Prescription Required
In stock
Manufacturer
GREENSTONE LLC.
SKU
59762500801

misoprostol 200 mcg tablet

Generic
$1.05 / tablet
$1.20 / tablet
$0.15 / tablet
+ -
1,000 tablets Available
Total Price:

Uses

Misoprostol, is used for reducing the risk of nonsteroidal anti-inflammatory agent (NSAIA)-induced gastric ulcer in patients at high risk of developing complications from these ulcers and in patients at high risk of developing gastric ulceration.Misoprostol has been used for the short-term treatment of active duodenal ulcer and for the short-term treatment of active, benign gastric ulcer. Misoprostol also has been used as maintenance therapy following healing of gastric ulcer to reduce ulcer recurrence.

Misoprostol is used as an adjunct to mifepristone for the medical termination of intrauterine pregnancy (i.e., medical abortion). The drug has been used for induction of labor and for treatment of serious postpartum hemorrhage in the presence of uterine atony.

Prevention of NSAIA-induced Ulcers

Misoprostol is used for reducing the risk of NSAIA-induced gastric ulcers in patients at high risk of developing complications (e.g., bleeding, perforation, death) from these ulcers, such as patients with a concomitant debilitating disease and geriatric patients, and in patients at high risk of developing gastric ulceration, such as those with a history of upper GI ulcer.While the drug also has been used for the prevention of NSAIA-induced duodenal ulcers in a limited number of patients, current evidence is insufficient to establish efficacy in these patients.

Serious adverse GI effects (e.g., bleeding, ulceration, perforation) can occur at any time in patients receiving chronic NSAIA therapy, and such effects may not be preceded by warning signs or symptoms. Results of studies to date are inconclusive concerning the relative risk of various NSAIAs in causing serious GI effects. In patients receiving prototypical NSAIAs and observed in clinical studies of several months' to 2-years' duration, symptomatic upper GI ulcers, gross bleeding, or perforation appeared to occur in approximately 1% of patients treated for 3-6 months and in about 2-4% of those treated for 1 year. These trends continue with long-term therapy and increase the likelihood of a serious GI event occurring at some time during the course of therapy. Studies have shown that patients with a history of peptic ulcer disease and/or GI bleeding who are receiving NSAIAs have a greater than tenfold higher risk for developing GI bleeding than patients without these risk factors. In addition to a history of ulcer disease, pharmacoepidemiologic studies have identified several comorbid conditions and concomitant therapies that may increase the risk for GI bleeding, including concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAIA therapy, smoking, alcoholism, older age, and poor general health status. In addition, geriatric or debilitated patients appear to tolerate GI ulceration and bleeding less well than other individuals, and most spontaneous reports of fatal NSAIA-induced GI effects have been in such patients. Therefore, consideration can be given to concomitant preventive therapy with misoprostol in these and other patients deemed at high risk of developing complications resulting from NSAIA-induced gastric ulcer or at high risk of developing such ulcers.

Efficacy of misoprostol for the prevention of NSAIA-induced gastric ulcer has been established principally in short-term studies (up to 3 months' duration). Therefore, although continuous misoprostol therapy for the duration of NSAIA use currently is recommended by the manufacturer, the long-term safety and efficacy and optimum duration of misoprostol therapy in patients receiving NSAIAs chronically remain to be established. In addition, although NSAIA-induced gastric injury is asymptomatic in most patients, most studies conducted to date have included only patients with symptomatic injury. It also should be recognized that while misoprostol is intended for use in the prevention of NSAIA-induced gastric injury in patients at high risk of complications from such injury, efficacy of the drug in most high-risk patient groups has not been specifically established. Despite the lack of such data, however, high-risk patients are thought to be most likely to benefit from prophylactic therapy with misoprostol.

Misoprostol has reduced the rate of endoscopically documented NSAIA-induced gastroduodenal mucosal injury in healthy individuals. The drug also has reduced the rate of gastroduodenal ulcer formation in osteoarthritic patients with GI symptoms but no evidence of ulcer prior to initiation of misoprostol. Gastroduodenal mucosal injury also has been reduced and healing of gastroduodenal ulcer promoted in patients with rheumatoid arthritis who had GI symptoms and evidence of mucosal injury and/or ulcer when misoprostol was initiated. However, misoprostol does not appear to be effective in reducing associated GI symptoms (e.g., pain).

