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    Prostaglandin Antiulcerants

    BOXED WARNING

    Abnormal fetal position, caesarean section, contraception requirements, ectopic pregnancy, fetal distress, herpes infection, incomplete abortion, labor, multiparity, obstetric delivery, placenta previa, pregnancy, pregnancy testing, reproductive risk, vaginal administration, vaginal bleeding, vasa previa

    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.

    DEA CLASS

    Rx

    DESCRIPTION

    Synthetic, oral prostaglandin E1 (PGE1) analog approved for prevention of gastric ulcers secondary to use of nonsteroidal antiinflammatory drugs (NSAIDs); taken for the duration of NSAID therapy
    Boxed warning regarding the abortifacient effects and reproductive risk; females of childbearing age must use adequate contraception with oral product use for NSAID-induced ulcer prevention
    Used off-label in obstetrics for cervical ripening and labor induction; also a recognized component of the FDA-approved mifepristone-regimen for termination of early pregnancy

    COMMON BRAND NAMES

    Cytotec

    HOW SUPPLIED

    Cytotec/Misoprostol Oral Tab: 100mcg, 200mcg

    DOSAGE & INDICATIONS

    For NSAID-induced ulcer prophylaxis in patients receiving NSAIDs and at high risk for gastric ulceration (e.g., elderly, past history of ulcer, concomitant debilitating disease, or concomitant systemic corticosteroid use).
    NOTE: Misoprostol is indicated to prevent NSAID-induced gastric ulcers but has not been shown to prevent duodenal ulcers.
    Oral dosage
    Adults

    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.

    For the short-term treatment of active duodenal ulcer† or gastric ulcer† unrelated to NSAID use.
    Oral dosage
    Adults

    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.

    For kidney transplant rejection prophylaxis† in patients who are currently receiving cyclosporine and prednisone.
    Oral dosage
    Adults

    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.

    For pregnancy termination†.
    For pregnancy termination in combination with mifepristone, at 49 days (7 weeks) or less of gestation dated from the first day of the last menstrual period.
    Oral dosage (FDA-approved regimen)
    Adult females

    The FDA-approved regimen is mifepristone (RU-486) 600 mg PO as a single dose. On day 3 (48 hours later) the patient returns to the prescriber. Unless complete termination is confirmed, administer 400 mcg (i.e., 2 x 200 mcg tablets) of misoprostol PO as a single dose; followed by emergency instruction and assessment of medication needs for cramps or GI symptoms (usually, the patient is observed after misoprostol for roughly 4 hours or until clinically stable). Complete termination occurs in the majority of patients within 4 to 24 hours after misoprostol. A follow-up visit roughly 14 days after the administration of mifepristone is needed to confirm termination. Treatment requires 3 office visits by the patient. Prescribers must also be able to provide/obtain surgical intervention in case of incomplete abortion or severe bleeding, and assure other types of needed emergency care. In a US study, 77% to 92% of pregnancies were successfully terminated using this regimen, depending on the week of gestation. Several other dosage regimens for combination mifepristone-misoprostol therapy exist; consult specific literature.

    For pregnancy termination† prior to the 63rd day of pregnancy in combination with intramuscular methotrexate.
    Vaginal dosage†
    Adult females

    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.

    For pregnancy termination† during the second trimester of pregnancy.
    Vaginal dosage†
    Adult females

    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.

    For cervical ripening induction† and labor induction† for obstetric delivery of a term pregnancy, or for labor induction following intrauterine fetal death†.
    Vaginal dosage†
    Adult females

    25 mcg vaginally (inserted into the posterior vaginal fornix) every 3 to 6 hours is considered effective for cervical ripening and induction of labor. Most off-label protocols limit duration of use to no longer than 24 hours (roughly 5 doses). Use of misoprostol in women with previous caesarean delivery or uterine surgery, or other conditions should be avoided because of the possibility of uterine rupture. Consult suggested guidelines, including contraindications and precautions for use. This includes the manufacturer's label, which discusses the off-label use of misoprostol vaginally for labor induction and situations which may increase risk for uterine rupture or other adverse outcomes. The use of higher dosages (50 mcg every 6 hours intravaginally) to induce labor may be appropriate in some situations, although an increased risk of complications has been reported with doses greater than 25 mcg/dose in term pregnancies. High doses (200 to 400 mcg vaginally inserted every 4 to 12 hours) to induce labor are reserved for patients of less than 28 weeks gestation with intrauterine fetal demise. Commercial vaginal dosage forms are under investigation.

