Misoprostol

Misoprostol is a drug used to prevent stomach ulcers in people who take certain arthritis or pain medicines such as nonsteroidal anti-inflammatory drugs (NSAIDs) including aspirin, that can cause ulcers. Misoprostol protects your stomach lining and decreases the amount of acid produced by your stomach. Misoprostol is also used sometimes to induce labor. Misoprostol is used in combination with mifepristone to end an early pregnancy or as elective termination of pregnancy (abortion). Talk to your doctor about the possible risks of using this drug for your condition. Misoprostol is available only with your doctor’s prescription.

Misoprostol may be prescribed for other uses; ask your doctor or pharmacist for more information.

Misoprostol comes as a tablet to take by mouth. Misoprostol is usually taken 4 times a day, after meals and at bedtime with food. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take misoprostol exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Misoprostol is a generally safe and well-tolerated drug, and currently, the toxic dose is unknown ¹.

Women should not take their first dose until the second or third day of their menstrual period (to be sure that they are not pregnant). Do not stop taking misoprostol without talking to your doctor.

Misoprostol may cause diarrhea, stomach cramps, or nausea in some people. These effects will usually disappear within a few days as your body adjusts to the medicine. However, check with your doctor if the diarrhea, cramps, or nausea is severe and/or does not stop after a week. Your doctor may have to lower the dose of misoprostol you are taking.

Misoprostol special precautions

Before taking misoprostol:

• tell your doctor and pharmacist if you are allergic to misoprostol or any other drugs.
• tell your doctor and pharmacist what prescription and nonprescription medications you are taking, especially antacids, aspirin, arthritis medications, and vitamins.
• tell your doctor if you are breast-feeding.

Contraindications

Misoprostol is contraindicated in those with previous allergic reaction or hypersensitivity to prostaglandin. Those at risk for gastric ulcers secondary to nonsteroidal anti-inflammatory drug (NSAID) use and are pregnant should not take misoprostol given the adverse effects reported during pregnancy.

Besides allergic reactions, there are no absolute contraindications for misoprostol’s gynecologic and obstetric indications given the lack of society-approved guidelines for these uses. Contraindications are relative to the drug’s desired effect and should be individualized depending on each patients risk factors. For example, given the increased risk of uterine rupture, those with previous caesarian sections should not take misoprostol to induce a medical abortion ².

Misoprostol and pregnancy

Do not use misoprostol if you are pregnant or planning to become pregnant. This medicine can cause miscarriage, premature birth, or birth defects if taken during pregnancy. You will need to have a negative pregnancy test within 2 weeks before you start using misoprostol. Continue to use birth control for at least 1 month after you stop using misoprostol. Tell your doctor right away if you become pregnant.

Begin using misoprostol on the 2nd or 3rd day of your next monthly period. This is to make sure you are not pregnant.

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to misoprostol or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Children

Appropriate studies have not been performed on the relationship of age to the effects of misoprostol in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of misoprostol in the elderly.

Breastfeeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Drug Interactions

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking misoprostol, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using misoprostol with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Phenylbutazone

Other interactions

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other medical problems

The presence of other medical problems may affect the use of misoprostol. Make sure you tell your doctor if you have any other medical problems, especially:

• Dehydration or
• Heart or blood vessel problems or
• Inflammatory bowel disease or
• Stomach ulcers, history of—Use with caution. May make these conditions worse.

Kidney disease—Use with caution. The effects may be increased because of the slower removal of the medicine from the body.

Misoprostol use

Misoprostol has four main effects ³:

1. Cytoprotection of the gastrointestinal mucosa
2. Uterotonic
3. Diarrhea
4. Abdominal pain (diarrhea and abdominal pain are considered adverse effects) ⁴.

Currently, misoprostol is U.S. Food and Drug Administration (FDA) approved only for the prevention and treatment of nonsteroidal anti-inflammatory drug (NSAID)-induced gastric ulcers in patients taking NSAIDs and at high risk for ulceration. It has an indication (but not FDA approved) in the short-term treatment of active duodenal or gastric ulcers with other causes ⁵.

Although misoprostol is used around the world in gynecology and obstetrics, however, none of these indications are FDA approved ³. The combination of misoprostol and mifepristone has reported widespread use for medical abortions with an acceptable safety profile. Unfortunately, reports of significant adverse events without significant data have hindered FDA approval. Therefore, there is an extensive debate between the governing societies regarding the dosing standardization of this regimen. It may receive approval once there is additional research, and there is an agreed dosing strategy ⁴.

