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Mechanism of Action
US Drug Names
NOTE: Misoprostol is indicated to prevent NSAID-induced gastric ulcers but has not been shown to prevent duodenal ulcers.
200 mcg PO four times per day, with meals and at bedtime. May reduce to 100 mcg PO four times daily in those who do not tolerate 200 mcg dose. A dosage of 50—100 mcg PO four times daily was as effective as the 200 mcg PO regimen in the prevention of gastric injury, and, for prevention of duodenal injury, doses of 100 mcg PO four times daily were equivalent to 200 mcg PO four times daily. In a 12-week, double-blind, placebo-controlled study of arthritis patients receiving NSAIDs, the protective effect of misoprostol appeared to be dose-related and plateaued between 200 mcg PO two to three times per day. The authors concluded that lower doses (e.g., 200 mcg PO either two or three times per day) be considered for prophylaxis of either gastric or duodenal ulcerations. Continue for the duration of NSAID therapy.
Safe and effective use has not been established.
A dose of 100—200 mcg PO four times per day, with meals and at bedtime for 4—8 weeks or until healing occurs; however, the use of misoprostol for the treatment of peptic ulcer unrelated to NSAIDs is controversial. Misoprostol in doses of 200 mcg PO four times per day has been effective for both gastric and duodenal ulcer but the efficacy is roughly equivalent to H2-receptor antagonists. Because adverse reactions are greater with misoprostol than with H2-antagonists, misoprostol is considered a second-line agent.
Safety and efficacy have not been established.
Misoprostol 200 mcg PO four times per day for the first 12 weeks after transplantation was utilized in one study. The number of patients experiencing acute rejection was significantly lower in the misoprostol group (26% vs 51%). Although it was not statistically significant, the number of patients who developed cyclosporine nephrotoxicity was higher in the misoprostol group.
On day 1, administer one 200 mg mifepristone tablet PO as a single dose. Between 24 to 48 hours later, administer misoprostol 800 mcg buccally; the patient should place two 200 mcg misoprostol tablets in each cheek pouch for 30 minutes and then swallow any remnants with water or another liquid. The duration of pregnancy may be determined from menstrual history and clinical examination. If the duration of pregnancy is uncertain or ectopic pregnancy is suspected, assess by ultrasonographic scan. Intrauterine devices (IUDs) should be removed prior to mifepristone treatment. Discuss an appropriate location for the patient to be when she takes misoprostol; expulsion could begin within 2 hours of administration, and typically occurs within 24 hours. Patients should be given emergency contact numbers for healthcare providers and instructed what to do if significant discomfort, excessive bleeding, or other adverse events occur. Follow-up assessment to confirm complete pregnancy termination and evaluate bleeding should occur approximately 7 to 14 days after mifepristone administration. If complete expulsion has not occurred, but the pregnancy is not ongoing, women may be treated with another dose of misoprostol 800 mcg buccally; a follow-up visit approximately 7 days later should occur to assess for complete termination.
Not a FDA-approved regimen. Consult specialized literature. In one study, 178 gravid women (of less than 63 days gestation) received methotrexate IM followed by misoprostol 800 mcg inserted vaginally 5 to 7 days later. Seven days after receiving the first dose of misoprostol, patients were offered a second dose if there was evidence of a persistent gestational sac. Ninety-six percent of women had a successful medical abortion after the first or second dose of misoprostol. Seventy-six percent of women successfully aborted within 12 hours after insertion of misoprostol.
Not a FDA-approved regimen. Consult specialized literature. A dose of 200 mcg (2 x 100 mcg tablets) inserted vaginally (placed into the posterior vaginal fornix) every 12 hours until successful abortion has been used. Approximately 89% of the second trimester patients receiving vaginal misoprostol aborted within 24 hours; all patients aborted within 38 hours.
25 mcg intravaginally every 3 to 6 hours.  50 mcg intravaginally every 6 hours may be appropriate in some situations, although an increased risk of complications (e.g., uterine hyperstimulation and fetal heart rate changes) has been reported.
