Side effects of misoprostol

Misoprostol Side Effects

Medically reviewed by Drugs.com. Last updated on Jan 8, 2019.

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In Summary

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

For the Consumer

Applies to misoprostol: oral tablet

Warning

Oral route (Tablet)

Administration of misoprostol to women who are pregnant can cause birth defects, abortion, premature birth, or uterine rupture. Uterine rupture has been reported when misoprostol was administered in pregnant women to induce labor or to induce abortion. The risk of uterine rupture increases with advancing gestational ages and with prior uterine surgery, including Cesarean delivery. Misoprostol should not be used for reducing the risk of NSAID-induced ulcers in women of childbearing potential unless the patient is at high risk of developing gastric ulcers or complications. Women must have a negative serum pregnancy test within 2 weeks prior to beginning therapy, use effective contraceptive measures, and initiate therapy only on the second or third day of the next normal menstrual period. Oral and written warnings of the hazards of misoprostol, including the risk of possible contraception failure, must be given to the patient prior to initiating therapy.

Along with its needed effects, misoprostol may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

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

Rare

  • 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 of misoprostol 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

For Healthcare Professionals

Applies to misoprostol: oral tablet

General

The most commonly reported side effects included uterine contractions/cramping, diarrhea, and abdominal pain.

Genitourinary

Uterine contractions/cramping usually occurred within hours of oral administration.

Heavy bleeding required hemostatic curettage in up to 1.4% of patients.

Very common (10% or more): Uterine contractions/cramping (up to 45%)

Common (1% to 10%): Endometritis, heavy bleeding, pelvic inflammatory disease

Rare (0.01% to 0.1%): Menorrhagia

Frequency not reported: Abnormal uterine contractions, breast pain, dysuria, hematuria, impotence, polyuria, postmenopausal vaginal bleeding, urinary tract infection, uterine hemorrhage, uterine perforation, uterine rupture

Gastrointestinal

Diarrhea usually occurred early in treatment, and was typically dose-related, self-limiting, and required discontinuation in approximately 2% of patients in clinical trials.

Very common (10% or more): Diarrhea (up to 40%), abdominal pain (up to 20%)

Common (1% to 10%): Constipation, dyspepsia, flatulence, nausea, vomiting

Uncommon (0.1% to 1%): Light to moderate cramping

Frequency not reported: Dysphagia, gastrointestinal bleeding, gastrointestinal inflammation and infection, gingivitis, loose stools, profound diarrhea, rectal disorder, reflux

Nervous system

Vagal symptoms included hot flush, dizziness, and chills.

Common (1% to 10%): Dizziness, headache

Rare (0.01% to 0.1%): Vagal symptoms

Frequency not reported: Abnormal taste, drowsiness, neuropathy, syncope

Other

Common (1% to 10%): Infection following abortion

Uncommon (0.1% to 1%): Fever/pyrexia

Rare (0.01% to 0.1%): Birth defects, chills, fetal death, malaise

Very rare (less than 0.01%): Serious/fatal septic shock, serious/fatal toxic shock

Dermatologic

Common (1% to 10%): Skin rash/rash

Rare (0.01% to 0.1%): Erythema nodosum, erythroderma, toxic epidermal necrolysis, urticaria

Frequency not reported: Alopecia, dermatitis, diaphoresis/increased sweating

Cardiovascular

Rare (0.01% to 0.1%): Hot flushes

Frequency not reported: Amniotic fluid embolism, arrhythmia, arterial thrombosis, cardiovascular accidents, cerebrovascular accident, chest pain, coronary artery spasm, edema, hypertension, hypotension, increased cardiac enzymes, myocardial infarction/fatal myocardial infarction, pallor, phlebitis, severe hypotension, thromboembolic events

Hypersensitivity

Very rare (less than 0.01%): Angioedema

Frequency not reported: Anaphylactic reaction, anaphylaxis, hypersensitivity

Respiratory

Frequency not reported: Bronchitis, bronchospasm, dyspnea, epistaxis, pneumonia, pulmonary embolism, upper respiratory tract infection

Metabolic

Frequency not reported: Appetite change, gout, increased alkaline phosphatase, increased nitrogen, severe dehydration, thirst, weight changes