It is used for termination of pregnancy in the first and second trimesters as either monotherapy or in combination with intramuscular methotrexate ⁴. Clinicians also use misoprostol as expectant management of missed and incomplete abortions.

At much smaller doses, misoprostol is used to induce cervical ripening and induce labor in full-term pregnancies. It may also be employed to induce labor following intrauterine fetal demise ⁶.

After labor, it also has a use for the treatment of postpartum uterine bleeding upon failure of uterine massage, and/or when other uterotonic medications are not readily available ⁷.

Administration

Currently, the only FDA approved route of administration is oral. Although not FDA approved, misoprostol may also be administered sublingually, buccally, vaginally, or rectally via digital placement of tablets or suppositories. Despite a plethora of studies comparing the efficacy and safety profiles of the different routes of administration for obstetric uses, there are no definitive conclusions regarding this use ⁸.

It is best to take medication at night time with meals to minimize gastrointestinal upset when given orally. Do not take with magnesium-containing antacids, as this combination may contribute to misoprostol-induced diarrhea.

Misoprostol medical abortion

Ultrasound should be carried out first to determine the viability of the pregnancy, whether it is uterine or ectopic. After that, the dating of pregnancy should be determined with the help of an ultrasonogram ⁹. The drugs used for medical pregnancy termination include mifepristone and misoprostol. Mifepristone is given orally during the first visit to an abortion clinic. It blocks progesterone synthesis in the female body required to continue the pregnancy. Misoprostol can be taken orally or vaginally about 36 to 72 hours after administration of mifepristone. It prompts the uterus to contract and expel the fetus, which may take a few hours to a few days. A physical examination is carried out after 1 to 2 weeks for the assessment of completion of termination of pregnancy or any other complication related to the abortion ¹⁰.

Misoprostol induction of labor

When evaluating women with a singleton pregnancy in the vertex presentation with a Bishop score of less than six, those who received a combination of induction methods, such as a Foley with Misoprostol or a Foley with Oxytocin, had a faster median time to delivery compared to those who received only Misoprostol or a Foley alone ¹¹. However, when adjusting for further variables, a Foley with Oxytocin was not better than a single induction method ¹². There are additional studies and Cochrane reviews comparing amniotomy alone to mechanical and pharmacological methods of induction ¹³. Regardless of data, it is recommended to discuss with the patient that the induction of labor often requires an amniotomy.

For cervical ripening with Misoprostol, there is a range of doses as well as routes of administration, such as orally, vaginally, or sublingually. Doses of misoprostol range from 25 micrograms (mcg) to 50mcg ¹⁴. If induction is planned in the setting of intrauterine fetal demise in the second trimester, the American Journal of Obstetrics and Gynecology supports higher doses of prostaglandins such as 400mcg every three hours for a maximum of five doses ¹⁵. Prostaglandin E2 (PGE2) is available as a vaginal insert and gel formulation. The gel formulation, Prepidil, is 0.5 milligrams (mg), and the insert, Cervidil, is 10mg ¹⁴. Further pharmacological methods include Pitocin, which is administered intravenously in varying dosing regimens ¹⁴. Dosing is often titrated so that contractions are two to three minutes apart to cause cervical dilation. Hospitals may have policies on the maximum dose of Oxytocin used for patients who are undergoing a trial of labor after cesarean section. Amniotomy with an Amnio Hook can be performed any time the cervix is dilated and is done based on the provider’s discretion. Factors that are taken into account prior to amniotomy include but are not limited to the fetal station, fetal head engagement, patient’s preference, and pain level at the time of amniotomy.

Misoprostol mechanism of action

Misoprostol is a synthetic prostaglandin E1 (PGE1) analog that inhibits basal and nocturnal gastric acid secretion through direct stimulation of prostaglandin E1 receptors on parietal cells in the stomach. This action inhibits gastric acid secretion secondary to stimulation from food, alcohol, NSAIDs, histamine, caffeine, etc. This effect tends to have a dose-dependent relationship.

Misoprostol induces mucus and bicarbonate secretion as well edema of the mucosa and submucosa which causes thickening of the mucosal bilayer, which results in a reduced backflow of hydrogen ions and improved regulation of mucosal blood flow, which ultimately leads to the preservation of the mucosa’s ability to produce new cells ⁴.