25 mcg PO every 2 hours. Vaginal administration produces greater clinical efficacy than the oral route; however, oral misoprostol use is associated with fewer abnormal fetal heart rate (FHR) patterns and episodes of uterine tachysystole with FHR deceleration when compared with vaginal administration. Oral use may result in fewer vaginal births within the first 24 hours vs. vaginal regimens; overall rates of vaginal birth appear similar.
200 to 400 mcg intravaginally every 4 to 12 hours in persons less than 28 weeks gestation with intrauterine fetal demise.
25 mcg PO every 2 hours.
600 mcg PO as a single dose.  Oxytocin plus misoprostol appears to be no more effective than oxytocin used alone for prophylaxis of postpartum hemorrhage, so standard protocols (e.g., use of oxytocin administration, uterine massage, and umbilical cord traction) are recommended in persons at risk. If there is inadequate uterine response and ongoing postpartum hemorrhage, then various uterotonics, including misoprostol, may be given in rapid succession if there are no contraindications. Consider misoprostol only for persons with asthma and hypertension.
800 mcg SL as a single dose.  Oxytocin plus misoprostol appears to be no more effective than oxytocin used alone for prophylaxis of postpartum hemorrhage, so standard protocols (e.g., use of oxytocin administration, uterine massage, and umbilical cord traction) are recommended in persons at risk. If there is inadequate uterine response and ongoing postpartum hemorrhage, then various uterotonics, including misoprostol, may be given in rapid succession if there are no contraindications. Consider misoprostol only for persons with asthma and hypertension.
600 to 1,000 mcg PR as a single dose. However, some guidelines no longer recommend rectal administration due to late onset of action. Oxytocin plus misoprostol appears to be no more effective than oxytocin used alone for prophylaxis of postpartum hemorrhage, so standard protocols (e.g., use of oxytocin administration, uterine massage, and umbilical cord traction) are recommended in persons at risk. If there is inadequate uterine response and ongoing postpartum hemorrhage, then various uterotonics, including misoprostol, may be given in rapid succession if there are no contraindications.
NOTE: Consult the contraindications section of the monograph before use.
As an alternative to traditional management, such as surgical or expectant management, misoprostol has shown efficacy and safety in women <= 13 weeks gestation with indicators of pregnancy failure. The dosage regimen was 800 mcg intravaginally (placed into the posterior vaginal fornix) on day 1, followed by a repeat dose on day 3 if expulsion was incomplete. The regimen was followed by vacuum aspiration on day 8 if expulsion was still incomplete.
800 mcg/day PO.
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Specific guidelines for dosage adjustments in renal impairment are not available. No routine dosage adjustment is recommended; however, the dose can be reduced if the usual dose is not tolerated (manufacturer information).
Because misoprostol is metabolized like a fatty acid, it is unlikely that hemodialysis enhances drug clearance.
Misoprostol is a synthetic, oral prostaglandin E1 (PGE1) analog. Misoprostol is effective for prevention of gastric ulcers secondary to use of nonsteroidal antiinflammatory drugs (NSAIDs) and should be taken for the duration of NSAID therapy. The drug may produce uterine contractions, uterine bleeding, and abortifacient effects and the products carry a boxed warning regarding the reproductive risks; adequate contraception is required in females of childbearing potential during oral use for prevention of NSAID-induced ulcers. Due to its ability to ripen the cervix and stimulate uterine contractions, misoprostol is used widely off-label in various obstetric protocols for cervical ripening and labor induction; these uses are not FDA-approved but are recommended in obstetric guidelines and are discussed in the oral product label. Misoprostol is a recognized component of the FDA-approved mifepristone-regimen for early pregnancy termination.
For storage information, see the specific product information within the How Supplied section.
Hazardous Drugs Classification
NOTE: Misoprostol is not approved by the FDA for intravaginal administration.
NOTE: Misoprostol is not approved by the FDA for rectal administration.