    For the prevention and/or treatment of postpartum bleeding†.
    For the prevention of postpartum bleeding† when other uterotonic agents are not available.
    Oral dosage
    Adult females

    400 to 600 mcg PO following the clamping of the umbilical cord. Because of the limited data regarding safety and efficacy for this indication, misoprostol should only be used in situations where conventional oxytocics are not readily available, storage requirements for oxytocics cannot be met, or when parenteral administration of conventional oxytocics is not feasible.

    Rectal dosage†
    Adult females

    400 mcg PR following the clamping of the umbilical cord. Because of the limited data regarding safety and efficacy for this indication, misoprostol should only be used in situations where conventional oxytocics are not readily available, storage requirements for oxytocics cannot be met, or when parenteral administration of conventional oxytocics is not feasible.

    For the treatment of postpartum bleeding† due to uterine atony when unresponsive to massage and other uterotonic agents are not available, or when unresponsive to massage and other uterotonic agents.
    Rectal dosage†
    Adult females

    800 to 1000 mcg PR. Because of the limited data regarding safety and efficacy for this indication, misoprostol should only be used in situations where conventional oxytocics are not readily available, storage requirements for oxytocics cannot be met, or when parenteral administration of conventional oxytocics is not feasible.

    For the medical management of early pregnancy failure†.
    NOTE: Consult the contraindications section of the monograph before use.
    Intravaginal dosage†
    Adult females

    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.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    800 mcg/day PO.

    Elderly

    800 mcg/day PO.

    Adolescents

    Safe and effective use has not been established.

    Children

    Safe and effective use has not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    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).
     
    Intermittent hemodialysis
    Because misoprostol is metabolized like a fatty acid, it is unlikely that hemodialysis enhances drug clearance.

    ADMINISTRATION

    Oral Administration

    Administer tablets orally with meals and at bedtime with food.

    Intravaginal Administration

    NOTE: Misoprostol is not approved by the FDA for intravaginal administration.
    Consult suggested guidelines for use. In general, most protocols limit the duration of vaginal use to 24 hours (5 doses).
    Administration of misoprostol for gynecologic or obstetric uses should be done under the supervision of a qualified health care professional with expertise in the field.
    Misoprostol tablets have been cut and administered intravaginally via digital placement in the posterior vaginal fornix; administer with sterile gloves.
    Extemporaneous formulations (e.g., vaginal gels or suppositories) have also been used.
    Frequent examinations of the cervix should be performed.
    Continually monitor maternal vital signs, fetal heart rate or fetal distress, and uterine contractions using established methods and as clinically recommended for the off-label indication for use. Be alert for signs and symptoms or tetanic uterine contractions/uterine hyperstimulation.

    Rectal Administration

    NOTE: Misoprostol is not approved by the FDA for rectal administration.
    Rectal administration has been used as an alternate route for gynecologic or obstetric uses. Follow the suggested guidelines for off-label use.
    Administration of misoprostol for gynecologic or obstetric uses should be done under the supervision of a qualified health care professional with expertise in the field.
    Misoprostol tablets have been cut and administered rectally; administer with proper gloving.
    Frequent examinations should be performed.
    Continually monitor maternal vital signs, fetal heart rate or fetal distress, and uterine contractions using established methods and as clinically recommended for the off-label indication for use. Be alert for signs and symptoms or tetanic uterine contractions/uterine hyperstimulation.

    STORAGE

    Cytotec:
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Misoprostol is contraindicated in patients with a history of allergy to misoprostol or with previous prostaglandin hypersensitivity.

