as heart attack and stroke, especially when used in high doses or for prolonged periods.
3. Renal Effects: Long-term use of diclofenac can lead to kidney problems, including reduced kidney function and fluid retention.
4. Allergic Reactions: Some individuals may experience allergic reactions to diclofenac or misoprostol, leading to skin rashes, itching, and in severe cases, anaphylaxis.
5. Liver Toxicity: Rare cases of liver damage have been reported with the use of diclofenac + misoprostol.
6. Hematologic Effects: Prolonged use of diclofenac may cause changes in blood cells, leading to anemia or increased bleeding time.
7. Central Nervous System Effects: Some individuals may experience headaches, dizziness, and nervousness while taking diclofenac + misoprostol.
8. Pregnancy Complications: Misoprostol is contraindicated during pregnancy as it can cause uterine contractions and lead to miscarriage or premature birth.

The clinically relevant drug interactions of Diclofenac + Misoprostol briefly summarized here

Clinical Impact of Hemostasis-Interfering Drugs: Warfarin and diclofenac together have a reducing effect on bleeding. Serious bleeding is more likely to occur when diclofenac and anticoagulants are used together than when either medication is taken by itself.

Hemostasis depends significantly on the release of serotonin by platelets. According to case-control and cohort epidemiological studies, taking an NSAID and a serotonin reuptake inhibitor together may increase the risk of bleeding more than taking an NSAID by itself.

Clinical Impact of Aspirin: Controlled clinical investigations have shown that taking NSAIDs and aspirin at the same time has no more therapeutic benefit than taking NSAIDs alone. In a clinical investigation, using an NSAID and aspirin at the same time was linked to a considerably higher incidence of GI adverse effects than taking an NSAID by itself.

Clinical Impact of Beta-blockers, ACE Inhibitors, and Angiotensin Receptor Blockers

Beta-blockers, such as propranolol, ACE inhibitors, and ARBs may have less of an antihypertensive effect when used with NSAIDs. Due to the increased risk of bleeding, it is generally not advised to take analgesic doses of aspirin at the same time as diclofenac sodium and misoprostol delayed-release tablets.

Low dose aspirin is not a substitute for diclofenac sodium and misoprostol delayed-release tablets for cardiovascular protection.

Co-administration of an NSAID with ACE inhibitors or ARBs may worsen renal function in individuals who are elderly, volume-depleted (including those taking diuretic therapy), or have renal impairment, including a possible case of acute renal failure. Usually, these effects are reversible.

The common side of Diclofenac + Misoprostol include the following

Abdominal pain, diarrhea, dyspepsia, nausea, and flatulence.

The use of Diclofenac + Misoprostol should be prudent in the following group of special populations:

Pregnancy

Risk Summary

Diclofenac sodium and misoprostol delayed-release tablets are contraindicated in pregnant women. If a woman becomes pregnant while taking diclofenac sodium and misoprostol delayed-release tablets, discontinue the drug and advise the woman of the potential risks to her and to a fetus.

There are no adequate and well-controlled studies of diclofenac sodium and misoprostol delayed-release tablets in pregnant women; however, there is information available about the active drug components of diclofenac sodium and misoprostol delayed-release tablets, diclofenac sodium and misoprostol. Administration of misoprostol to pregnant women can cause uterine rupture, abortion, premature birth, or birth defects.Congenital anomalies sometimes associated with fetal death have been reported subsequent to the unsuccessful use of misoprostol as an abortifacient, but the drug’s teratogenic mechanism has not been demonstrated. Use of NSAIDS, including diclofenac a component of diclofenac sodium and misoprostol delayed-release tablets, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. There are clinical considerations when misoprostol and diclofenac are used in pregnant women. In reproduction studies with pregnant rabbits, there were no skeletal or visceral malformations when the combination of diclofenac sodium and misoprostol was administered during organogenesis at doses less than the maximum recommended human doses (MRHD); however, embryotoxicity was observed at this exposure. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as diclofenac, resulted in increased pre- and post-implantation loss.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Maternal Adverse Reactions

Misoprostol may produce uterine contractions, uterine bleeding, and expulsion of the products of conception. Misoprostol has been used to ripen the cervix, to induce labor, and to treat postpartum hemorrhage, outside of its approved indication. A major adverse effect of these uses is hyperstimulation of the uterus. Uterine rupture, amniotic fluid embolism, severe bleeding, shock, and maternal death have been reported when misoprostol was administered to pregnant women to induce labor to induce abortion beyond the eighth week of pregnancy. Higher doses of misoprostol, including the 100 mcg tablet, may increase the risk of complications from uterine hyperstimulation. Diclofenac sodium and misoprostol delayed-release tablets, which contains 200 mcg of misoprostol, is likely to have a greater risk of uterine hyperstimulation than the 100 mcg tablet of misoprostol. Abortions caused by misoprostol may be incomplete.

