a) 100 mcg and 200 mcg tablets (Prod Info Cytotec(R) oral tablets, 2009).
b) DICLOFENAC/MISOPROSTOL: 50 mg/200 mcg, 75 mg/200 mcg tablets (Prod Info ARTHROTEC(R) oral tablets, 2010).

a) 250 mcg/mL solution for injection (Prod Info Hemabate(R) IM injection, 2006).

a) 0.5 mg/3 g vaginal gel; 0.3 mg/hr vaginal insert; 20 mg vaginal suppository (Prod Info CERVIDIL(R) vaginal insert, 2010; Prod Info Prepidil(R) cervical gel, 2010; Prod Info PROSTIN E2(R) vaginal suppositories, 2006).

1) Adverse effects of these agents following therapeutic doses include nausea, vomiting, diarrhea, abdominal pain, constipation, seizures, headache, dizziness, fatigue, malaise, elevated liver enzymes, and uterine bleeding or rupture. Postpartum DIC has been reported during postmarketing use of dinoprostone cervical gel and vaginal insert (less than 1 in 1000 labors for dinoprostone cervical gel).

1) MILD TO MODERATE TOXICITY: Few cases of severe poisoning exist. Overdose effects are anticipated to be an extension of adverse effects observed following therapeutic doses. Abdominal cramping, diarrhea, headache, dizziness, and uterine contraction and bleeding may occur.
2) SEVERE TOXICITY: In rare cases, hypertension, tachycardia, fever, tremor, rhabdomyolysis, renal insufficiency, and elevated liver enzymes have occurred. Hyperthermia, increased pulse, and increased respiratory rate may result from an acute overdose. In pregnant patients, uterine contractions, hemorrhage, and fetal death have occurred. One patient developed gastric and esophageal necrosis and upper gastrointestinal bleeding after misoprostol overdose. Misoprostol causes uterine contractions resulting in a miscarriage. Metabolic acidosis was reported in an acute misoprostol overdose case.

1) Patients may only need observation. Treatment is symptomatic and supportive.

1) Symptomatic and supportive care is the mainstay of treatment. Consultation should be made with obstetrics and gynecology in cases of uterine hypertonicity or bleeding after ingestion.

1) Because the toxic dose of misoprostol has not been well-established, consider administering activated charcoal in patients taking a dose that is greater than therapeutic dose as well as in any pregnant patient that is not purposely taking misoprostol to induce abortion or labor.
2) PREHOSPITAL: Activated charcoal should be considered early in the course after a significant ingestion in patients who are protecting their airways and have not yet manifested signs of toxicity. If a patient is displaying signs of moderate to severe toxicity, it is likely that most of the drug has been absorbed, and activated charcoal is not likely to be helpful. In this case, activated charcoal can be aspirated if patient becomes somnolent.
3) HOSPITAL: Consider decontamination if a patient presents promptly after an ingestion overdose and is not manifesting symptoms of toxicity. Patients eligible for decontamination with oral charcoal include inadvertent overdoses in children and intentional overdoses in adults. If the drug has been inserted vaginally it should be removed.

1) Perform early in patients with symptoms of airway compromise, although this is unlikely to be necessary in misoprostol-only ingestions.

1) None.

1) Antiemetics may be used to control nausea.

1) No specific treatment is required. IV fluids should be given if the patient is dehydrated from diarrhea associated with misoprostol ingestion.

1) Simple oral analgesics can be given, if tolerated. If the patient is nauseated, IV analgesics can be given.

1) Diarrhea and abdominal cramping should be treated with oral or IV fluids. Oral or IV opioids can be given as well as antispasmotics, such as dicyclomine 20 mg orally.

1) Administer IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur.

1) Hemodialysis is not of value for misoprostol overdose because of the high degree of protein binding.