Hematologic

Frequency not reported: Abnormal differential, anemia, increased erythrocyte sedimentation rate, purpura, thrombocytopenia

Psychiatric

Frequency not reported: Anxiety, confusion, depression, loss of libido, neurosis

Musculoskeletal

Frequency not reported: Arthralgia, back pain, myalgia, muscle cramps. stiffness

Ocular

Frequency not reported: Abnormal vision, conjunctivitis

Hepatic

Frequency not reported: Abnormal hepatobiliary function

Renal

Frequency not reported: Glycosuria

1. “Product Information. Cytotec (misoprostol).” Searle, Skokie, IL.

2. Cerner Multum, Inc. “Australian Product Information.” O 0

3. Cerner Multum, Inc. “UK Summary of Product Characteristics.” O 0

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

Some side effects may not be reported. You may report them to the FDA.

Medical Disclaimer

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Consumer resources

  • Misoprostol
  • Misoprostol (Advanced Reading)

Other brands: Cytotec

Professional resources

  • Misoprostol (AHFS Monograph)
  • … +2 more

Related treatment guides

  • Abortion
  • Cervical Ripening
  • Gynecological Conditions
  • Duodenal Ulcer
  • … +4 more

Misoprostol

Misoprostol is the generic form of the brand-name drug Cytotec, which is used to prevent ulcers in people who take certain arthritis or pain medicines.

Misoprostol is a synthetic prostaglandin. It works by protecting the stomach lining and decreasing stomach acid secretion.

The Food and Drug Administration (FDA) approved the medication in 1988. The drug was originally manufactured by G.D. Searle & Company, and generic forms of misoprostol are now made by several drug manufacturers.

Misoprostol and Abortion

Misoprostol is sometimes used off-label to end an early pregnancy. (Off-label use means that the FDA has not approved the drug for this purpose.)

The drug is most effective when it’s used in combination with methotrexate or mifepristone. Misoprostol can be given orally, buccally (dissolved between the gums and cheek), or vaginally for this purpose.

The FDA has reported that a few women have died from severe infection after having an abortion using mifepristone and vaginal misoprostol.

You should call your doctor immediately if you experience any signs of infection, which may include weakness, pain, muscle aches, nausea, and diarrhea. This rare infection may not cause a fever.

Misoprostol is also sometimes used off-label to induce labor or decrease blood loss after delivery of a baby. However, the FDA has issued an alert about the potential dangers of using misoprostol for these purposes. The risks include a torn uterus, the need for a hysterectomy, and death of the mother and baby.

Pregnancy and Misoprostol

Misoprostolis a Pregnancy Category X drug, which means it is likely to harm an unborn baby, causing birth defects and premature birth. The drug can also harm the pregnant woman, causing uterine rupture, uterine bleeding, miscarriage, or an incomplete miscarriage. You should use an effective form of birth control while taking misoprostol and for at least one month after you stop using it.

Women shouldn’t take their first dose of misoprostol until the second or third day of their menstrual period to ensure that they aren’t pregnant.

It’s not known whether this drug passes into breast milk or if it could harm a breastfeeding baby. You should talk to your doctor about these risks.

Misoprostol Warnings

Before taking misoprostol, you should tell your doctor if you have:

  • Inflammatory bowel disease (IBD)
  • Irritable bowel syndrome (IBS)
  • Any other intestinal problems
  • Heart disease

You should also alert your physician if you suspect you are dehydrated before taking this medicine.

This drug must be taken regularly for you to benefit. Don’t stop taking misoprostol without first talking to your doctor.

Call your doctor if you experience severe nausea, stomach pain, or diarrhea lasting several days while on misoprostol.

What are the Side Effects of a Medical Abortion?

Unexpected pregnancy is scary, and it can make most women feel very concerned and alone. If pregnancy wasn’t a part of your plan, and you’re considering a medical abortion, consider the following side effects – as well as each of your options – so you can make the most empowering decision for you, based on facts and not fear.

What does the medical abortion process look like?

A medical abortion, also known as the abortion pill, requires two different medications that must be prescribed by a doctor in order to terminate a pregnancy: mifepristone and misoprostol.