In several short-term (about 1-week duration) studies in a limited number of healthy individuals receiving a NSAIA (e.g., aspirin, ibuprofen, naproxen, tolmetin), reported rates of endoscopically documented gastric or duodenal mucosal injury were 10-30% in those receiving oral misoprostol dosages of 100 or 200 mcg 4 times daily and 70-75% in those receiving placebo. In a limited number of healthy individuals, misoprostol also has been more effective than sucralfate in preventing aspirin-induced gastroduodenal mucosal injury and more effective than cimetidine in preventing tolmetin-induced gastric but not duodenal mucosal injury.

In a multicenter controlled study in patients with osteoarthritis who were receiving chronic NSAIA therapy (e.g., 3 months or longer with ibuprofen, naproxen, or piroxicam) and had GI symptoms but no endoscopic evidence of gastric ulcer, 100 or 200 mcg of misoprostol 4 times daily reduced the rate of NSAIA-induced gastric ulcer formation; at 12 weeks, 21-30% of patients receiving placebo developed gastric ulcers while only 1.4-3 or 6-8% of patients receiving the 200- or 100-mcg regimen, respectively, developed such ulcers. However, the 100-mcg regimen was less effective than the 200-mcg regimen, producing a significant reduction in gastric ulcer formation compared with placebo in only one of the study groups. In addition, misoprostol was not effective in relieving associated GI symptoms (e.g., daytime or nocturnal abdominal pain, nausea, vomiting, anorexia) with either regimen.

In a study in patients with rheumatoid arthritis who were receiving aspirin therapy for at least 4 weeks and had GI symptoms and endoscopically confirmed gastric and/or duodenal injury, 8 weeks of concomitant misoprostol (200 mcg 4 times daily) therapy promoted gastroduodenal healing, including healing of ulcers. Healing of gastric or duodenal mucosal injury occurred at 8 weeks in 70 or 86%, respectively, of patients receiving misoprostol compared with 25 or 53%, respectively, of those receiving placebo, and healing of gastroduodenal ulcers occurred in 67% of patients receiving the drug compared with 26% of those receiving placebo. There was similar evidence of misoprostol-induced healing at 4 weeks. Misoprostol also appeared to prevent formation of new ulcers and did not interfere with the efficacy of aspirin as determined by relief of pain and stiffness, reduction of swelling, improvement of mobility and grip strength, or erythrocyte sedimentation rate (ESR).

For information on the use of misoprostol in fixed combination with diclofenac, a NSAIA,

Gastric Ulcer

Acute Therapy

Misoprostol has been used in the short-term treatment of active, benign, gastric ulcer. However, the drug does not appear to offer any superiority over H2-receptor antagonists and is less effective than these agents in relieving ulcer pain. Because misoprostol is associated with severe adverse effects (e.g., fetal mortality, premature birth, birth defects), it is not considered a drug of choice for the treatment of peptic ulcer disease (e.g., gastric ulcer) and is not included in the current American College of Gastroenterology (ACG) guidelines for the treatment of this condition.

Current epidemiologic and clinical evidence supports a strong association between gastric infection with H. pylori and the pathogenesis of gastric ulcers, and the ACG, National Institutes of Health (NIH), and most clinicians currently recommend that all patients with initial or recurrent gastric ulcer and documented H. pylori infection receive anti-infective therapy for treatment of the infection. The choice of a particular regimen should be based on the rapidly evolving data on optimal therapy, including consideration of the patient's prior exposure to anti-infective agents, the local prevalence of resistance, patient compliance, and costs of therapy.(See Duodenal Ulcer: Acute Therapy, in Uses.) For a more complete discussion of H. pylori infection, including details about the efficacy of various regimens and rationale for drug selection, .

Maintenance Therapy

Misoprostol has been used in reduced dosage for up to 14 months in a limited number of patients as maintenance therapy following healing of active gastric ulcer to reduce ulcer recurrence. However, additional studies are needed to evaluate the safety and efficacy of maintenance therapy with the drug.

Duodenal Ulcer

Acute Therapy

Misoprostol has been used for the short-term treatment of endoscopically or radiographically confirmed active duodenal ulcer. Limited data suggest that misoprostol also may be effective in some patients with duodenal ulcer refractory to H2-antagonist therapy. However, misoprostol does not appear to be effective in reducing daytime and nocturnal pain or antacid consumption in patients with duodenal ulcers; aluminum-containing antacids have been used concomitantly with the drug as needed for relief of pain.

Some clinicians state that misoprostol does not appear to offer any superiority over other existing antiulcer therapies for active duodenal ulcers in terms of healing efficacy, dosing schedule, or recurrence after treatment, but is less effective in relieving associated GI pain. Because misoprostol may represent a risk of uterine bleeding and/or abortion when inadvertently used by pregnant women, it is not considered a drug of choice for the treatment of peptic ulcer disease (e.g., duodenal ulcer) and is not included in the current ACG guidelines for the treatment of this condition.

