Misoprostol

Keep all appointments with your doctor.

Ask your pharmacist any questions you have about refilling your prescription.

It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies.

The following have been reported as adverse events in subjects receiving Cytotec:

Gastrointestinal

In subjects receiving Cytotec 400 or 800 mcg daily in clinical trials, the most frequent gastrointestinal adverse events were diarrhea and abdominal pain. The incidence of diarrhea at 800 mcg in controlled trials in patients on NSAIDs ranged from 14–40% and in all studies (over 5,000 patients) averaged 13%. Abdominal pain occurred in 13–20% of patients in NSAID trials and about 7% in all studies, but there was no consistent difference from placebo.

Diarrhea was dose related and usually developed early in the course of therapy (after 13 days), usually was self-limiting (often resolving after 8 days), but sometimes required discontinuation of Cytotec (2% of the patients). Rare instances of profound diarrhea leading to severe dehydration have been reported. Patients with an underlying condition such as inflammatory bowel disease, or those in whom dehydration, were it to occur, would be dangerous, should be monitored carefully if Cytotec is prescribed. The incidence of diarrhea can be minimized by administering after meals and at bedtime, and by avoiding coadministration of Cytotec with magnesium-containing antacids.

Gynecological

Women who received Cytotec during clinical trials reported the following gynecological disorders: spotting (0.7%), cramps (0.6%), hypermenorrhea (0.5%), menstrual disorder (0.3%) and dysmenorrhea (0.1%). Postmenopausal vaginal bleeding may be related to Cytotec administration. If it occurs, diagnostic workup should be undertaken to rule out gynecological pathology. (See BOXED WARNINGS.)

Elderly

There were no significant differences in the safety profile of Cytotec in approximately 500 ulcer patients who were 65 years of age or older compared with younger patients.

Additional adverse events which were reported are categorized as follows:

Incidence greater than 1%

In clinical trials, the following adverse reactions were reported by more than 1% of the subjects receiving Cytotec and may be causally related to the drug: nausea (3.2%), flatulence (2.9%), headache (2.4%), dyspepsia (2.0%), vomiting (1.3%), and constipation (1.1%). However, there were no significant differences between the incidences of these events for Cytotec and placebo.

Causal relationship unknown

The following adverse events were infrequently reported. Causal relationships between Cytotec and these events have not been established but cannot be excluded:

Body as a whole: aches/pains, asthenia, fatigue, fever, chills, rigors, weight changes.

Skin: rash, dermatitis, alopecia, pallor, breast pain.

Special senses: abnormal taste, abnormal vision, conjunctivitis, deafness, tinnitus, earache.

Respiratory: upper respiratory tract infection, bronchitis, bronchospasm, dyspnea, pneumonia, epistaxis.

Cardiovascular: chest pain, edema, diaphoresis, hypotension, hypertension, arrhythmia, phlebitis, increased cardiac enzymes, syncope, myocardial infarction (some fatal), thromboembolic events (e.g., pulmonary embolism, arterial thrombosis, and CVA).

Gastrointestinal: GI bleeding, GI inflammation/infection, rectal disorder, abnormal hepatobiliary function, gingivitis, reflux, dysphagia, amylase increase.

Hypersensitivity: anaphylactic reaction

Metabolic: glycosuria, gout, increased nitrogen, increased alkaline phosphatase.

Genitourinary: polyuria, dysuria, hematuria, urinary tract infection.

Nervous system/Psychiatric: anxiety, change in appetite, depression, drowsiness, dizziness, thirst, impotence, loss of libido, sweating increase, neuropathy, neurosis, confusion.

Musculoskeletal: arthralgia, myalgia, muscle cramps, stiffness, back pain.

Blood/Coagulation: anemia, abnormal differential, thrombocytopenia, purpura, ESR increased.

Misoprostol is part of the drug class:

• Prostaglandin Oxytocics

Misoprostol can cause birth defects, premature birth, uterine rupture, miscarriage, or incomplete miscarriage and dangerous uterine bleeding. Do not use misoprostol if you are pregnant.

If you are able to become pregnant, you will need to have a negative pregnancy test before starting this treatment. You will also need to use effective birth control to prevent pregnancy during treatment.

Take the missed dose as soon as you remember. However, if it is almost time for the next dose, skip the missed dose and take only the next regularly scheduled dose. Do not take a double dose of this medication.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

In the U.S.