Mifepristone

The first drug of a medical abortion is mifepristone, which is typically taken while at the doctor’s office. Mifepristone blocks the flow of progesterone, a hormone that is necessary for a pregnancy to continue.

The second drug in the medical abortion process is usually taken at home, between 24-48 hours after mifepristone. Misoprostol causes the uterus to contract, like labor, in order to expel the embryo from the uterus.

What are the most common side effects of a medical abortion?

The most commonly experienced side effects of a medical abortion are felt after taking misoprostol, and include the following:

  • Intense cramping
  • Bleeding heavier than a period
  • Diarrhea
  • Abdominal pain unrelated to cramping
  • Dizziness
  • Headaches
  • Mild fever
  • Hot flashes
  • Chills
  • Light lactation

What are the more serious medical abortion complications?

There are a few long-term or serious complications that could arise from a medical abortion, including:

  • An allergic reaction to the medication
  • Infection
  • Incomplete abortion requiring a surgical procedure to complete

What side effects indicate a serious complication?

While not as common, some women experience more intense side effects that could suggest a serious complication has occurred. If any of these side effects are felt following a medical abortion, medical attention should be sought immediately:

  • Severe pain
  • Fever
  • Passing clots for two or more hours that are or exceed the size of a lemon
  • Strong, unusual smelling vaginal discharge
  • Excessive bleeding, defined as using two or more pads in an hour

Are there any other complications to consider?

Something to consider if you’re thinking about a medical abortion is how it may affect you emotionally or mentally. While all women are at some degree of risk for experiencing the following emotional side effects of a medical abortion, you may be at higher risk depending on your situation. Emotional side effects of abortion include:

  • Regret
  • Guilt
  • Shame
  • Anger
  • Relationship difficulties
  • Inability to sleep
  • Nightmares
  • Anxiety
  • Depression
  • Suicidal thoughts or feelings

Women who are at higher risk for experiencing these side effects include those who feel pressured or trapped into a medical abortion, those who have struggled with mental health in the past, and those who believe abortion is morally or ethically wrong. Contact Hopeline for more information about emotional side effects or to speak to someone knowledgeable and professional prior to an abortion procedure.

How do I know if a medical abortion is right for me?

Choosing a medical abortion for your unexpected pregnancy is a big decision to make. No matter what you choose, it is a decision that you will have to live with, so it needs to be one you are physically and emotionally okay with.

If you’re unexpectedly pregnant and not sure of what to do next, Hopeline can help. Schedule an appointment for no-cost and confidential services at our center today.

Sources:

Healthline

American Pregnancy

Mayo Clinic

Cytotec

SIDE EFFECTS

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

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%

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.

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.

Read the entire FDA prescribing information for Cytotec (Misoprostol)