Cases of amniotic fluid embolism, which resulted in maternal and fetal death, have been reported with use of misoprostol during pregnancy. Severe vaginal bleeding, retained placenta, shock, and pelvic pain have also been reported. These women were administered misoprostol vaginally and/or orally over a range of doses.

Diclofenac sodium and misoprostol delayed-release tablets are contraindicated in pregnant women. If a woman is or becomes pregnant while taking this drug, the drug should be discontinued and the patient apprised of the potential hazard to the fetus.

Fetal/Neonatal Adverse Reactions

Misoprostol

Misoprostol may endanger pregnancy (may cause abortion) and thereby cause harm to the fetus when administered to a pregnant woman. Use of misoprostol for the induction of labor in the third trimester was associated with uterine hyperstimulation with resulting changes in the fetal heart rate (fetal bradycardia) and fetal death (misoprostol is not approved for this use). Diclofenac sodium and misoprostol delayed-release tablets are contraindicated in pregnant women.

Diclofenac

Premature Closure of Fetal Ductus Arteriosus:

NSAIDs, including diclofenac, can cause premature closure of the fetal ductus arteriosus at about 30 weeks gestation and later in pregnancy (see Data).

Oligohydramnios/Neonatal Renal Impairment:

Use of NSAIDs, including diclofenac, at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment (see Data).

Labor or Delivery

There are no studies on the effects of diclofenac sodium and misoprostol delayed-release tablets or diclofenac during labor or delivery. In animal studies, NSAIDS, including diclofenac, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. In humans, some case reports and studies have associated misoprostol with risk of stillbirth, uterine hyperstimulation, perineal tear, amniotic fluid embolism, severe bleeding, shock, uterine rupture and death. The risk of uterine rupture associated with misoprostol use in pregnancy may occur at any gestational age, and increases with advancing gestational age and with prior uterine surgery, including cesarean delivery. Grand multiparity also appears to be a risk factor for uterine rupture.

Data

Human Data

Misoprostol

Several reports in the literature associate the use of misoprostol during the first trimester of pregnancy with skull defects, cranial nerve palsies, facial malformations, and limb defects.

Diclofenac

Data from observational studies regarding potential embryo-fetal risks of NSAID use (including diclofenac) in the first or second trimesters of pregnancy are inconclusive.

Premature Closure of Fetal Ductus Arteriosus:

Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus.

Oligohydramnios/Neonatal Renal Impairment:

Published studies and post-marketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis.

Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain.

Animal Data

The reproductive and developmental effects of both the combination of diclofenac sodium and misoprostol and each component of diclofenac sodium and misoprostol delayed-release tablets alone have been studied in animals. In all studies there was no evidence of teratogenicity. In an oral teratology study in pregnant rabbits, diclofenac sodium and misoprostol delayed-release tablets was administered at dose combinations (diclofenac and misoprostol, 250:1 ratio) up to 10 mg/kg/day diclofenac sodium (120 mg/m2/day, 0.8 times the MRHD based on body surface area) and 0.04 mg/kg/day misoprostol (0.48 mg/m2/day, 0.8 times the MRHD based on body surface area) and there was no evidence of teratogenicity. At the high dose, there was evidence of embryotoxicity (resorption and decreased fetal body weight) and maternal toxicity (decreased food intake and weight gain).

In oral teratology studies with misoprostol in pregnant rats at doses up to 1.6 mg/kg/day (9.6 mg/m2/day, 16 times the MRHD based on body surface area) and pregnant rabbits at doses up to 1.0 mg/kg/day (12 mg/m2/day, 20 times the MRHD based on body surface area), there was no evidence of teratogenicity.