1) HOME CRITERIA: Patients should be evaluated by a healthcare professional if they are symptomatic after a therapeutic dose, or if they are/might be pregnant and the medication was not prescribed to terminate pregnancy or induce labor. Any patient reporting an intentional overdose should be evaluated in the emergency department.
2) OBSERVATION CRITERIA: Patients with deliberate ingestions should be sent to a healthcare facility for observation. Any patient with symptoms should be observed until symptoms improve or resolve.
3) ADMISSION CRITERIA: Patients with significant symptoms and/or abnormal vital signs should be admitted. Pregnant patients with symptoms of vaginal bleeding or contractions should be evaluated by an obstetrician/gynecologist.
4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear. Obstetrician/gynecologist should be consulted for any case of excessive uterine bleeding or contractions and in the case of inadvertent administration to a pregnant woman who does not desire early pregnancy termination.

1) Falsely attributing patient's symptoms to misoprostol when the true underlying cause is due to another etiology.

1) Misoprostol is rapidly absorbed; Vd: 40 L; protein binding: 81% to 89%. It is primarily metabolized in the gut parietal cells. Misoprostol acid is an active metabolite. Eighty percent is excreted in the urine with less than 1% unchanged. Half-life is approximately 20 to 40 minutes.

1) Spontaneous abortion, spontaneous labor, viral or bacterial causes of diarrhea.

1) WITH THERAPEUTIC USE
2) WITH POISONING/EXPOSURE

1) WITH THERAPEUTIC USE
2) WITH POISONING/EXPOSURE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH POISONING/EXPOSURE