Pharmacists can play an important role in counseling women who experience early pregnancy loss. It is important for patients to know that routine activities, such as exercise, sexual intercourse, and working, do not cause early pregnancy loss. About 50% of all cases of early pregnancy loss are attributable to fetal chromosomal abnormalities.1
The American College of Obstetricians and Gynecologists (ACOG) defines early pregnancy loss as a nonviable, intrauterine pregnancy with either an empty gestational sac or a gestational sac containing an embryo or fetus without a heartbeat within the first 12 weeks of gestation.1 During the first trimester, the terms “early pregnancy loss,” “miscarriage,” and “spontaneous abortion” are used interchangeably.1 Options for early pregnancy loss include allowing the miscarriage to progress naturally (expectant management), medical treatment, and surgical evacuation.2
Here are 5 things pharmacists should know about misoprostol for early pregnancy loss management:
1. Misoprostol has been studied for early pregnancy loss. Misoprostol, a prostaglandin E1 analogue, reduces the need of suction dilation and curettage (D&C) by up to 60% and shortens the time to completion compared with placebo.1 The addition of mifepristone (progesterone receptor antagonist) to misoprostol has been studied as a treatment for early pregnancy loss. However, there is insufficient evidence to demonstrate that this regimen is superior to misoprostol alone. The ACOG does not recommend the routine use of mifepristone for the treatment of early pregnancy loss.1
2. Vaginal administration of misoprostol is recommended for increased efficacy. The recommended dose of misoprostol is 800 mcgs (4 200-mcg tablets) inserted vaginally.1 Study results have demonstrated that vaginal administration is more effective than oral use of misoprostol. One dose is about 70% effective, and 2 is about 84% effective.1
3. Patient counseling is important for appropriate administration. Pharmacists should educate patients about the proper administration of the tablets. Administration should take place in the morning or early afternoon. Patients should wash their hands with soap and water and place each tablet one at a time into the vagina as high as possible. Instruct patients to rest for about 30 minutes after inserting the medication.
4. Tell patients that heavy bleeding may occur. Bleeding usually occurs within 4 to 48 hours after misoprostol administration. If bleeding does not occur within 48 hours, then a repeat misoprostol dose should be administered.1 Counsel patients that bleeding is usually heavier than menses and is generally accompanied by severe cramping. It is normal to see the passage of blood clots and tissue. Heavy bleeding and cramping usually last for about 4 hours. Patients should be relaxing during this time and not engaging in strenuous activity. Educate patients about the importance of having a family member or friend stay with them for support. Recommend that patients contact their obstetrician-gynecologist (OB-GYN) if they are soaking 2 maxi pads per hour for 2 consecutive hours.1 Misoprostol adverse effects may include diarrhea and dizziness. Light bleeding may last for about 2 weeks.
Patients may take OTC acetaminophen to help manage the pain or prescription pain medication (eg, acetaminophen with codeine), along with the misoprostol may be used. It is important for patients not to take both OTC and prescription pain medication to avoid exceeding the daily recommended dose of acetaminophen.
Women who are Rh(D) negative should receive Rh(D)-immune globulin within 72 hours of the first misoprostol administration.1
5. Follow-up is important after misoprostol administration. Advise patients to follow up with their OB-GYN within 7 to 14 days for an ultrasound to ensure the complete passage of tissue.1 If tissue remains, then patients can repeat the misoprostol dose or have a D&C.1
Pharmacists can provide education and support for patients experiencing early pregnancy loss.
RELATED CONTENT

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  • Multivitamins May Help Reduce Miscarriage Risk

REFERENCES

HOW TO USE: This medicine comes with a patient information leaflet. Read it carefully. If you have any questions about this drug, ask your doctor, nurse, or pharmacist.Dosage is based on your medical condition and response to therapy.If you are taking this drug to prevent stomach ulcers, take it by mouth usually four times a day, after meals and at bedtime to minimize diarrhea, or as directed by your doctor.If you are taking this medication for abortion, take it by mouth exactly as directed by your doctor.If you are using this medication to start labor, your healthcare professional will insert it into your vagina.Avoid taking antacids that contain magnesium while using misoprostol because they may make the diarrhea it causes worse. If you need an antacid, consult your doctor or pharmacist to help you choose a product.For ulcer prevention, continue to take this drug for as long as you take NSAIDs. Use this medication regularly in order to get the most benefit from it. Remember to use it at the same times each day.Inform your doctor if your condition persists or worsens.

SIDE EFFECTS: Nausea or stomach cramps may occur. If any of these effects persist or worsen, notify your doctor or pharmacist promptly.Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.Diarrhea is common with misoprostol and usually occurs about two weeks after you start taking it, and lasts for about a week. Be sure to keep up your intake of fluids and minerals/electrolytes to prevent dehydration. Persistent diarrhea may sometimes lead to a large loss of your body’s water and minerals. Tell your doctor immediately if you develop any of these serious signs of dehydration and mineral imbalance: severe dizziness, decreased amount of urine, mental/mood changes, muscle weakness, slow/irregular heartbeat.Tell your doctor immediately if any of these unlikely but serious side effects occur: menstrual problems or irregularities, unusual/heavy vaginal bleeding.A very serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction may include: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.In the US -Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.In Canada – Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking misoprostol, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.Before using this medication, tell your doctor or pharmacist your medical history, especially of: stomach/intestinal disease (e.g., inflammatory bowel disease), risk factors for uterine rupture when this drug is used vaginally (e.g., prior Cesarean delivery, uterine surgery, five or more previous pregnancies).Daily use of alcohol and tobacco may increase your risk for stomach bleeding. Limit alcohol beverages and stop smoking. Consult your doctor or pharmacist for more information.If you are taking this medication in combination with mifepristone to end a pregnancy, an incomplete abortion may rarely occur. It is very important for you to be closely monitored by your doctor and to keep your scheduled appointments to follow your progress. Be sure to have clear instructions from your doctor about who to call and what to do in case of an emergency. Expect vaginal bleeding after you take the combined medicine, however tell your doctor immediately if you develop any unlikely symptoms such as severe/prolonged vaginal bleeding, signs of infection (e.g., fever, chills), or fainting.This drug must not be used during pregnancy to prevent stomach ulcers because of possible harm to an unborn baby (see also Warnings). If you are of childbearing age, use effective birth control methods while taking misoprostol and for at least one month or one completed menstrual cycle after you stop taking it. If you become pregnant or think you may be pregnant, inform your doctor immediately.This medication passes into breast milk. However, this drug is unlikely to harm a nursing infant. Consult your doctor before breast-feeding.