In oral teratology studies with diclofenac sodium in pregnant mice at doses up to 20 mg/kg/day (60 mg/m2/day, 0.4 times the MRHD based on body surface area), pregnant rats at doses up to 10 mg/kg/day (60 mg/m2/day, 0.4 times the MRHD based on body surface area) and pregnant rabbits at doses up to 10 mg/kg/day (120 mg/m2/day, 0.8 times the MRHD based on body surface area), there was no evidence of teratogenicity.

Lactation

Risk Summary

No lactation studies have been conducted with diclofenac sodium and misoprostol delayed-release tablets; however, limited published literature reports that diclofenac and the active metabolite of misoprostol are present in breast milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for diclofenac sodium and misoprostol delayed-release tablets and any potential adverse effects on the breastfed infant from the diclofenac sodium and misoprostol delayed-release tablets or from the underlying maternal condition.

Females and Males of Reproductive Potential

Diclofenac sodium and misoprostol delayed-release tablets are not recommended in women of childbearing potential. If diclofenac sodium and misoprostol delayed-release tablets are prescribed, patients must be advised of the abortifacient property and warned not to give the drug to others.

Pregnancy Testing

Verify pregnancy status for females of reproductive potential within 2 weeks prior to initiating diclofenac sodium and misoprostol delayed-release tablets.

Contraception

Females

Diclofenac sodium and misoprostol delayed-release tablets can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with diclofenac sodium and misoprostol delayed-release tablets.

Diclofenac sodium and misoprostol delayed-release tablets may be prescribed if the patient:

Has had a negative serum pregnancy test within 2 weeks prior to beginning therapy.

Is capable of complying with effective contraceptive measures.

Has received both oral and written warnings of the hazards of misoprostol, the risk of possible contraception failure, and the danger to other women of childbearing potential should the drug be taken by mistake.

Will begin diclofenac sodium and misoprostol delayed-release tablets only on the second or third day of the next normal menstrual period.

Advise females to inform their healthcare provider of a known or suspected pregnancy.

Infertility

Females

Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including diclofenac, a component of diclofenac sodium and misoprostol delayed-release tablets, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including diclofenac sodium and misoprostol delayed-release tablets, in women who have difficulties conceiving or who are undergoing investigation of infertility.

Pediatric Use

Safety and effectiveness of diclofenac sodium and misoprostol delayed-release tablets in pediatric patients have not been established.

Geriatric Use

Geriatric patients (those 65 years of age and older), compared to younger adult patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. In addition, the risk of diclofenac-associated adverse reactions may be greater in geriatric patients with renal impairment or those taking concomitant ACE inhibitors or ARBs.

Avoid use of diclofenac sodium and misoprostol delayed-release tablets in geriatric patients with cardiovascular and/or renal risk factors. If use cannot be avoided, use the lowest recommended dosage for the shortest duration and monitor for cardiac and renal adverse reactions. Monitor renal function in geriatric patients during treatment with diclofenac sodium and misoprostol delayed-release tablets, especially in patients with concomitant use of ACE inhibitors or ARBs.

Of the 2,184 patients in clinical studies with diclofenac sodium and misoprostol delayed-release tablets, 557 (25.5%) were 65 years of age and over. No overall differences in effectiveness were observed between these patients and younger adult patients, and other reported clinical experience has not identified differences in effectiveness between geriatric patients and younger adult patients, but greater sensitivity of some older individuals cannot be ruled out.

No clinically meaningful differences in the pharmacokinetics of diclofenac and misoprostol were observed in geriatric patients compared to younger adult patients.

Renal Impairment

Diclofenac and misoprostol are primarily excreted by the kidney. Long-term administration of NSAIDs has resulted in renal toxicity. Correct volume status in dehydrated or hypovolemic patients prior to initiating diclofenac sodium and misoprostol delayed-release tablets. Monitor renal function, especially during concomitant use of ACE inhibitors or ARBs. Also, monitor renal function in patients with hepatic impairment. Avoid the use of diclofenac sodium and misoprostol delayed-release tablets in patients with advanced renal disease. If use cannot be avoided in patients with advanced renal disease, use the lowest dosage for the shortest duration, monitor the patient’s renal function and monitor for clinical signs of worsening renal function.