Current epidemiologic and clinical evidence supports a strong association between gastric infection with Helicobacter pylori and the pathogenesis of duodenal and gastric ulcers; long-term H. pylori infection also has been implicated as a risk factor for gastric cancer. The ACG, NIH, and most clinicians currently recommend that all patients with initial or recurrent duodenal or gastric ulcer and documented H. pylori infection receive anti-infective therapy for treatment of the infection. Anti-H. pylori regimens that combine one or more anti-infective agents (e.g., clarithromycin, amoxicillin) with a bismuth salt and/or an antisecretory agent (e.g., omeprazole, lansoprazole, H2-receptor antagonist) have been used successfully for H. pylori eradication. The choice of a particular regimen should be based on the rapidly evolving data on optimal therapy, including consideration of the patient's prior exposure to anti-infective agents, the local prevalence of resistance, patient compliance, and costs of therapy. For a more complete discussion of H. pylori infection, including details about the efficacy of various regimens and rationale for drug selection, and .

Termination of Pregnancy

Misoprostol is used as an adjunct to mifepristone for medical termination of an intrauterine pregnancy. Although Pharmacia, the manufacturer of misoprostol, states that it has not conducted and does not intend to conduct research to support such usage, use of misoprostol with mifepristone for termination of pregnancy is included in the approved labeling of mifepristone in the US and in Europe, and the American College of Obstetricians and Gynecologists (ACOG) states that misoprostol is necessary for termination of pregnancy with mifepristone. For a complete discussion of the use of misoprostol with mifepristone for this indication,

Other Obstetric Uses

ACOG states that misoprostol has been used effectively (e.g., 25 mcg every 3-6 hours intravaginally using tablets formulated for oral administration) to improve cervical inducibility (cervical ''ripening'') in pregnant women with a medical or obstetric need for labor induction. Although Pharmacia, the manufacturer of misoprostol, states that it has not conducted and does not intend to conduct research to support use in pregnancy (e.g., labor induction), vaginal administration of misoprostol appears to be safe and effective for induction of labor in appropriately selected women with unfavorable cervices. However, such use in women with prior uterine surgery or cesarean section should be avoided because of the risk of possible uterine rupture.

Misoprostol also has been used for prevention or treatment of serious postpartum hemorrhage in the presence of uterine atony.

Other Uses

Misoprostol has been used in a limited number of patients for the management of fat malabsorption associated with cystic fibrosis, and for the management of hemorrhagic gastritis, reflux esophagitis, alcohol-induced gastritis, and NSAIA-induced nephropathy. The drug has been effective in some patients with these conditions, but further studies are needed.

Dosage and Administration

Administration

Misoprostol usually is administered orally. The incidence of misoprostol-induced diarrhea may be minimized by administering the drug in divided doses after meals and at bedtime and by avoiding concomitant administration with a magnesium-containing or other laxative antacid.

Misoprostol also has been administered intravaginally using tablets formulated for oral administration.

Dosage

Prevention of NSAIA-Induced Ulcers

For reducing the risk of NSAIA-induced gastric ulcer, the usual adult dosage of misoprostol is 200 mcg 4 times daily. Dosage can be reduced to 100 mcg 4 times daily in patients who do not tolerate the usual dosage; however, this reduced dosage may be somewhat less effective in preventing NSAIA-induced gastric ulcers. Misoprostol dosages of 200 mcg twice daily also have been used for reducing the risk of NSAIA-induced gastric ulcer. The optimum duration of misoprostol therapy has not been elucidated and safety and efficacy have been established in controlled studies only for periods up to 3 months' duration; however, the manufacturer currently recommends that the drug be continued for the duration of NSAIA therapy.

Gastric Ulcer

For the short-term treatment of active, benign gastric ulcer, a misoprostol dosage of 100 or 200 mcg 4 times daily for 8 weeks has been used in adults.

Duodenal Ulcer

For the short-term treatment of active duodenal ulcer, misoprostol dosages of 100 or 200 mcg 4 times daily or 400 mcg twice daily for 4-8 weeks have been used in adults.

Termination of Pregnancy

When misoprostol is used as an adjunct to mifepristone for the medical termination of an intrauterine pregnancy, 400 mcg of misoprostol is administered orally on day 3 (2 days after mifepristone administration) unless abortion has occurred and has been confirmed by clinical examination or ultrasonographic scan.