• Cytotec

Available Dosage Forms:

• Tablet

Therapeutic Class: Endocrine-Metabolic Agent

Pharmacologic Class: Prostaglandin

For safe and effective use of misoprostol, do not take more of it, do not take it more often, and do not take it for a longer time than ordered by your doctor. Taking too much of misoprostol may increase the chance of unwanted effects. Do not change the dose or stop using misoprostol without checking first with your doctor.

misoprostol should come with a patient information leaflet. Read and follow these instructions carefully. Ask your doctor if you have any questions.

Misoprostol is best taken with or after meals and at bedtime, unless otherwise directed by your doctor. To help prevent loose stools, diarrhea, and abdominal cramping, always take misoprostol with food or milk.

Do not give misoprostol to another person.

Dosing

The dose of misoprostol will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of misoprostol. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (tablets):
  • To prevent stomach ulcers in patients taking NSAIDs:
    • Adults—200 micrograms (mcg) four times a day with food. Other patients may need 100 mcg four times a day with food. Take the last dose of the day at bedtime.
    • Children—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of misoprostol, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

• If you have an allergy to misoprostol or any other part of misoprostol.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you are getting oxytocin.

This is not a list of all drugs or health problems that interact with this medicine.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take misoprostol with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about this medicine, please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take misoprostol or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to misoprostol. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Review Date: October 4, 2017

Misoprostol oral tablets contain either 100 mcg or 200 mcg of Misoprostol, a synthetic prostaglandin E1 analog.

Misoprostol contains approximately equal amounts of the two diastereomers presented below with their enantiomers indicated by (±):

Misoprostol is a water-soluble, viscous liquid.

Inactive ingredients of tablets are hydrogenated castor oil, hypromellose, microcrystalline cellulose, and sodium starch glycolate.

Caution should be employed when administering Misoprostol to patients with pre-existing cardiovascular disease.

Information for patients

Women of childbearing potential using Misoprostol to decrease the risk of NSAID-induced ulcers should be told that they must not be pregnant when Misoprostol therapy is initiated, and that they must use an effective contraception method while taking Misoprostol.

See boxed WARNINGS.

Misoprostol is intended for administration along with nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, to decrease the chance of developing an NSAID-induced gastric ulcer.

Misoprostol should be taken only according to the directions given by a physician.

If the patient has questions about or problems with Misoprostol, the physician should be contacted promptly.

THE PATIENT SHOULD NOT GIVE Misoprostol TO ANYONE ELSE. Misoprostol has been prescribed for the patient's specific condition, may not be the correct treatment for another person, and may be dangerous to the other person if she were to become pregnant.

The Misoprostol package the patient receives from the pharmacist will include a leaflet containing patient information. The patient should read the leaflet before taking Misoprostol and each time the prescription is renewed because the leaflet may have been revised.

Keep Misoprostol out of the reach of children.

SPECIAL NOTE FOR WOMEN: Misoprostol may cause birth defects, abortion (sometimes incomplete), premature labor or rupture of the uterus if given to pregnant women.

Misoprostol is available only as a unit-of-use package that includes a leaflet containing patient information. See Patient Information at the end of this labeling.

Drug interactions

See Clinical Pharmacology. Misoprostol has not been shown to interfere with the beneficial effects of aspirin on signs and symptoms of rheumatoid arthritis. Misoprostol does not exert clinically significant effects on the absorption, blood levels, and antiplatelet effects of therapeutic doses of aspirin. Misoprostol has no clinically significant effect on the kinetics of diclofenac or ibuprofen.

Prostaglandins such as Misoprostol may augment the activity of oxytocic agents, especially when given less than 4 hours prior to initiating oxytocin treatment. Concomitant use is not recommended.

Animal toxicology

A reversible increase in the number of normal surface gastric epithelial cells occurred in the dog, rat, and mouse. No such increase has been observed in humans administered Misoprostol for up to 1 year.

An apparent response of the female mouse to Misoprostol in long-term studies at 100 to 1000 times the human dose was hyperostosis, mainly of the medulla of sternebrae. Hyperostosis did not occur in long-term studies in the dog and rat and has not been seen in humans treated with Misoprostol.