SLIDESHOW

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CLINICAL PHARMACOLOGY

Pharmacokinetics

Misoprostol is extensively absorbed, and undergoes rapid de­esterification to its free acid, which is responsible for its clinical activity and, unlike the parent compound, is detectable in plasma. 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.

In normal volunteers, Cytotec (misoprostol) is rapidly absorbed after oral administration with a Tmax of misoprostol acid of 12 ± 3 minutes and a terminal half-life of 20–40 minutes.

There is high variability of plasma levels of misoprostol acid between and within studies but mean values after single doses show a linear relationship with dose over the range of 200–400 mcg. No accumulation of misoprostol acid was noted in multiple dose studies; plasma steady state was achieved within two days.

Maximum plasma concentrations of misoprostol acid are diminished when the dose is taken with food and total availability of misoprostol acid is reduced by use of concomitant antacid. Clinical trials were conducted with concomitant antacid, however, so this effect does not appear to be clinically important.

After oral administration of radiolabeled misoprostol, about 80% of detected radioactivity appears in urine. Pharmacokinetic studies in patients with varying degrees of renal impairment showed an approximate doubling of T½, Cmax, and AUC compared to normals, but no clear correlation between the degree of impairment and AUC. In subjects over 64 years of age, the AUC for misoprostol acid is increased. No routine dosage adjustment is recommended in older patients or patients with renal impairment, but dosage may need to be reduced if the usual dose is not tolerated.

Drug interaction studies between misoprostol and several nonsteroidal anti-inflammatory drugs showed no effect on the kinetics of ibuprofen or diclofenac, and a 20% decrease in aspirin AUC, not thought to be clinically significant.

Pharmacokinetic studies also showed a lack of drug interaction with antipyrine and propranolol when these drugs were given with misoprostol. Misoprostol given for 1 week had no effect on the steady state pharmacokinetics of diazepam when the two drugs were administered 2 hours apart.

The serum protein binding of misoprostol acid is less than 90% and is concentration-independent in the therapeutic range.

After a single oral dose of misoprostol to nursing mothers, misoprostol acid was excreted in breast milk. The maximum concentration of misoprostol acid in expressed breast milk was achieved within 1 hour after dosing and was 7.6 pg/ml (CV 37%) and 20.9 pg/ml (CV 62%) after single 200 μg and 600 μg misoprostol administration, respectively. The misoprostol acid concentrations in breast milk declined to < 1 pg/ml at 5 hours post-dose.

Pharmacodynamics

Misoprostol has both antisecretory (inhibiting gastric acid secretion) and (in animals) mucosal protective properties. NSAIDs inhibit prostaglandin synthesis, and a deficiency of prostaglandins within the gastric mucosa may lead to diminishing bicarbonate and mucus secretion and may contribute to the mucosal damage caused by these agents. Misoprostol can increase bicarbonate and mucus production, but in man this has been shown at doses 200 mcg and above that are also antisecretory. It is therefore not possible to tell whether the ability of misoprostol to reduce the risk of gastric ulcer is the result of its antisecretory effect, its mucosal protective effect, or both.