Induction of Labor

Although an optimal misoprostol dosage regimen for cervical ripening and induction of labor remains to be determined, the American College of Obstetricians and Gynecologists (ACOG) states that misoprostol 25 mcg (¼ of a 100-mcg oral tablet) given intravaginally can be considered for the initial dose. Subsequent 25-mcg doses have been administered every 3-6 hours.

Dosage in Renal Impairment and in Geriatric Patients

Routine reduction of misoprostol dosage in patients with renal impairment or in geriatric patients does not appear to be necessary; however, if patients are unable to tolerate the usual adult dosage, dosage can be reduced.

Cautions

Misoprostol generally is well tolerated. The frequency of adverse effects does not appear to be affected by patient age in adults. The most frequent adverse effects associated with misoprostol therapy involve the GI tract (e.g., diarrhea, nausea, abdominal pain).

GI Effects

Diarrhea is the most common adverse effect of misoprostol. In controlled clinical studies in patients receiving NSAIAs, the incidence of diarrhea associated with a misoprostol dosage of 800 mcg daily was 14-40%. In all studies (including those in which the drug was being studied for the treatment of acute duodenal or gastric ulcers), the incidence of diarrhea averaged 13% with dosages of 400-800 mcg daily. Diarrhea, which appears to be dose related, usually is apparent after about 2 weeks of misoprostol therapy, and generally is self-limiting, often resolving within about a week after onset. However, diarrhea has been severe enough to require discontinuance of misoprostol therapy in about 2% of patients receiving the drug for the prevention of NSAIA-induced ulcer. Profound diarrhea (e.g., voluminous, watery diarrhea) and resultant severe dehydration has been reported rarely in patients receiving misoprostol therapy; such diarrhea also has resulted in severe metabolic acidosis and can be life-threatening. Patients with inflammatory bowel disease may be at increased risk of developing such diarrhea during misoprostol therapy (e.g., secondary to an unmasking or exacerbation of a previously quiescent GI inflammatory condition). Misoprostol-induced diarrhea may be minimized by administering the drug in divided doses after meals and at bedtime and by avoiding concomitant administration with a magnesium-containing or other laxative antacid.

Abdominal pain occurred in about 13-20% of patients receiving misoprostol concomitantly with NSAIAs and in about 7% overall in studies with the drug, but the incidence of this effect did not differ consistently from that reported with placebo. Nausea, flatulence, dyspepsia, vomiting, and constipation occur in about 1-4% of patients receiving misoprostol, but the incidences of these effects were similar to those reported with placebo. Pancreatitis has been reported rarely in patients receiving the drug.

GI bleeding, GI inflammation and/or infection, rectal disorder, gingivitis, dysgeusia, reflux, changes in appetite, and dysphagia also have been reported, but a causal relationship to misoprostol has not been established. The possibility that preexisting NSAIA-induced gastropathy can progress following initiation of misoprostol therapy should be considered.

Nervous System Effects

Headache occurs in about 2% of patients receiving misoprostol. Asthenia, fatigue, anxiety, depression, drowsiness, dizziness, peripheral neuropathy, confusion, and neurosis also have been reported, but a causal relationship to misoprostol has not been established. Vertigo and lethargy have been reported rarely in patients receiving the drug.

Genitourinary and Renal Effects

Menstrual irregularities (e.g., cramps, dysmenorrhea, hypermenorrhea, spotting) have occurred in 0.1-0.7% of women receiving misoprostol in clinical studies. Postmenopausal vaginal bleeding may also occur in some women receiving the drug; if such bleeding occurs, the possibility of an underlying gynecologic abnormality should be ruled out. Spontaneous abortions have occurred in pregnant women receiving the drug. Uterine rupture has been reported in pregnant women following administration of misoprostol to induce labor or to induce abortion beyond the eighth week of pregnancy; death of the fetus has occurred in some cases.(See Cautions: Pregnancy, Fertility, and Lactation.)

Polyuria, dysuria, hematuria, and urinary tract infection have been reported in patients receiving misoprostol, but a causal relationship to the drug has not been established.

Hematologic Effects

Anemia, abnormal differential blood cell count, thrombocytopenia, and increased erythrocyte sedimentation rate (ESR) have been reported in patients receiving misoprostol, although these effects have not been directly attributed to the drug.

Ocular and Otic Effects

Visual abnormalities, conjunctivitis, deafness, tinnitus, and earache have been reported in patients receiving misoprostol, but a causal relationship to the drug has not been established.

Dermatologic and Sensitivity Reactions

Rash, dermatitis, alopecia, pallor, purpura, and diaphoresis have been reported in patients receiving misoprostol, although these effects have not been directly attributed to the drug. Anaphylaxis has been reported in patients receiving misoprostol.