1) WITH THERAPEUTIC USE
2) WITH POISONING/EXPOSURE

1) WITH THERAPEUTIC USE

1) WITH POISONING/EXPOSURE

1) WITH POISONING/EXPOSURE

1) WITH THERAPEUTIC USE

1) WITH POISONING/EXPOSURE

1) WITH THERAPEUTIC USE

1) HYPERTHERMIA

1) WITH THERAPEUTIC USE
2) WITH POISONING/EXPOSURE

1) WITH POISONING/EXPOSURE

1) WITH POISONING/EXPOSURE

1) WITH THERAPEUTIC USE
2) MISOPROSTOL

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) During a prospective followup study of pregnancies exposed to misoprostol during the first trimester, the incidence rates of spontaneous abortion, in utero fetal death (IUFD), and premature birth were higher compared with controls groups. Of the 236 pregnancies exposed to misoprostol, the incidence rate of spontaneous abortion before 22 gestational weeks was 12.3% compared with 8.3% in the control group (n=255) (odds ratio (OR), 1.54; 95% CI, 0.78 to 3.06). IUFD was reported in 3 pregnancies exposed to misoprostol compared with 0 pregnancies in the control group. Premature birth was reported in 9.9% of misoprostol-exposed pregnancies and 3% of control group pregnancies (OR, 3.51; 95% CI, 1.38 to 8.9; p less than 0.01). In addition, major birth defects, including cleft lip, cleft palate, right equinovarus, and atrial septal defects, were reported in 6 pregnancies in the misoprostol-exposed group compared with 4 pregnancies in the control group. One infant from the misoprostol-exposed group with a severe trismus with retrognathism, microstomia, soft palate closure defects, patent ductus arteriosus, and right equinovarus, died of cardiorespiratory complications after 2.5 months. The total rate of birth defects was higher in the misoprostol-exposed group compared with the control group (4% and 1.8%, respectively) (OR, 2.2; 95% CI, 0.6 to 7.7). Among the 6 major malformations reported in the misoprostol-exposed group, 3 were consistent with malformations attributed to misoprostol use during pregnancy compared with 0 in the control group (Vauzelle et al, 2013).
2) Although the teratogenic mechanism of misoprostol has not been demonstrated, congenital anomalies, some fatal, have been reported following the unsuccessful use of misoprostol as an abortifacient. Skull defects, cranial nerve palsies, facial malformations, and limb defects during the first trimester of pregnancy have been associated with misoprostol use in a number of literature reports (Prod Info Cytotec(R) oral tablets, 2009).
3) A case report describes Moebius and Poland syndrome in a male newborn exposed to misoprostol. The patient's mother was administered misoprostol 400 mcg both orally and vaginally at 5 weeks gestation as an abortifacient but only resulted in slight bleeding. Upon examination, the infant was found to have bilateral facial paralysis, a rounded face, narrow palpebral fissures, cupid's bow lips, arched palate, micrognathia, and hypoplasia with absence of pectoralis major nipple. Proximal syndactyly of second and third fingers and bilateral club foot were also observed. The Moebius and Poland syndrome is thought to be associated with vascular disruption caused by misoprostol during the critical gestational period (Pachajoa & Isaza, 2011).
4) A systematic, quantitative review of 4 case-control studies revealed that prenatal exposure to misoprostol was associated with an increased risk of teratogenic effects such as Mobius sequence and terminal transverse limb defects. Included were newborns and children less than 2 years of age, with a total of 4899 cases of congenital defects (n=4673, n=96, n=93, and n=37) and 5742 controls (n=4980, n=96, n=279, and n=387, respective to cases). Misoprostol exposure was determined by interviewing the mothers; however the length of exposure to misoprostol was not available. In 2 of the studies, misoprostol doses of 200 to 1600 mcg were used either orally, vaginally, or via both routes. Overall, misoprostol exposure during the first trimester occurred in 80 cases. The combined odds ratio (OR) for any congenital defect was 3.56 (95% confidence interval (CI), 0.98 to 12.98); however, there was significant heterogeneity between the studies (p less than 0.0001). Excluding the study with the greatest sample size yielded an OR of 5.56 (95% CI, 1.22 to 25.41; p (for heterogeneity)=0.01). The combined OR for Mobius sequence (congenital palsies of the sixth and seventh cranial nerves, with or without paralysis of other cranial nerves, and associated with limb anomalies and craniofacial defects) in children exposed to misoprostol was 25.31 (95% CI, 11.11 to 57.66; p (for heterogeneity)=0.71). The combined OR for terminal transverse limb defects was 11.86 (95% CI, 4.86 to 28.9; p (for heterogeneity)=0.62) (da Silva Dal Pizzol et al, 2006).
5) A retrospective review of 96 mothers who gave birth to infants with Mobius syndrome and 96 mothers who gave birth to infants with neural tube defects, was conducted to determine the use of misoprostol during the first trimester of pregnancy. Among the mothers of the 96 infants with Mobius syndrome, 47 (49%) had used misoprostol during the first trimester of pregnancy. Of the 47 women, 46 had used misoprostol as an abortifacient and one woman had used misoprostol to treat peptic ulcer disease. Three mothers (3%) of the 96 infants with neural tube defects had used misoprostol during their pregnancies (odds ratio 29.7, 95% confidence interval 11.6 to 76) (Pastuszak et al, 1998).
6) Intrauterine growth restriction, developmental delays, facial dysmorphology, and multiple anomalies, including anisocoria, bowing of the tibias, bilateral transverse palmer creases, bilateral fifth-finger clinodactyly, external rotation of the feet, and ventriculomegaly, occurred in infants who were exposed to methotrexate and misoprostol during the first trimester following failed medical termination of the pregnancies (Yedlinsky et al, 2005).
7) Subtherapeutic doses of misoprostol caused no significant changes in fetal heart rate but did cause uterine artery constriction. In a prospective observational study, 40 pregnant women in their first trimester were given a single 200-mcg oral dose of misoprostol to determine the effects on uterine arterial blood flow and fetal heart rate. The dose used in the study was subtherapeutic for termination of the pregnancy. While there were no significant changes in fetal heart rate, uterine artery vasoconstriction did occur. This may explain the occurrence of congenital abnormalities associated with misoprostol use in early pregnancy. The author suggests a similar study be done in animals so that the effects on uterine artery vasoconstriction can be investigated further (Yip et al, 2000).
8) A series of observational cohort studies suggested that misoprostol does not cause an increased rate of congenital anomalies when used during pregnancy. Of 3 pregnant women who took the drug, one discontinued the drug before the last menstrual period and 2 were exposed during the first trimester. Of the 2 exposed during the first trimester, there was one birth without congenital anomalies; the outcome of the other pregnancy was unknown (Wilton et al, 1998).
9) Five cases of localized frontal and/or temporal open defects of the cranium and overlying scalp have been reported in (presumably) full-term infants associated with failed attempts at self-abortion with misoprostol during the first trimester of pregnancy (Fonseca et al, 1991). Data have been received by a teratogenic effects reporting network concerning 29 cases of alleged maternal use of misoprostol in failed attempts at self-abortion during the first trimester of pregnancy. Of 17 evaluable cases, no cranial defects were observed (Schuler et al, 1992).
10) CASE REPORT: Clinical findings and MRI abnormalities consistent with Moebius syndrome were identified in a 10-month-old girl who presented at a pediatric clinic with talipes equinovarus and neuro-psycho-motor delays. MRI results included images characteristic of lobar holoprosencephaly. The child was exposed to an unknown amount of misoprostol in utero; however, it is unclear during which trimester the ingestion occurred. Prenatal care was not received by the mother and the infant was born at 30-weeks gestation weighing 2.93 g (Pirmez et al, 2010).