Diarrhea is the most commonly reported adverse reaction occurring during misoprostol therapy (14—40%); however, it is usually self-limiting. Misoprostol-induced diarrhea has been associated with metabolic acidosis and dehydration and, in rare instances, has been severe enough to require discontinuance of the drug. Diarrhea is dose-related and usually occurs within the initial 2 weeks of treatment, with resolution of symptoms after 8 days. Abdominal pain (7—20%), nausea/vomiting (3.2%), flatulence (2.9%), constipation (1.1%), and dyspepsia (2%) also have been reported during misoprostol therapy, but the frequency of these symptoms was not significantly different from that reported in patients receiving placebo. In a study of elderly patients receiving misoprostol and a NSAID regularly for 6 months, diarrhea, abdominal pain, and flatulence occurred significantly more often in the group receiving misoprostol 100—200 mcg PO four times per day than in the group not receiving prophylaxis with misoprostol.
Headache (2.4%) is the most commonly reported CNS effect of misoprostol therapy. Other CNS effects, including vertigo and lethargy, occur much less frequently.
After combination therapy of oral mifepristone and intravaginal misoprostol for pregnancy termination, cases of serious systemic bacterial infection, including sepsis/septic shock and rare sepsis-related fatalities, have been reported. Between 2000 and 2009, 8 cases of serious bacterial infections and sepsis following the use of oral mifepristone and vaginal misoprostol were reported in the US; bringing the US rate of fatal Clostridium sordellii and C. perfringens infections to 0.58 per 100,000 medical abortions. Several cases involved off-label dosing consisting of 200 mg of oral mifepristone followed by 800 mcg of intra-vaginally placed misoprostol. The FDA, in its investigation of the cases, tested lots of both mifepristone and misoprostol tablets and did not find evidence of contamination with Clostridium sordellii. None of these patients presented with elevated temperatures; however, they did present with sinus tachycardia, low blood pressure, leukocytosis, and very high red blood cell counts. The patients also had other atypical symptoms including weakness, nausea/vomiting, or diarrhea with or without abdominal pain. No causal relationship has been established between these events and the mifepristone-misoprostol regimen for termination of pregnancy. In addition, when misoprostol was used for the management of postpartum hemorrhage, reports of high fevers (greater than 40 degrees C or 104 degrees F), accompanied by autonomic and central nervous system effects, such as tachycardia, disorientation, agitation, and convulsions were reported. These fevers were transient in nature. Supportive therapy should be dictated by the patient’s clinical presentation. A sustained fever of 100.4 degrees F or higher, severe abdominal pain, pelvic tenderness, or prolonged heavy bleeding more than 24 hours after a medical abortion may be an indication of infection; however, practitioners should also be alert to atypical presentations of serious infection and sepsis including leukocytosis, tachycardia, hemoconcentration, syncope, and more general symptoms such as abdominal discomfort or general malaise (including weakness, nausea/vomiting, or diarrhea).
In clinical trials for prevention of NSAID-induced stomach ulceration, misoprostol caused the following side effects in female patients: spotting (0.7%, breakthrough bleeding), cramps (0.6%), menstrual irregularity (0.3%), and dysmenorrhea (0.1%). Postmenopausal vaginal bleeding may be related to misoprostol use, but should be evaluated. Misoprostol can increase the frequency and intensity of uterine contractions in both gravid and nonpregnant women. The risk of teratogenesis from misoprostol use during pregnancy is unclear but of concern. Due to its stimulatory effects on uterine contractility, misoprostol should not be used during pregnancy (FDA pregnancy category X) for the prevention of NSAID-induced ulceration. Anecdotal reports of congenital anomalies and fetal death have been received (manufacturers information) when fetal drug exposure occurs during the first trimester. A review of drugs and pregnancy lists Moebius sequence as a potential complication of misoprostol use. Serious adverse events have been reported following the use of misoprostol in pregnant women for off-label uses such as termination of pregnancy, cervical ripening, or labor induction. Such side effects include maternal or fetal death; infection; uterine hyperstimulation; cervical laceration, uterine rupture requiring uterine surgical repair, hysterectomy or salpingo-oophorectomy; amniotic fluid embolism; meconium passage; meconium staining of the amniotic fluid; severe vaginal bleeding; retained placenta; shock; fetal bradycardia; pelvic pain or uterine pain; and caesarean delivery. In addition to the known and unknown acute risks to the mother and fetus, the effect of misoprostol on the later growth, development and functional maturation of the child when the drug is used for induction of labor or cervical ripening is unknown. When used off-label for the prevention and treatment of postpartum bleeding, oral or rectal administration of misoprostol have been associated with chills, shivering, diarrhea and hyperthermia (or pyrexia) in up to 30—40% of patients.