Cardiovascular Effects

Chest pain, edema, diaphoresis, hypotension, hypertension, arrhythmia, phlebitis, increased serum concentrations of cardiac enzymes, syncope, myocardial infarction (some fatal), and thromboembolic events (e.g., pulmonary embolism, arterial thrombosis, cerebrovascular accident) have been reported in patients receiving misoprostol, but a causal relationship to the drug has not been established.

Hepatic Effects

Abnormal hepatobiliary function and increased serum alkaline phosphatase or aminotransferase concentrations have been reported in patients receiving misoprostol, but these effects have not been directly attributed to the drug.

Respiratory Effects

Upper respiratory tract infection, bronchitis, bronchospasm, dyspnea, pneumonia, and epistaxis have been reported in patients receiving misoprostol, but a causal relationship to the drug has not been established.

Other Adverse Effects

Fever, rigors, weight change, thirst, breast pain, impotence, loss of libido, arthralgia, myalgia, muscle cramps, stiffness, and back pain have been reported in patients receiving misoprostol, but these effects have not been directly attributed to the drug.

Precautions and Contraindications

Patients receiving misoprostol for reducing the risk of NSAIA-induced gastric ulcer should be advised about such use and that the drug should be used only as directed. A copy of the patient information provided by the manufacturer should be given to each patient receiving the drug, and the latest version should be issued with each prescription refill. Patients should be instructed to read the patient information before initiation of misoprostol therapy and every time the prescription is refilled, since the information may have been revised. It is particularly important that all patients understand misoprostol's abortifacient properties and attendant risks (See Cautions: Pregnancy, Fertility, and Lactation), and that the drug is intended only for their use for the specific condition for which it was prescribed. Sharing the drug with another individual, particularly a woman of childbearing potential, could be hazardous. Patients should be advised to contact their clinician promptly if they have problems with or questions about misoprostol.

Because severe adverse cardiovascular effects have been reported with misoprostol, the manufacturer states that the drug should be used with caution in patients with preexisting cardiovascular disease.

Because misoprostol may exacerbate intestinal inflammation and produce severe diarrhea in patients with inflammatory bowel disease, the drug should be used with extreme caution in these patients and their condition monitored carefully. Because dehydration rarely may occur secondary to misoprostol-induced diarrhea, the drug also should be used with careful monitoring in patients prone to dehydration or in whom its consequences would be dangerous.

Misoprostol should not be used in pregnant women for reducing the risk of NSAIA-induced gastric ulcers. Misoprostol also should not be used for reducing the risk of NSAIA-induced gastric ulcers in women of childbearing potential unless the woman is at high risk of developing gastric ulcers or of complications resulting from NSAIA-induced gastric ulcers. Misoprostol therapy should not be initiated in such women until the possibility of pregnancy has been excluded and an effective method of contraception has been started.(See Cautions: Pregnancy, Fertility, and Lactation.)

Misoprostol is contraindicated in patients with known hypersensitivity to prostaglandins.

Pediatric Precautions

Safety and efficacy of misoprostol in children younger than 18 years of age have not been established.

Mutagenicity and Carcinogenicity

No evidence of misoprostol-induced mutagenicity was seen with several in vitro test systems, including the microbial (Ames test), mammalian (mouse lymphoma), sister chromatid exchange, Saccharomyces cerevisiae point mutation, and cell transformation assays, all performed with and without metabolic activation.

No evidence of carcinogenic potential was seen in rats and mice receiving oral misoprostol dosages up to 2.4 and 16 mg/kg (about 150 and 1000 times the usual human dosage) for 24 and 21 months, respectively. Hyperplasia of the gastric mucosa was observed in dogs receiving oral misoprostol dosages of 300 mcg/kg daily for 13 weeks. A reversible increase in the number of normal surface gastric epithelial cells was observed in dogs, rats, and mice receiving misoprostol orally; however, increases of gastric epithelial cells were not observed in humans receiving the drug for 1 year. In addition, antral biopsy did not reveal evidence of histopathologic abnormalities in patients with gastric or duodenal ulcer receiving oral misoprostol dosages of 100 or 200 mcg 4 times daily for 4 or 8 weeks. Hyperostosis (mainly of the medulla sternebrae) was observed in female mice receiving 100-1000 times the usual human dosage; however, this effect was not observed in long-term toxicity studies in dogs or rats, and has not been reported to date in humans receiving the drug.