Carcinogenesis, mutagenesis, impairment of fertility

There was no evidence of an effect of Misoprostol on tumor occurrence or incidence in rats receiving daily doses up to 150 times the human dose for 24 months. Similarly, there was no effect of Misoprostol on tumor occurrence or incidence in mice receiving daily doses up to 1000 times the human dose for 21 months. The mutagenic potential of Misoprostol was tested in several in vitro assays, all of which were negative.

Misoprostol, when administered to breeding male and female rats at doses 6.25 times to 625 times the maximum recommended human therapeutic dose, produced dose-related pre- and post-implantation losses and a significant decrease in the number of live pups born at the highest dose. These findings suggest the possibility of a general adverse effect on fertility in males and females.

Pregnancy

See boxed WARNINGS. Congenital anomalies sometimes associated with fetal death have been reported subsequent to the unsuccessful use of Misoprostol as an abortifacient, but the drug's teratogenic mechanism has not been demonstrated. Several reports in the literature associate the use of Misoprostol during the first trimester of pregnancy with skull defects, cranial nerve palsies, facial malformations, and limb defects.

Misoprostol is not fetotoxic or teratogenic in rats and rabbits at doses 625 and 63 times the human dose, respectively.

See boxed WARNINGS. Misoprostol may endanger pregnancy (may cause abortion) and thereby cause harm to the fetus when administered to a pregnant woman. Misoprostol may produce uterine contractions, uterine bleeding, and expulsion of the products of conception. Abortions caused by Misoprostol may be incomplete. If a woman is or becomes pregnant while taking this drug to reduce the risk of NSAID-induced ulcers, the drug should be discontinued and the patient apprised of the potential hazard to the fetus.

Labor and delivery

Misoprostol can induce or augment uterine contractions. Vaginal administration of Misoprostol, outside of its approved indication, has been used as a cervical ripening agent, for the induction of labor and for treatment of serious postpartum hemorrhage in the presence of uterine atony. A major adverse effect of the obstetrical use of Misoprostol is uterine tachysystole which may progress to uterine tetany with marked impairment of uteroplacental blood flow, uterine rupture (requiring surgical repair, hysterectomy, and/or salpingo-oophorectomy), or amniotic fluid embolism and lead to adverse fetal heart changes. Uterine activity and fetal status should be monitored by trained obstetrical personnel in a hospital setting.

The risk of uterine rupture associated with Misoprostol use in pregnancy increases with advancing gestational ages and prior uterine surgery, including Cesarean delivery. Grand multiparity also appears to be a risk factor for uterine rupture.

The use of Misoprostol outside of its approved indication may also be associated with meconium passage, meconium staining of amniotic fluid, and Cesarean delivery. Maternal shock, maternal death, fetal bradycardia, and fetal death have also been reported with the use of Misoprostol.

Misoprostol should not be used in the third trimester in women with a history of Cesarean section or major uterine surgery because of an increased risk of uterine rupture.

Misoprostol should not be used in cases where uterotonic drugs are generally contraindicated or where hyperstimulation of the uterus is considered inappropriate, such as cephalopelvic disproportion, grand multiparity, hypertonic or hyperactive uterine patterns, or fetal distress where delivery is not imminent, or when surgical intervention is more appropriate.

The effect of Misoprostol on later growth, development, and functional maturation of the child when Misoprostol is used for cervical ripening or induction of labor has not been established. Information on Misoprostol's effect on the need for forceps delivery or other intervention is unknown.

Nursing mothers

Misoprostol is rapidly metabolized in the mother to Misoprostol acid, which is biologically active and is excreted in breast milk. There are no published reports of adverse effects of Misoprostol in breast-feeding infants of mothers taking Misoprostol. Caution should be exercised when Misoprostol is administered to a nursing woman.

Pediatric use

Safety and effectiveness of Misoprostol in pediatric patients have not been established.

• Cytotec

Misoprostol is a synthetic prostaglandin E1 analog that replaces the protective prostaglandins consumed with prostaglandin-inhibiting therapies (eg, NSAIDs); has been shown to induce uterine contractions

Absorption

Rapid and extensive; food decreases absorption of misoprostol acid

Metabolism

Hepatic; rapid deesterification to misoprostol acid (active)

Excretion

Urine (80%)

Cervical ripening and labor induction

Based on the American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin No. 107: Induction of Labor, misoprostol tablets administered intravaginally for cervical ripening and labor induction is effective and recommended in the management of this condition [ACOG 107 2009].