Cardiovascular and allergic adverse reactions have been reported infrequently during treatment with misoprostol; although a causal relationship between misoprostol and these events has not been established, it cannot be excluded. Such adverse events include chest pain (unspecified), edema, diaphoresis, hypotension, hypertension, arrhythmia, phlebitis, increased cardiac enzymes, syncope, myocardial infarction (some fatal), thromboembolic events (e.g., pulmonary embolism, arterial thrombosis, cerebrovascular accident (stroke), rash (unspecified), and anaphylactoid reactions including anaphylaxis.
Misoprostol is contraindicated in patients with a history of allergy to misoprostol or with previous prostaglandin hypersensitivity.
Misoprostol is contraindicated during pregnancy for use to reduce the risk of stomach ulcers associated with NSAIDs (the FDA-approved indication). This agent causes reproductive risk, including uterine contractions, miscarriage, and other problems if administered during pregnancy. Drug-induced miscarriages may be result in incomplete abortion, necessitating hospitalization or surgery. Although misoprostol is contraindicated in pregnancy due to its stimulatory effects on uterine contractility, it appears teratogenesis is also a possibility with this drug. Several reports in the literature associate the use of this drug during the first trimester with skull defects, cranial nerve palsies, facial malformations, and limb defects. Misoprostol should be promptly discontinued if pregnancy occurs during treatment with this agent for the approved indication. Misoprostol should not be used for reducing the risk of NSAID-induced ulcers in females of childbearing potential unless the patient is at high risk of complications from gastric ulcers associated with use of the NSAID, or is at high risk of developing gastric ulceration. In such patients, misoprostol may be prescribed if the patient 1) exhibits a negative serum pregnancy testing within 2 weeks of initiating therapy, 2) follows contraception requirements, using effective and reliable birth control during misoprostol use, 3) receives both oral and written warnings on the potential hazards, and 4) initiates therapy only on the second or third day of the next normal menstrual period. The manufacturer does not contraindicate the use of misoprostol during or following labor and obstetric delivery for off-label uses and recognizes these off-label uses within the special populations information of the label. Misoprostol is widely used off-label in obstetric practice as a cervical ripening agent to induce labor, for term obstetric delivery, for treatment of serious postpartum hemorrhage in the presence of uterine atony, and as part of the FDA-approved regimen for use with mifepristone (RU-486) for termination of pregnancy of 49 days or less. The mifepristone-misoprostol regimen is not effective for treating ectopic pregnancy.  Guidelines on the use of misoprostol for obstetric indications, including vaginal administration, have been published. Off-label administration of misoprostol during labor and obstetric delivery for term pregnancy or for labor induction following fetal demise should proceed with caution. Do not use misoprostol or other methods of cervical ripening or labor induction in term pregnancy if contraindications to the induction of labor exist, such as umbilical cord prolapse, active genital herpes infection, vasa previa or complete placenta previa, or if unexplained vaginal bleeding is present during the current pregnancy. Do not use if there are ominous fetal heart rate tracings (acute fetal distress) or abnormal fetal position (e.g., transverse fetal lie). Avoid use of misoprostol in the third trimester in patients with previous caesarean section or uterine surgery because of the increased risk for uterine rupture and other adverse effects; women with multiple gestation (eminent or grand multiparity) or women who have had 6 or more previous pregnancies are also be at increased risk and may not be appropriate candidates for labor induction with prostaglandin analogs. Using a higher dosage of misoprostol than recommended in term pregnancies increases the risk of maternal adverse events. Protocols for labor induction following fetal demise use larger misoprostol doses than those used in term pregnancies, and an increased incidence of maternal adverse effects has not been noted in these cases. As indicated by the clinical situation, monitor maternal vital signs, fetal heart rate (FHR), signs of fetal distress, and uterine contractions. Be alert for signs and symptoms of tetanic uterine contractions/uterine hyperstimulation. Serious adverse events have been reported following off-label use of misoprostol in pregnant women. The manufacturer of misoprostol has not conducted controlled studies of the drug for cervical ripening or labor induction. In addition to the known and unknown acute risks to the mother and fetus, the effect of misoprostol on the later growth, development and functional maturation of the child when the drug is used for induction of labor or cervical ripening has not been established. Information on misoprostol's effect on the need for forceps delivery or other intervention is unknown.