In vitro studies on canine parietal cells using tritiated misoprostol acid as the ligand have led to the identification and characterization of specific prostaglandin receptors. Receptor binding is saturable, reversible, and stereospecific. The sites have a high affinity for misoprostol, for its acid metabolite, and for other E type prostaglandins, but not for F or I prostaglandins and other unrelated compounds, such as histamine or cimetidine. Receptor-site affinity for misoprostol correlates well with an indirect index of antisecretory activity. It is likely that these specific receptors allow misoprostol taken with food to be effective topically, despite the lower serum concentrations attained.

Misoprostol produces a moderate decrease in pepsin concentration during basal conditions, but not during histamine stimulation. It has no significant effect on fasting or postprandial gastrin nor on intrinsic factor output.

Effects On Gastric Acid Secretion

Misoprostol, over the range of 50–200 mcg, inhibits basal and nocturnal gastric acid secretion, and acid secretion in response to a variety of stimuli, including meals, histamine, pentagastrin, and coffee. Activity is apparent 30 minutes after oral administration and persists for at least 3 hours. In general, the effects of 50 mcg were modest and shorter lived, and only the 200-mcg dose had substantial effects on nocturnal secretion or on histamine and meal-stimulated secretion.

Uterine Effects

Cytotec has been shown to produce uterine contractions that may endanger pregnancy. (See BOXED WARNINGS.)

Other Pharmacologic Effects

Cytotec does not produce clinically significant effects on serum levels of prolactin, gonadotropins, thyroid-stimulating hormone, growth hormone, thyroxine, cortisol, gastrointestinal hormones (somatostatin, gastrin, vasoactive intestinal polypeptide, and motilin), creatinine, or uric acid. Gastric emptying, immunologic competence, platelet aggregation, pulmonary function, or the cardiovascular system are not modified by recommended doses of Cytotec.

Clinical Studies

In a series of small short-term (about 1 week) placebo-controlled studies in healthy human volunteers, doses of misoprostol were evaluated for their ability to reduce the risk of NSAID-induced mucosal injury. Studies of 200 mcg q.i.d. of misoprostol with tolmetin and naproxen, and of 100 and 200 mcg q.i.d. with ibuprofen, all showed reduction of the rate of significant endoscopic injury from about 70–75% on placebo to 10–30% on misoprostol. Doses of 25–200 mcg q.i.d. reduced aspirin-induced mucosal injury and bleeding.

Reducing The Risk Of Gastric Ulcers Caused By Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

Two 12-week, randomized, double-blind trials in osteoarthritic patients who had gastrointestinal symptoms but no ulcer on endoscopy while taking an NSAID compared the ability of 200 mcg of Cytotec, 100 mcg of Cytotec, and placebo to reduce the risk of gastric ulcer (GU) formation. Patients were approximately equally divided between ibuprofen, piroxicam, and naproxen, and continued this treatment throughout the 12 weeks. The 200-mcg dose caused a marked, statistically significant reduction in gastric ulcers in both studies. The lower dose was somewhat less effective, with a significant result in only one of the studies.

Reduction of Risk of Gastric Ulcers Induced by Ibuprofen, Piroxicam, or Naproxen

In these trials there were no significant differences between Cytotec and placebo in relief of day or night abdominal pain. No effect of Cytotec in reducing the risk of duodenal ulcers was demonstrated, but relatively few duodenal lesions were seen.

In another clinical trial, 239 patients receiving aspirin 650–1300 mg q.i.d. for rheumatoid arthritis who had endoscopic evidence of duodenal and/or gastric inflammation were randomized to misoprostol 200 mcg q.i.d. or placebo for 8 weeks while continuing to receive aspirin. The study evaluated the possible interference of Cytotec on the efficacy of aspirin in these patients with rheumatoid arthritis by analyzing joint tenderness, joint swelling, physician’s clinical assessment, patient’s assessment, change in ARA classification, change in handgrip strength, change in duration of morning stiffness, patient’s assessment of pain at rest, movement, interference with daily activity, and ESR. Cytotec did not interfere with the efficacy of aspirin in these patients with rheumatoid arthritis.

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 Cytotec for up to 1 year.

An apparent response of the female mouse to Cytotec 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 Cytotec.

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