1) DINOPROSTONE
2) MISOPROSTOL

1) Abortion, including incomplete abortions, premature birth, and birth defects, have been reported with misoprostol use during pregnancy. Pregnant women treated with misoprostol to induce labor or to induce abortion beyond week 8 of gestation have experienced uterine rupture. Maternal use of misoprostol may also produce uterine contractions and uterine bleeding (Prod Info Cytotec(R) oral tablets, 2009).
2) CASE REPORT: A 29-year-old pregnant woman at 5 weeks gestation self-administered 1 mg of oral misoprostol and 7 mg of intravaginal misoprostol to induce abortion, and presented to the emergency department 3 hours later with fever (a tympanic temperature of 43 degrees C), chills, confusion, agitation, tremors, hallucinations, and tachycardia. Laboratory analysis showed acute renal failure (1.8 mg/dL creatinine), rhabdomyolysis (7690 units/L creatine kinase), compensated metabolic acidosis, and slightly elevated liver enzymes. She was intubated and treated aggressively with IV hydration, antipyretics, and sedatives. Sixteen hours after treatment she was asymptomatic and extubated. Renal failure resolved within 36 hours. However, vaginal bleeding developed 48 hours after admission and a complete abortion was confirmed with sonography. Upon examination 16 days after admission the woman was found to be healthy (Barros et al, 2011).
3) CASE REPORT: A 19-year-old pregnant woman at 31 weeks gestation who ingested 6000 mcg of misoprostol and 8 mg of trifluoperazine presented to the emergency department 2 hours later. She developed hypertonic uterine contractions with subsequent fetal death (Bond & Van Zee, 1994).
4) One study by the manufacturer indicated that of 111 pregnant women receiving misoprostol during the first trimester of pregnancy, approximately 50% experienced drug-induced bleeding and 7% had drug-induced complete or incomplete abortions (Anon, 1985a).
5) CASE REPORT: A 42-year-old pregnant woman (gravida 10, para 10) presented to the ED with severe abdominal cramping, vomiting, diarrhea, headache, lethargy, and nonmalodorous blood-stained vaginal discharge after ingesting 12 oral misoprostol tablets (200 mcg each) to terminate her pregnancy at 9.2 weeks of gestation. Vital signs included a pulse rate of 140 beats/min and blood pressure of 90/60 mmHg. Endometrial remnants were observed in the uterine cavity using a transvaginal ultrasonography. Laboratory results also revealed hypokalemia and hypocalcemia. Despite supportive care, including IV antibiotics, fluids, and vasopressors, her condition deteriorated. At this time, a total body CT scan revealed pleural effusions and ascites. She underwent a revision of the uterine cavity and curettage and continued to receive supportive care, including plasma and platelets transfusions, and therapeutic abdominal paracentesis, but died of refractory hypotension and sepsis with disseminated intravascular coagulation. Throughout her hospitalization a fever was not reported. Autopsy findings revealed cutaneous petechiae, diffuse subcutaneous edema, nonhemorrhagic peritoneal fluid, an enlarged uterus, and hematic pleural effusion. All histological findings were consistent with septic shock as the cause of death (Cittadini et al, 2014).