Animal data suggest that the use of misoprostol may have an adverse general effect on fertility in males and females. Use this drug with caution in male or female patients undergoing medical management for infertility.
According to the manufacturer, caution is advised if misoprostol is administered to a breast-feeding woman. Because misoprostol is quickly metabolized in the body to misoprostol acid, it is unlikely that misoprostol itself would be distributed into breast milk. However, biologically active misoprostol acid has been shown to be excreted in breast milk after a single oral dose of misoprostol. Misoprostol concentrations in breast milk appear to be low following singular doses or short-dosing periods, such as might occur in off-label use for cervical ripening or off-label for post-partum hemorrhage; breast-feeding may be acceptable in these scenarios following a waiting period to avoid peak milk concentrations. In clinical evaluation, maximum misoprostol acid concentrations were achieved in breast milk within 1 hour after dosing and were 7.6 pg/mL and 20.9 pg/mL after single 200 mg and 600 mg misoprostol doses, respectively. Concentrations of misoprostol acid in expressed breast milk declined to 1 pg/mL at 5 hours post-dose. Although there are no published reports of adverse effects from misoprostol in breast-feeding infants, the ingestion of misoprostol acid may cause significant diarrhea in a nursing infant. Potential alternatives to consider for lactating patients when considering longer-term treatment or prophylaxis for GI ulcers include famotidine , which is considered to be compatible with breast-feeding. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated maternal condition.
The safety and effectiveness of misoprostol have not been established in children.
Misoprostol can exacerbate intestinal inflammation and cause diarrhea in patients with inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis). Therefore, the drug should be used cautiously in these patients. Dehydration can occur due to misoprostol-induced diarrhea and patients who are predisposed to dehydration or diarrhea should be monitored carefully while receiving misoprostol.
The half-life of misoprostol is prolonged in patients with renal disease. Currently, dosage adjustments in the presence of renal impairment do not appear necessary; however, dosage adjustments may become warranted if the usual dose cannot be tolerated.
Administer misoprostol cautiously to patients with pre-existing cardiac disease; although a causal relationship is unknown, patients receiving misoprostol have experienced cardiovascular adverse reactions (see Adverse Reactions).
Combination therapy of mifepristone and intravaginal misoprostol, when used for pregnancy termination, has been associated with cases of serious bacterial infection, including, although rare, fatal sepsis and septic shock. As of March 2006, 5 deaths due to serious bacterial infections and sepsis following the use of mifepristone and vaginal misoprostol have been reported in the US. Four of the 5 cases involved off-label dosing consisting of 200 mg of oral mifepristone followed by 800 mcg of intra-vaginally placed misoprostol. In 4 of the 5 cases, Clostridium sordellii has been identified as the causative organism; the circumstances of the additional death is being reviewed by the FDA. The FDA tested lots of both mifepristone and misoprostol tablets and did not find evidence of contamination with Clostridium sordellii. None of these patients presented with a fever; however, they did present with sinus tachycardia, low blood pressure, leukocytosis, and very high red blood cell counts. The patients also had other atypical symptoms including weakness, nausea/vomiting, or diarrhea with or without abdominal pain. No causal relationship has been established between these events and the mifepristone-misoprostol regimen for termination of pregnancy; however, the health care practitioners involved in the patient's evaluation and care should be alert to the possibility of such events. A sustained fever >= 100.4 degrees F, severe abdominal pain, pelvic tenderness, or prolonged heavy bleeding, more than 24 hours after a medical abortion may be an indication of infection and warrant intervention; however, practitioners should also be alert to atypical presentations including leukocytosis, tachycardia, hemoconcentration, syncope, and more general symptoms such as abdominal discomfort or general malaise (including weakness, nausea, vomiting, or diarrhea).
