Misoprostol Information
Misoprostol () Warnings
Misoprostol () ADMINISTRATION TO WOMEN WHO ARE PREGNANT CAN CAUSE ABORTION, PREMATURE BIRTH, OR BIRTH DEFECTS. UTERINE RUPTURE HAS BEEN REPORTED WHEN Misoprostol () WAS ADMINISTERED IN PREGNANT WOMEN TO INDUCE LABOR OR TO INDUCE ABORTION BEYOND THE EIGHTH WEEK OF PREGNANCY (see also and ). Misoprostol () SHOULD NOT BE TAKEN BY PREGNANT WOMEN TO REDUCE THE RISK OF ULCERS INDUCED BY NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs) (see , , and ).
PATIENTS MUST BE ADVISED OF THE ABORTIFACIENT PROPERTY AND WARNED NOT TO GIVE THE DRUG TO OTHERS.
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 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
Misoprostol () Description
Misoprostol () oral tablets contain either 100 mcg or 200 mcg of Misoprostol () , a synthetic prostaglandin E 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.
Misoprostol () Clinical Pharmacology
Misoprostol () is extensively absorbed, and undergoes rapid de-esterification 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, Misoprostol () is rapidly absorbed after oral administration with a T 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 T, C, 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
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
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.
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 Misoprostol () , 100 mcg of Misoprostol () , 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.
In these trials there were no significant differences between Misoprostol () and placebo in relief of day or night abdominal pain. No effect of Misoprostol () 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 Misoprostol () 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. Misoprostol () did not interfere with the efficacy of aspirin in these patients with rheumatoid arthritis.
Misoprostol () Indications And Usage
Misoprostol () is indicated for reducing the risk of NSAID (nonsteroidal anti-inflammatory drugs, including aspirin)–induced gastric ulcers in patients at high risk of complications from gastric ulcer, eg, the elderly and patients with concomitant debilitating disease, as well as patients at high risk of developing gastric ulceration, such as patients with a history of ulcer. Misoprostol () has not been shown to reduce the risk of duodenal ulcers in patients taking NSAIDs. Misoprostol () should be taken for the duration of NSAID therapy. Misoprostol () has been shown to reduce the risk of gastric ulcers in controlled studies of 3 months' duration. It had no effect, compared to placebo, on gastrointestinal pain or discomfort associated with NSAID use.
Misoprostol () Contraindications
See boxed
Misoprostol () should not be taken by anyone with a history of allergy to prostaglandins.
Misoprostol () Warnings
Misoprostol () Precautions
Caution should be employed when administering Misoprostol () to patients with pre-existing cardiovascular disease.
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
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.
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 abortion (sometimes incomplete), premature labor, or birth defects if given to pregnant women.
Misoprostol () is available only as a unit-of-use package that includes a leaflet containing patient information. See at the end of this labeling.
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 () .
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 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.
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 the hyperstimulation of the uterus 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. Pelvic pain, retained placenta, severe genital bleeding, shock, fetal bradycardia, and fetal and maternal death have been reported.
There may be an increased risk of uterine tachysystole, uterine rupture, meconium passage, meconium staining of amniotic fluid, and Cesarean delivery due to uterine hyperstimulation with the use of higher doses of Misoprostol () , including the manufactured 100 mcg tablet. The risk of uterine rupture increases with advancing gestational ages and with prior uterine surgery, including Cesarean delivery. Grand multiparity also appears to be a risk factor for uterine rupture.
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.
Misoprostol () Adverse Reactions
The following have been reported as adverse events in subjects receiving Misoprostol () :
In subjects receiving Misoprostol () 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 Misoprostol () (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 Misoprostol () is prescribed. The incidence of diarrhea can be minimized by administering after meals and at bedtime, and by avoiding coadministration of Misoprostol () with magnesium-containing antacids.