Pregnancy, Fertility, and Lactation

Pregnancy

Misoprostol exhibits abortifacient activity and therefore can cause serious fetal harm when administered to pregnant women. Misoprostol should not be used in pregnant women for reducing the risk of NSAIA-induced gastric ulcers. The drug also should not be used for reducing the risk of NSAIA-induced gastric ulcers in women of childbearing potential unless the woman is at high risk of developing gastric ulcers or of complications resulting from NSAIA-induced gastric ulcers; such women should not receive misoprostol until pregnancy is excluded and other necessary precautions are ensured.

Misoprostol has been reported to produce uterine contractions and to stimulate uterine bleeding and total or partial expulsion of the products of conception in pregnant women. Spontaneous abortions induced by the drug may be incomplete, may require hospitalization and/or surgery, and can result in dangerous uterine bleeding, premature birth, or birth defects.

Intravaginal use of misoprostol may result in 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. Use of intravaginal misoprostol dosages exceeding 25 mcg may be associated with an increased risk of uterine tachysystole, uterine rupture, meconium passage, meconium staining of amniotic fluid, and cesarean delivery resulting from uterine hyperstimulation. The risk of uterine rupture increases with advancing gestational age, prior uterine surgery (including cesarean delivery), and grand multiparity; the American College of Obstetricians and Gynecologists (ACOG) states that intravaginal use of misoprostol for cervical ripening or labor induction is not recommended in patients with a previous cesarean delivery or prior major uterine surgery.

Ruptured ectopic pregnancy (which rarely results in fatal hemorrhage); serious, rarely fatal, bacterial (e.g., Clostridium sordellii) infection and sepsis; or myocardial infarction has been reported in a limited number of patients receiving mifepristone and intravaginal misoprostol for termination of pregnancy; a causal relationship to the regimen has not been established.

Congenital abnormalities, sometimes associated with fetal death, have been reported subsequent to the unsuccessful use of misoprostol as an abortifacient. Some data indicate that use of misoprostol during the first trimester of pregnancy has been associated with skull defects, cranial nerve palsies, facial malformations, and limb defects; however, the precise mechanism(s) for these teratogenic effects has not been fully elucidated. Effects of misoprostol on later growth, development, and functional maturation of the child whose mother received the drug for cervical ripening or labor induction have not been established. The effects of misoprostol on the need for forceps delivery or other intervention are not known.

Currently, it is recommended that misoprostol be used for reducing the risk of NSAIA-induced gastric ulcers in women of childbearing potential only if they are at high risk of complications resulting from NSAIA-induced gastric ulceration or are at high risk of developing gastric ulceration. Such therapy should be initiated in such women only after determining that they are reliable and able to comply with effective contraceptive measures and ensuring that they have received both oral and written warnings concerning the hazards associated with misoprostol therapy, the risk of possible contraceptive failure, and the danger to other women of childbearing potential should the drug be taken by them. In addition, a reliable, blood pregnancy test must be performed within 2 weeks prior to beginning misoprostol therapy and the drug should not be provided to the patient until the pregnancy test is reported as negative, initiating therapy on the second or third day of the next normal menstrual cycle.

If misoprostol is inadvertently administered during pregnancy or if the patient becomes pregnant while receiving the drug for reducing the risk of NSAIA-induced gastric ulcer, misoprostol should be discontinued and the patient informed of the potential hazard to the fetus.

Reproduction studies in rats and rabbits using oral misoprostol dosages up to 10 and 1 mg/kg (625 and 63 times the usual human dosage), respectively, have not revealed evidence of fetotoxicity or teratogenicity. However, increased fetal resorption occurred in rabbits, suggesting possible embryotoxicity.

Fertility

Reproduction studies in male and female rats using oral misoprostol dosages of 0.1-10 mg/kg daily (6.25-625 times the usual human dosage) have revealed dose-related pre- and post-implantation losses and a decrease in the number of live offspring at the highest dosage administered. These effects suggest that the drug may impair fertility in both males and females.

Lactation

It is not known whether misoprostol and/or misoprostol acid cross the placenta or are distributed into milk in humans, but such distribution of unchanged misoprostol is unlikely since the drug is metabolized rapidly to the free acid following oral administration. Because it is not known whether misoprostol acid is distributed into milk, the manufacturer recommends that misoprostol not be used in nursing women since breast-fed infants could develop clinically important diarrhea if the free acid did distribute into milk.