Early pregnancy loss

Based on the American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin No. 150: Early Pregnancy Loss, misoprostol given for early pregnancy loss is effective and recommended for patients who desire to shorten the time to complete expulsion and prefer to avoid surgical evacuation [ACOG 150 2015].

Incomplete or missed abortion (treatment)

Based on the American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin No. 427: Misoprostol for Postabortion Care, misoprostol given for treatment of incomplete or missed abortion in women <12 weeks gestation is effective and recommended in the management of this condition [ACOG 427 2009].

Postpartum hemorrhage (prevention/treatment)

Based on the International Federation of Gynecology and Obstetrics (FIGO) Prevention of Postpartum Hemorrhage With Misoprostol guidelines and the FIGO Treatment of Postpartum Hemorrhage With Misoprostol guidelines, misoprostol given for the prevention and treatment of postpartum hemorrhage is effective and recommended in the management of this condition [FIGO, 2012a], [FIGO, 2012b].

Administer with food and avoid magnesium containing antacids (minimizes diarrhea); last dose of the day should be taken at bedtime. Therapy should continue through the duration of NSAID therapy.

Termination of intrauterine pregnancy: Refer to Mifepristone monograph.

Commonly reported side effects of misoprostol include: abdominal pain. See below for a comprehensive list of adverse effects.

American College of Obstetricians and Gynecologists (ACOG) Recommendations:
25 mcg vaginally every 3 to 6 hours
-Some patients may require doses of 50 mcg every 6 hours

Comments:
-The manufacturer states that use outside of the approved indication should be reserved for hospital use only.
-Some experts state that this drug is a more efficient method of labor (compared to oxytocin) in patients before 28 weeks' gestation.
-Higher doses may be associated with a higher risk of adverse events (e.g., uterine tachysystole with fetal heart rate decelerations).
-Use should be avoided during the third trimester or in patients with a history of cesarean delivery or major uterine surgery.

Use: Cervical ripening and labor induction in women with premature rupture of membranes

ACOG Recommendations:
800 to 1000 mcg rectally once

Use: Management of postpartum hemorrhage

International Federation of Gynecology Obstetrics (FIGO) Recommendations:
600 mcg orally OR 800 mcg sublingually once immediately after delivery

Comments:
-The manufacturer states that use outside of the approved indication should be reserved for hospital use only.
-Prior to administration of treatment, abdominal palpitation is recommended to confirm that there are no additional babies in utero.
-The dose is not based upon the patient's weight.
-The addition of this drug to oxytocin was not shown to provide additional benefit, but may increase the risk of adverse events.

Use: Prevention of postpartum hemorrhage in settings where oxytocin is not available

Administration advice:
-Doses should be taken with food, with the last dose taken before bedtime.
-When this drug is used for medical termination of pregnancy, intrauterine devices in situ should be removed before use.

Storage requirements:
-Protect from moisture; store below 30C.

General:
-Treatment has not been shown to reduce the risk of duodenal ulcers in patients taking NSAIDs.
-Meconium passage, meconium staining of amniotic fluid, cesarean delivery, maternal shock, maternal death, fetal bradycardia, and fetal death have occurred after the use of tablet formulations for labor and delivery.
-Controlled studies over 3 months have shown a reduction in the risk of gastric ulcers; however, this drug did not have an effect on NSAID-associated gastrointestinal pain/discomfort compared to placebo.
-New pregnancies can occur between expulsion and menses resumption; contraception should be resumed immediately.

Monitoring:
-Genitourinary: Vaginal bleeding
-Metabolic: Signs/symptoms of dehydration
-Other: Incomplete abortion, retained placenta

Patient advice:
-Patients should not give this drug to anyone else.
-Patients undergoing medical termination of pregnancy should avoid traveling far from the prescribing center until complete expulsion is documented.
-Patients should seek immediate medical treatment if signs/symptoms of infection or excessive vaginal bleeding occur during use.
-Patients of childbearing potential should be told to use effective contraception during treatment. Patients should discontinue treatment and should speak to a healthcare provider immediately if pregnancy occurs.
-Patients should be instructed to read the included leaflet each time the prescription is filled.