    Abnormal fetal position, caesarean section, contraception requirements, ectopic pregnancy, fetal distress, herpes infection, incomplete abortion, labor, multiparity, obstetric delivery, placenta previa, pregnancy, pregnancy testing, reproductive risk, vaginal administration, vaginal bleeding, vasa previa

    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.

    Infertility

    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.

    Breast-feeding, diarrhea

    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 wait 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, 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 or ranitidine , which are considered by the American Academy of Pediatrics as likely 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 condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Children

    The safety and effectiveness of misoprostol have not been established in children.

    Dehydration, inflammatory bowel disease, ulcerative colitis

    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.

    Renal disease

    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.

    Cardiac disease

    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).

    Fever, infection, sepsis

    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).

    ADVERSE REACTIONS

    Severe

    teratogenesis / Delayed / Incidence not known
    uterine rupture / Early / Incidence not known
    cervical laceration / Early / Incidence not known
    fetal death / Delayed / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    pulmonary embolism / Delayed / Incidence not known
    stroke / Early / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    thrombosis / Delayed / Incidence not known

    Moderate

    hyperthermia / Delayed / 30.0-40.0
    constipation / Delayed / 1.1-1.1
    sinus tachycardia / Rapid / Incidence not known
    fetal bradycardia / Delayed / Incidence not known
    uterine contractions / Early / Incidence not known
    uterine pain / Early / Incidence not known
    vaginal bleeding / Delayed / Incidence not known
    hypotension / Rapid / Incidence not known
    chest pain (unspecified) / Early / Incidence not known
    edema / Delayed / Incidence not known
    phlebitis / Rapid / Incidence not known
    hypertension / Early / Incidence not known

    Mild

    diarrhea / Early / 14.0-40.0
    chills / Rapid / 30.0-40.0
    shivering / Rapid / 30.0-40.0
    abdominal pain / Early / 7.0-20.0
    nausea / Early / 3.2-3.2
    vomiting / Early / 3.2-3.2
    flatulence / Early / 2.9-2.9
    headache / Early / 2.4-2.4
    dyspepsia / Early / 2.0-2.0
    breakthrough bleeding / Delayed / 0.7-0.7
    menstrual irregularity / Delayed / 0.3-0.3
    dysmenorrhea / Delayed / 0.1-0.1
    vertigo / Early / Incidence not known
    lethargy / Early / Incidence not known
    infection / Delayed / Incidence not known
    weakness / Early / Incidence not known
    syncope / Early / Incidence not known
    agitation / Early / Incidence not known
    leukocytosis / Delayed / Incidence not known
    fever / Early / Incidence not known
    pelvic pain / Delayed / Incidence not known
    diaphoresis / Early / Incidence not known
    rash / Early / Incidence not known

    DRUG INTERACTIONS

    Aluminum Hydroxide; Magnesium Hydroxide: (Moderate) Magnesium hydroxide may contribute to misoprostol-induced diarrhea; avoid concomitant use.
    Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Moderate) Magnesium hydroxide may contribute to misoprostol-induced diarrhea; avoid concomitant use.
    Calcium Carbonate; Magnesium Hydroxide: (Moderate) Magnesium hydroxide may contribute to misoprostol-induced diarrhea; avoid concomitant use.
    Magnesium Hydroxide: (Moderate) Magnesium hydroxide may contribute to misoprostol-induced diarrhea; avoid concomitant use.
    Oxytocin: (Major) In certain cases, oxytocin can be used in combination with other oxytocics for therapeutic purposes. However, in the augmentation of labor, oxytocin administration is usually withheld until after the last dose of intravaginal misoprostol. There is a risk of severe uterine hypertony occurring, with possible uterine rupture or cervical laceration when misoprostol and oxytocin are used at the same time. These products should be used concomitantly only under adequate supervision, with particular attention to ensure adequate cervical dilation has occurred.

    PREGNANCY AND LACTATION

    Pregnancy

    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.

    MECHANISM OF ACTION

    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.

    PHARMACOKINETICS

    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.

    Oral Route

    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.

    Other Route(s)

    Vaginal Route
    Misoprostol is also well absorbed by the intravaginal route.