Drug Interactions

Food and Antacids

Food and antacids decrease the rate of absorption of misoprostol, resulting in delayed and decreased peak plasma concentrations of misoprostol acid, the active metabolite of the drug. Antacids and possibly food also appear to decrease the oral bioavailability of misoprostol; however, it has been suggested that such decreases may not be clinically important since misoprostol's activity in protecting the GI mucosa appears to be local rather than systemic.(See Pharmacokinetics: Absorption.) Magnesium-containing antacids also may increase the incidence of misoprostol-induced diarrhea. Therefore, if concomitant administration of an antacid is necessary, a magnesium-containing or other laxative antacid should be avoided and a constipating (e.g., aluminum-containing) antacid used instead.

Effects on Hepatic Clearance of Drugs

Misoprostol does not appear to interfere with the metabolism of drugs, including diazepam or propranolol, by the hepatic cytochrome P-450 (microsomal) enzyme system. While some alteration in plasma propranolol concentrations was reported in a study in a limited number of healthy adults, a subsequent study failed to confirm these findings. Metabolism of aminopyrine or antipyrine and half-life and/or AUCs of the drugs do not appear to be affected substantially by misoprostol.

Nonsteroidal Anti-inflammatory Agents

No substantial pharmacokinetic interactions between misoprostol and ibuprofen, piroxicam, or diclofenac have been observed to date.

Absorption or peak plasma concentrations of misoprostol or aspirin do not appear to be affected substantially by concomitant administration, although AUCs of aspirin may be decreased by about 20% when the drugs are administered concomitantly. This interaction does not appear to be clinically important since misoprostol did not interfere with the efficacy of aspirin as determined by relief of pain and stiffness, reduction of swelling, improvement of mobility and grip strength, or erythrocyte sedimentation rate (ESR) in patients with rheumatoid arthritis who received usual dosages of the drugs concomitantly.

In a study in a limited number of healthy individuals receiving oral indomethacin 75 mg twice daily concomitantly with oral misoprostol 400 mcg twice daily, steady-state plasma indomethacin concentrations reportedly were decreased by 20-60%. However, reanalysis of data from this study using different statistical methods suggested that oral bioavailability of indomethacin was not affected substantially by concomitant misoprostol. Further studies are needed to determine whether a potential pharmacokinetic interaction exists between the drugs.

Other Drugs

In animals, misoprostol has been effective in reversing cyclosporine-induced nephrotoxicity. Misoprostol increased GFR, urinary flow rate, renal blood flow, sodium excretion, and urinary osmolarity and decreased renal vascular resistance in such animals. The drug had little effect on renal function and renal hemodynamics in animals not treated with cyclosporine. There is preliminary evidence that misoprostol may have similar beneficial renal effects in cyclosporine-treated patients, but additional study and experience are needed.

Pharmacokinetics

Absorption

Misoprostol is rapidly and almost completely absorbed from the GI tract; however, the drug undergoes extensive and rapid first-pass metabolism (de-esterification) to form misoprostol acid (the free acid), the principal and active metabolite of the drug. There is evidence from animal studies that such metabolism may occur at least in part in the GI tract (e.g., in parietal cells). An average of 88% of a dose of misoprostol reportedly is absorbed following oral administration in healthy individuals, but only negligible amounts of unchanged drug are attained in plasma. The rate and extent of absorption of misoprostol tablets reportedly are similar to those of an oral solution of the drug (not commercially available in the US).

Food and antacids decrease the rate of absorption of misoprostol, resulting in delayed and decreased peak plasma concentrations of misoprostol acid. Following oral administration of single 400-mcg doses of misoprostol, average peak plasma misoprostol acid concentrations of approximately 810 pg/mL occur within about 14 minutes in the fasted state compared with approximately 690 pg/mL within about 20 minutes when the drug is taken with antacids and approximately 300 pg/mL within about 1 hour when taken with food. The extent of absorption also appears to be decreased by antacids and possibly by food, but it has been suggested that such decreases may not be clinically important since the GI effects of misoprostol appear to be local rather than systemic.

There is considerable interindividual variation in plasma concentrations attained with a given dose of misoprostol; however, it appears that plasma concentrations of the free acid increase linearly with single misoprostol doses of 200-400 mcg. Following oral administration of a single 200- or 400-mcg dose of misoprostol in fasting, healthy individuals, average peak plasma misoprostol acid concentrations of approximately 310-400 or 500-1020 pg/mL, respectively, occur within 14-20 minutes. However, substantially higher plasma concentrations have been reported using a thin-layer radiochromatographic assay rather than a radioimmunoassay.

Steady-state plasma concentrations of misoprostol acid generally are reached within 48 hours following continuous dosing and average about 690 pg/mL with misoprostol dosages of 400 mcg every 12 hours. Accumulation of misoprostol acid does not appear to occur during chronic administration of misoprostol.

