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.[24347]

Headache (2.4%) is the most commonly reported CNS effect of misoprostol therapy. Other CNS effects, including vertigo and lethargy, occur much less frequently.[29358]

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.[55669] 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.[29358] 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.[24291] 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.[29358]

Misoprostol is contraindicated during pregnancy for use to reduce the risk of stomach ulcers associated with NSAIDs (the FDA-approved indication).[29358] 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.[29358] 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.[29358] 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.[28003] [29358] Guidelines on the use of misoprostol for obstetric indications, including vaginal administration, have been published.[27317] 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.[27317] 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.[27317] 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.[27317] 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.[29358]

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.

Misoprostol is compatible with breast-feeding. Misoprostol passes into milk in small amounts with a relative infant dose of 0.04%. Due to this minimal amount of infant exposure, no infant adverse effects are expected.[70364] [70365] 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.[45834]

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).