The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of Diclofenac + Misoprostol

Symptoms of acute overdosage with diclofenac sodium and misoprostol delayed-release tablets should be treated with supportive and symptomatic therapy. There are no specific antidotes. In case of acute overdosage, emesisis and/or gastric lavage may be considered dependent upon amount ingested and time since ingestion. The use of oral activated charcoal may help to reduce the absorption of diclofenac sodium and misoprostol. Induced diuresis may be beneficial because diclofenac sodium and misoprostol metabolites are excreted in the urine. The effect of dialysis or hemoperfusion on the elimination of diclofenac sodium (99% protein bound) and misoprostol acid remains unproven.

Pharmacokinetics of Diclofenac + Misoprostol

Diclofenac

Inhibition of cyclooxygenase (COX-1 and COX-2) is part of diclofenac's, as well as other NSAIDs, mechanism of action, albeit its exact mechanism of action is unknown.

Prostaglandin (PG) production is potently inhibited in vitro by diclofenac. Effects in vivo have been induced by diclofenac concentrations attained during therapy. The ability of bradykinin to cause pain in animal models is enhanced by prostaglandins' sensitization of afferent neurons. Mediators of inflammation are prostaglandins. Diclofenac inhibits the production of prostaglandins, thus it's possible that this causes a reduction in prostaglandin levels in peripheral tissues, which would explain how it works.

Misoprostol

Misoprostol is a synthetic PGE1 analog with mucosal protection and antisecretory effects on the stomach. NSAIDs prevent the synthesis of prostaglandins. The mucosal damage brought on by NSAIDs may be exacerbated by a lack of prostaglandins inside the stomach and duodenal mucosa. This may result in decreased bicarbonate and mucus output.

Misoprostol has been found to be both antisecretory and to stimulate the formation of bicarbonate and mucus at doses of 200 mcg and higher. Therefore, it is impossible to determine whether misoprostol's capacity to lower the incidence of gastric and duodenal ulcers is due to its mucosal protective impact, its antisecretory activity, or both..

Pharmacodynamics:

Diclofenac:

Absorption: Diclofenac is completely absorbed from the GI tract after oral administration; bioavailability is only about 50% due to extensive first-pass metabolism.

Distribution: Diclofenac appears to be widely distributed, with significant amounts in synovial fluid. Protein binding is roughly 99%, primarily to albumin. The Vd of diclofenac is approximately 0.55 L/kg. Extensive and rapid hydroxylation and conjugation occur in the liver via cytochrome P450 (CYP) CYP2C9 and CYP3A4; UGT2B7 and CYP2C8 may also play a role.

Metabolism: The major metabolite, 4-hydroxy-diclofenac, has very weak pharmacologic activity. The formation of 4-hydroxy diclofenac is primarily mediated by CYP2C9.

Excretion: About 65% of a dose is excreted in the urine and about 35% in the bile. Little to no unchanged diclofenac is excreted in the urine, with the remainder as metabolites or conjugates of the drug. The elimination half-life is approximately 2 hours.

Misoprostol:

Absorption: Misoprostol is absorbed rapidly after oral administration.

Distribution: The plasma protein binding of misoprostol acid, the active metabolite of misoprostol, is less than 90% and is concentration-independent in the therapeutic range.

Metabolism: Misoprostol is rapidly and extensively metabolized to misoprostol acid.

Excretion: After administration of a radio-labeled dosage, approximately 70% of detected radioactivity appears in the urine. The elimination half-life of misoprostol acid is approximately 30 minutes.

Therapeutic Benefits of Diclofenac + Misoprostol

Diclofenac and misoprostol combination is used to relieve the symptoms of arthritis (eg, osteoarthritis or rheumatoid arthritis) in patients who may develop stomach or duodenal ulcers from taking nonsteroidal anti-inflammatory drugs (NSAIDs). Diclofenac is a nonsteroidal anti-inflammatory drug (NSAID) used to relieve symptoms of arthritis such as inflammation, swelling, stiffness, and joint pain. Misoprostol is used to decrease the risk of having stomach and bowel ulcers.

• https://www.clinicalkey.com/#!/content/drug_monograph/6-s2.0-1019?scrollTo=#Kinetics
• https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=df8b8660-0c24-4848-8bea-c1b935090c66
• https://medlineplus.gov/druginfo/meds/a699002.html
• https://www.drugs.com/mtm/diclofenac-and-misoprostol.html
• https://www.goodrx.com/arthrotec/what-is