Peak plasma misoprostol acid concentrations and areas under the plasma concentration-time curves (AUCs) in patients with renal impairment (creatinine clearance of 0.5-37 mL/minute) were about twofold those observed in patients with normal renal function; however, no clear correlation was established between AUCs achieved and degree of renal impairment. AUCs of misoprostol acid also may be increased in geriatric patients (older than 64 years of age) compared with those in younger adults, probably secondary to decreased volume of distribution (Vd) in geriatric patients; however, peak plasma concentrations do not appear to be affected.

Following single 50- to 200-mcg oral doses of misoprostol, inhibition of gastric acid secretion under basal and nocturnal conditions and also when stimulated by food, histamine, pentagastrin, or caffeine is apparent within 30 minutes, reaches a maximum within 60-90 minutes, and persists for at least 3 hours. The degree and duration of inhibition of gastric acid secretion produced by misoprostol are directly related to the dose with single misoprostol doses of 200-400 mcg. It appears that misoprostol doses exceeding 400 mcg do not produce further increases in inhibition of gastric acid secretion. In animals, doses smaller than those necessary for inhibition of gastric acid secretion have provided protection of the gastric mucosa. In humans, however, a relationship between dose and mucosal protective activity has not been established since therapeutic effects (e.g., prevention of injury) on the gastroduodenal mucosa have been observed principally with antisecretory doses.

Distribution

Distribution of misoprostol into human body tissues and fluids has not been fully characterized. Following oral administration of misoprostol in rats, the drug is widely distributed, achieving concentrations in stomach, intestines, liver, blood, and kidneys that are 6-73 times that in plasma.

Misoprostol acid is approximately 80-90% bound to serum proteins. Protein binding of the drug does not appear to be affected by plasma concentrations of misoprostol acid or misoprostol in the therapeutic range, age of the patient, or concomitant administration of other highly protein-bound drugs.

It is not known whether misoprostol and/or the free acid cross the placenta or are distributed into milk. However, because of rapid metabolism to misoprostol acid following oral administration of the drug, it is unlikely that unchanged misoprostol is distributed into milk.

Elimination

Misoprostol is rapidly metabolized to misoprostol acid (the free acid) following oral administration. The parent drug reportedly has a half-life of 6 minutes in vitro. Plasma concentrations of the free acid and other metabolites of the drug appear to decline in a biphasic manner. Following oral administration of misoprostol in healthy adults, the elimination half-life of the free acid is about 20-40 minutes. Following oral administration of radiolabeled drug in healthy adults, the half-life of misoprostol metabolites averages about 1.5 hours in the initial distribution phase, corresponding principally to organic metabolites of the drug, and about 144-177 hours in the terminal elimination phase, corresponding principally to radiolabeled water.

In patients with renal impairment (creatinine clearance of 0.5-37 mL/minute), half-life may be increased twofold compared with that in patients with normal renal function. It appears that half-life of misoprostol is not increased in geriatric patients.

The exact metabolic fate of misoprostol has not been clearly established, but the drug is rapidly and extensively metabolized, principally via de-esterification to form misoprostol acid, which is pharmacologically active. Animal evidence suggests that de-esterification of the drug may occur at least in part in the GI tract (e.g., in parietal cells). Misoprostol acid undergoes extensive, rapid β-oxidation of the α side chain to form the tetranor metabolite of misoprostol acid, and omega-oxidation of the β side chain with subsequent ketone reduction to form prostaglandin F analogs. Studies in animals indicate that misoprostol acid is approximately as potent as misoprostol in inhibiting gastric acid secretion; the dinor and tetranor metabolites of misoprostol acid appear to be pharmacologically inactive.

Following oral or IV administration of misoprostol, the free acid and other metabolites of the drug are excreted mainly in urine; smaller amounts of metabolites are excreted in feces, probably via biliary elimination. Only negligible amounts of unchanged drug are excreted in urine following oral or IV administration. Following a single oral 200-mcg dose of misoprostol in healthy adults, about 73% of the dose is excreted in urine and about 15% in feces within 7 days; most urinary excretion occurs within 8-24 hours. The principal urinary metabolites are the dinor and tetranor of misoprostol acid. In healthy adults, less than 1% of a single oral dose of misoprostol is excreted in urine as unchanged drug and misoprostol acid. Approximately 5% of a single oral dose is excreted in feces within 24 hours as the dinor and tetranor of misoprostol acid.

Write Your Own Review
You're reviewing:MISOPROSTOL 200 MCG TABLET
Your Rating