1) Misoprostol is classified as FDA pregnancy category X (Prod Info Cytotec(R) oral tablets, 2009).
2) Carboprost and dinoprostone are classified as FDA pregnancy category C (Prod Info Prepidil(R) cervical gel, 2010; Prod Info CERVIDIL(R) vaginal insert, 2010; Prod Info PROSTIN E2(R) vaginal suppositories, 2006; Prod Info HEMABATE(R) injection, 2002).
3) Although misoprostol is not indicated for vaginal use, this drug has been administered vaginally as a ripening agent, for labor induction, or for treating serious postpartum hemorrhage in the presence of uterine atony. When used obstetrically, misoprostol can hyperstimulate the uterus and this may progress to uterine tetany with marked impairment of uteroplacental blood flow uterine rupture or amniotic fluid embolism. Pelvic pain, retained placenta, severe genital bleeding, shock, fetal bradycardia, and fetal and maternal death have been observed with vaginal misoprostol during pregnancy (Prod Info Cytotec(R) oral tablets, 2009).

1) Misoprostol is rapidly metabolized to misoprostol acid in the mother. Misoprostol acid was excreted in breast milk following a single oral misoprostol dose to nursing mothers. Within 1 hour after single 200-mcg and 600-mcg misoprostol doses were administered, the maximum concentration of misoprostol acid in expressed breast milk was 7.6 picograms (pg)/mL (coefficient of variation (CV), 37%) and 20.9 pg/mL (CV, 62%), respectively. Five hours after misoprostol administration, the misoprostol acid concentrations in breast milk decreased to less than 1 pg/mL (Prod Info Cytotec(R) oral tablets, 2009).

1) In animal fertility studies, breeding male and female rats treated with misoprostol doses 6.25 times to 625 times the maximum recommended human dose produced dose-related pre- and post-implantation losses and a significant reduction in the number of live offspring born at the highest dose (Prod Info Cytotec(R) oral tablets, 2009). Long-term fertility studies have not been conducted with dinoprostone (Prod Info CERVIDIL(R) vaginal insert, 2010).

1) At the time of this review, no data were available to assess the carcinogenic potential of this agent.

A) Patients with significant symptoms and/or abnormal vital signs should be admitted. Pregnant patients with symptoms of vaginal bleeding or contractions should be evaluated by an obstetrician/gynecologist.

A) Patients should be evaluated by a healthcare professional if they are symptomatic after a therapeutic dose, or if they are/might be pregnant and the medication was not prescribed to terminate pregnancy or induce labor. Any patient reporting an intentional overdose should be evaluated in the emergency department.

A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear. Obstetrician/gynecologist should be consulted for any case of excessive uterine bleeding or contractions and in the case of inadvertent administration to a pregnant woman who does not desire early pregnancy termination.

A) Patients with deliberate ingestions should be sent to a healthcare facility for observation. Any patient with symptoms should be observed until symptoms improve or resolve.

A) Patients with significant symptoms and/or abnormal vital signs should be admitted. Pregnant patients with symptoms of vaginal bleeding or contractions should be evaluated by an obstetrician/gynecologist.

A) Patients should be evaluated by a healthcare professional if they are symptomatic after a therapeutic dose, or if they are/might be pregnant and the medication was not prescribed to terminate pregnancy or induce labor. Any patient reporting an intentional overdose should be evaluated in the emergency department.