Mechanism of Action: Misoprostol inhibits basal and nocturnal gastric acid secretion through a direct action on the parietal cell. Parietal cells contain receptors that have high affinity for prostaglandins of the E series. Misoprostol can inhibit gastric acid secretion secondary to stimulation from food, alcohol, NSAIDs, histamine, pentagastrin, or caffeine, and this effect appears to be more pronounced with increasing doses. H2-antagonists, however, appear to be more potent than misoprostol in the ability to inhibit gastric acid output, especially at night.
Misoprostol also exerts a mucosal protectant effect that may contribute to its effectiveness in treating ulcers. It has been suggested that the cytoprotective effect is secondary to mucus and bicarbonate secretion, prevention of mucus bilayer disruption, reduction of backflow of hydrogen ions, regulation of mucosal blood flow, and protection of the mucosal capacity to produce cells. Misoprostol reduces pepsin concentrations under basal conditions; however, histamine-stimulated secretion is not affected.
Because prostaglandins can affect many tissues, other actions of misoprostol have been identified. Misoprostol may increase the frequency of uterine contractions, which is responsible for its abortifacient capability and ability to promote labor and cervical ripening. Increases in the amplitude and frequency of uterine contractions reduces cervical tone, which produces cervical dilation. In addition, misoprostol has been shown to improve renal function in renal transplant patients treated with cyclosporine and prednisone; misoprostol may offset cyclosporine-induced intrarenal vasoconstriction.
Misoprostol is administered orally, and is administered 'off-label' by the vaginal route.
After systemic absorption, misoprostol undergoes rapid de-esterification to misoprostol acid, which is responsible for the drug's clinical activity and, unlike the parent compound, is detectable in plasma. Animal data suggest that a portion of this metabolism occurs in the parietal cell. The alpha-side chain undergoes beta-oxidation and the beta-side chain undergoes omega oxidation followed by reduction of the ketone to give prostaglandin F analogs. The metabolism is similar to that of other fatty acids. The serum protein binding of misoprostol acid is < 90% and is concentration-independent. Misoprostol distribution has not been fully elucidated. It is unknown whether this agent crosses the placenta or is distributed into breast milk, but because misoprostol can stimulate uterine contractions, it should not be used during pregnancy (see Contraindications). Misoprostol does not affect the hepatic cytochrome P450 enzyme system. Less than 1% of a dose is excreted in the urine as unchanged drug. After administration of a radiolabeled dosage, roughly 80% of the total radioactivity is detected in the urine.
When given orally, misoprostol is absorbed rapidly (Tmax 12 +/- 3 minutes) and extensively (88%). Mean plasma concentration values for misoprostol acid after single doses show a linear relationship within a dosage range of 200—400 mcg. Inhibition of gastric acid secretion occurs approximately 30 minutes following a single oral dose, reaching a maximum effect within 60—90 minutes. No accumulation of misoprostol acid occurs with continued dosing; plasma steady state levels are achieved within 2 days. Maximum plasma concentrations of misoprostol acid are diminished when an oral dose is taken with food and total availability of misoprostol acid is reduced by the concomitant use of antacid. Clinical trials were conducted with concurrent antacid, however, so this effect does not appear to be clinically relevant. The effect of food on misoprostol's activity is also clinically insignificant and the drug should be given with food. The duration and intensity of gastric acid inhibition is dose-related, with a probable ceiling effect at 400 mcg.
Misoprostol is also well absorbed by the intravaginal route.
Pharmacokinetic studies in patients with varying degrees of renal impairment showed an approximate doubling of half-life, Cmax, and AUC compared to normal adults, but no clear correlation between the degree of renal impairment and AUC. No routine dosage adjustment is recommended in patients with renal impairment, unless the usual dose is not tolerated (see Dosage). Because misoprostol is metabolized like a fatty acid, it is unlikely that hemodialysis enhances drug clearance.
In the elderly (> 64 years of age), the AUC for misoprostol acid is increased. No routine dosage adjustment is recommended in older patients, unless the usual dose is not tolerated (see Dosage).
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