Uterotonic effects are caused by prostaglandin binding to smooth muscle cells in the uterine lining; this is responsible for its abortifacient properties, as well as its ability to promote labor and cervical ripening. Cervical dilation is produced primarily via degradation of collagen in the connective tissue of the stroma and reduction in cervical tone from increased amplitude and frequency of contractions. Its uterotonic properties are also used to decrease postpartum bleeding ¹⁶.

Abdominal pain and diarrhea are thought to be a result of exposure to the misoprostolic acid released during metabolism, as symptoms seem to correlate with the misoprostolic acid peak plasma concentration ⁴.

Misoprostol dosage

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.

What should I do if I forget a dose?

Take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

Misoprostol side effects

The most commonly reported adverse effects are generally mild and include shivering/chills, diarrhea, abdominal pain, hyperthermia, nausea, vomiting, flatulence, constipation, dyspepsia, headache, breakthrough bleeding, and menstrual irregularity. Less reported mild side effects include syncope, lethargy, weakness, and vertigo.

Moderate to severe reactions are less common and include hypotension, sinus tachycardia, fetal bradycardia, uterine contractions and pain, vaginal bleeding, edema, myocardial infarction, uterine rupture, cervical laceration, fetal death, teratogenesis, pulmonary embolism, anaphylactoid reactions, and thrombosis.

The most frequently encountered side effects include self-limiting diarrhea and abdominal pain, thought to be secondary to exposure to the misoprostolic acid released during its metabolism. The basis for this line of reasoning is the observation that symptom severity tends to correlate with misoprostolic acid’s peak plasma concentration ⁴.

Fever and chills are relatively common and thought to be secondary to the effect of prostaglandin on the hypothalamus. These mild side effects occur most commonly when misoprostol is administered in relatively large doses, such as to treat postpartum hemorrhage ¹⁷.

Congenital defects correlate with exposure to misoprostol in early pregnancy. However, no data shows misoprostol to be directly related to embryotoxic/fetotoxic or teratogenic effects. Mutagenetic studies have been negative. Defects are thought to be due to a decrease in fetal blood supply during contractions induced by misoprostol. Additionally, there seems to be a relationship between the time of exposure and the range of defects observed. Most common defects are in the central nervous system and limbs. Mobius syndrome also correlates with misoprostol exposure ¹⁷.

The use of prostaglandins in cervical ripening correlates with an increased risk of tachysystole, non-reassuring fetal heart rate, and fetal hypoxemia ¹⁶.

There is a risk for uterine rupture with misoprostol use. This risk tends to be highest when misoprostol is used for labor induction in the third trimester, especially in conjunction with other risk factors such as previous caesarian section. Rupture is rare during a first-trimester medical abortion using misoprostol. However, as with all uterine ruptures, there is a risk for subsequent uterine infection ¹⁷.

Check with your doctor immediately if any of the following side effects occur:

Rare side effects

• cramps
• heavy bleeding
• painful menstruation

Incidence not known

• bladder pain
• bloody nose
• bloody or black, tarry stools
• bloody or cloudy urine
• blurred vision
• body aches or pain
• chest pain
• chills
• confusion
• constipation
• cough
• difficult, burning, or painful urination
• difficulty with breathing
• difficulty with moving
• difficulty with swallowing
• dizziness
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• ear congestion
• feeling unusually cold
• fever
• frequent urge to urinate
• headache
• hives, itching, or skin rash
• loss of voice
• lower back or side pain
• muscle pain or stiffness
• nasal congestion
• nervousness
• pain in the joints
• pale skin
• pounding in the ears
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• runny nose
• severe stomach pain
• shivering
• slow or fast heartbeat
• sneezing
• sore throat
• sweating
• tightness in the chest
• troubled breathing with exertion
• unusual bleeding or bruising
• unusual tiredness or weakness
• vomiting of blood or material that looks like coffee grounds

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

• abdominal or stomach pain
• diarrhea

Less common

• acid or sour stomach
• belching
• bloated
• excess air or gas in the stomach or intestines
• full feeling
• heartburn
• indigestion
• passing gas
• stomach discomfort or upset

Incidence not known

• blistering, crusting, irritation, itching, or reddening of the skin
• breast pain
• burning, dry, or itching eyes
• change in taste
• continuing ringing or buzzing or other unexplained noise in the ears
• cracked, dry, scaly skin
• depression
• discharge, excessive tearing
• hair loss or thinning of the hair
• hearing loss
• lack or loss of strength
• paleness of the skin
• redness, pain, swelling of the eye, eyelid, or inner lining of the eyelid
• weight changes

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

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