A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear. Obstetrician/gynecologist should be consulted for any case of excessive uterine bleeding or contractions and in the case of inadvertent administration to a pregnant woman who does not desire early pregnancy termination.

A) Patients with deliberate ingestions should be sent to a healthcare facility for observation. Any patient with symptoms should be observed until symptoms improve or resolve.

1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
2) CHARCOAL DOSE

1) CHARCOAL ADMINISTRATION
2) CHARCOAL DOSE

1) Misoprostol plasma concentrations are not clinically useful or readily available.
2) No specific lab work is needed in most patients.
3) Monitor vital signs and mental status.
4) A CBC, INR, and PTT should be ordered in cases of excessive vaginal bleeding.
5) Monitor serum electrolytes in patients with severe diarrhea and/or dehydration.
6) Monitor liver enzymes in patients with significant symptoms or large overdose.
7) A pregnancy test should be ordered in any woman of childbearing age that presents after ingestion of misoprostol. If the patient is pregnant, monitor the fetus (ultrasound, fetal heart rate, and tocographic monitoring).

1) SUMMARY
2) DIAZEPAM
3) NO INTRAVENOUS ACCESS
4) LORAZEPAM
5) PHENOBARBITAL
6) OTHER AGENTS

1) 250 to 500 mcg IM (abortion), 250 mcg IM (postpartum hemorrhage control), 0.5 to 3 mg intravaginally (abortion) (Prod Info Hemabate(R) IM injection, 2006).

1) CERVICAL GEL: The recommended dose is one syringe (0.5 mg) inserted into the cervical canal just below the level of the internal os. A repeat dose of 0.5 mg may be given after 6 hours. MAXIMUM DOSE: 1.5 mg/24 hours (Prod Info Prepidil(R) cervical gel, 2010).
2) VAGINAL INSERT: The recommended dose is one 10-mg insert placed transversely in the posterior fornix of the vagina. Remove upon onset of active labor or 12 hours after insertion (Prod Info CERVIDIL(R) vaginal insert, 2010).
3) VAGINAL SUPPOSITORY: The recommended dose is one 20-mg suppository every 3 to 5 hours until abortion occurs. Continuous administration longer than 2 days is not recommended (Prod Info PROSTIN E2(R) vaginal suppositories, 2006).

1) The recommended dose is 100 to 200 mcg ORALLY 4 times daily with meals and at bedtime (Prod Info Cytotec(R) oral tablets, 2009).
2) Early pregnancy termination dosing is 400 mcg orally once in conjunction with mifepristone (Prod Info MIFEPREX(R) oral tablets, 2005).
3) In studies, misoprostol (600 to 2400 mcg/day orally divided 2 to 4 times a day) has been used to treat chronic constipation (Roarty et al, 1997).

1) CERVICAL GEL, VAGINAL SUPPOSITORY: Safety and efficacy have not been established in pediatric patients (Prod Info Prepidil(R) cervical gel, 2010; Prod Info PROSTIN E2(R) vaginal suppositories, 2006).
2) VAGINAL INSERT: Although not specifically studied in pediatric patients, safety and efficacy are expected to be the same for adolescents as in adults (Prod Info CERVIDIL(R) vaginal insert, 2010).

1) Safety and efficacy have not been established in pediatric patients (Prod Info Cytotec(R) oral tablets, 2009).

1) 70-160 mg/kg (Budavari, 1989a)

1) 27-138 mg/kg (Budavari, 1989a)

1) 40-62 mg/kg (Budavari, 1989a)

1) 81-100 mg/kg (Budavari, 1989a)

a) After two weeks of treatment, there was a significant decrease in IgM-rheumatoid factor in the misoprostol group compared to placebo.
b) In addition, lymphocytes obtained from patients taking misoprostol showed a decreased in vitro sensitivity to inhibition by PGE.
c) All other immunologic tests including total lymphocyte count, T cell or T cell subset count, serum immunoglobulins, or mitogen response were not significantly different from controls.