There were no significant differences in the safety profile of Misoprostol () 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:
The following adverse events were infrequently reported. Causal relationships between Misoprostol () and these events have not been established but cannot be excluded:
Body as a whole:
Skin:
Special senses:
Respiratory:
Cardiovascular:
Gastrointestinal:
Hypersensitivity:
Metabolic:
Genitourinary:
Nervous system/Psychiatric:
Musculoskeletal:
Blood/Coagulation:
Misoprostol () Overdosage
The toxic dose of Misoprostol () in humans has not been determined. Cumulative total daily doses of 1600 mcg have been tolerated, with only symptoms of gastrointestinal discomfort being reported. In animals, the acute toxic effects are diarrhea, gastrointestinal lesions, focal cardiac necrosis, hepatic necrosis, renal tubular necrosis, testicular atrophy, respiratory difficulties, and depression of the central nervous system. Clinical signs that may indicate an overdose are sedation, tremor, convulsions, dyspnea, abdominal pain, diarrhea, fever, palpitations, hypotension, or bradycardia. Symptoms should be treated with supportive therapy.
It is not known if Misoprostol () acid is dialyzable. However, because Misoprostol () is metabolized like a fatty acid, it is unlikely that dialysis would be appropriate treatment for overdosage.
Misoprostol () Dosage And Administration
The recommended adult oral dose of Misoprostol () for reducing the risk of NSAID-induced gastric ulcers is 200 mcg four times daily with food. If this dose cannot be tolerated, a dose of 100 mcg can be used. (See .) Misoprostol () should be taken for the duration of NSAID therapy as prescribed by the physician. Misoprostol () should be taken with a meal, and the last dose of the day should be at bedtime.
Misoprostol () How Supplied
Misoprostol () 100-mcg tablets are white, round, with G and 5007 debossed on one side; supplied as:
Misoprostol () 200-mcg tablets are white, hexagonal, with G debossed above and 5008 debossed below the line on one side; supplied as:
Misoprostol () Patient Information
Read this leaflet before taking Misoprostol () and each time your prescription is renewed, because the leaflet may be changed.
Misoprostol () is being prescribed by your doctor to decrease the chance of getting stomach ulcers related to the arthritis/pain medication that you take.
Do not take Misoprostol () to reduce the risk of NSAID-induced ulcers if you are pregnant. (See boxed .) Misoprostol () can cause abortion (sometimes incomplete which could lead to dangerous bleeding and require hospitalization and surgery), premature birth, or birth defects. It is also important to avoid pregnancy while taking this medication and for at least one month or through one menstrual cycle after you stop taking it. Misoprostol () has been reported to cause the uterus to rupture (tear) when given after the eighth week of pregnancy. Rupture (tearing) of the uterus can result in severe bleeding, hysterectomy, and/or maternal or fetal death.
If you become pregnant during Misoprostol () therapy, stop taking Misoprostol () and contact your physician immediately. Remember that even if you are on a means of birth control it is still possible to become pregnant. Should this occur, stop taking Misoprostol () and contact your physician immediately.
Misoprostol () may cause diarrhea, abdominal cramping, and/or nausea in some people. In most cases these problems develop during the first few weeks of therapy and stop after about a week. You can minimize possible diarrhea by making sure you take Misoprostol () with food.
Because these side effects are usually mild to moderate and usually go away in a matter of days, most patients can continue to take Misoprostol () . If you have prolonged difficulty (more than 8 days), or if you have severe diarrhea, cramping and/or nausea, call your doctor.
Take Misoprostol () only according to the directions given by your physician.
Do not give Misoprostol () to anyone else. It has been prescribed for your specific condition, may not be the correct treatment for another person, and would be dangerous if the other person were pregnant.
This information sheet does not cover all possible side effects of Misoprostol () . This patient information leaflet does not address the side effects of your arthritis/pain medication. See your doctor if you have questions.
Keep out of reach of children.
Misoprostol ()
Misoprostol () Principal Display Panel - Mcg Tablet Bottle
Misoprostol () Principal Display Panel - Mcg Tablet Bottle
