Misoprostol

Light yellow oil

Viscous liquid

1.6mg/mL

Water-soluble

1.64e-02 g/L

Breast Feeding; Lactation; Milk, Human; Abortifacient Agents, Nonsteroidal; Anti-Ulcer Agents; Prostaglandins; Oxytocics; Gastrointestinal Agents

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Medicines for medical abortion

Danger

H301 (100%): Toxic if swallowed [Danger Acute toxicity, oral]

P203, P264, P270, P280, P301+P316, P318, P321, P330, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 40 reports by companies from 3 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

Concurrent use /of magnesium-containing antacids/ with misoprostol may aggravate misoprostol induced diarrhea.

This study aimed to investigate the effect of acetaminophen on the hepatic microvasculature using a vascular casting technique. Acetaminophen was admin at a dose of 650 mg/kg body weight (ip) to fasted male Long Evans rats. Microvascular casting was performed at various points after drug admin. Liver casts from control rats showed good patency with normal hepatic microvasculature. Thirty-six hr after overdose with acetaminophen, liver casts showed rounded centrilobular cavities of various sizes, representing regions in which cast-filled sinusoids were absent with relatively normal microvasculature within periportal regions. Evidence of microvascular injury occurred as early as 5 hr after acetaminophen overdose. This injury consisted of changes to centrilobular sinusoids inc areas of incomplete filling and dilated centrilobular sinusoids. Misoprostol ... treatment (6 x 25 ug/kg) given before and after acetaminophen admin markedly reduced the extent of microvascular injury with only small focal unfilled areas in the casts and a generally intact microvasculature. In conclusion, this study shows that overdosage with acetaminophen resulted in an extensive, characteristic pattern of hepatic microvascular injury in the centrilobular region. The results also suggest that microvascular injury is an early event in the pathogenesis of acetaminophen hepatotoxicity. Misoprostol was found to protect against injury occurring at the microvascular level.

Cyclosporin A has markedly improved graft survival in transplant patients but its side effects, such as renal toxicity and hypertension, pose management problems in transplant recipients. This toxicity has been attributed to prostaglandin inhibition. Concurrent admin of misoprostol ... prevents chronic cyclosporin A-induced nephrotoxicity but not hypertension in rats.

The effects of misoprostol on indomethacin-induced decline in renal function were studied in 6 normotensive and 6 hypertensive female patients (mean age 60.5 yr) who were given 25 mg of indomethacin every 6 hr for 3 days, 200 ug of misoprostol every 6 hr for 3 days, and both together for 3 days, with a 4 day washout period between treatments. All patients received a salt-restricted diet, and the hypertensive patients were treated with hydrochlorothiazide. Three of the hypertensive patients and 3 of the normotensive patients had a decr in glomerular filtration rate (GFR) assoc with indomethacin therapy. when misoprostol was given with the indomethacin, 4 of these 6 patients did not experience a decline in GFR. It in concluded that misoprostol ameliorates indomethacin-induced renal dysfunction in salt-restricted and diuretic-treated middle aged women with normal serum creatinine.

Misoprostol ... was given simultaneously with acetylsalicylic acid in a double-blind, placebo-controlled randomized prospective study of 32 healthy human male subjects. Fecal blood loss was measured for 8 days ... Aspirin (650 mg qid) and misoprostol (25 ug qid) or placebo were given during days 3, 4, and 5. there was a significant (P < 0.05) incr in median blood loss ... from 0.81 to 6.05 ml/day in the aspirin with placebo group (n=16). Median blood loss was incr (from 0.75 to 3.75 ml/day)in the aspirin with misoprostol group (n=16), but this was significantly less ... than the placebo group. Mean serum salicylate concn in the placebo and misoprostol groups were similar (7.8 and 6.8 ug/ml, respectively). There were no significant changes in laboratory values in any of the subjects studied, nor were any major side-effects encountered. This study demonstrates that oral misoprostol reduced aspirin-induced GI bleeding even when admin simultaneously and at a dose level below its threshold for significant acid inhibition. This indicates a potential role for misoprostol in the prevention of gastric mucosal damage in selected patients.

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

Misoprostol is generally safe and well-tolerated at standard doses of 400 to 800 mcg.However, a rare case of maternal death has been reported following a misoprostol overdose. A self-administered overdose of 12 mg for a medical abortion resulted in upper gastrointestinal bleeding, hemodynamic instability, and multiorgan failure. Emergency laparotomy revealed gastric and esophageal necrosis, and the patient ultimately succumbed to cardiac arrest despite adequate resuscitation efforts.

Misoprostol should not be used in pregnant women or women of childbearing age. In one clinical trial, bleeding occurred in about 50% of pregnant women in the first trimester, and complete or incomplete abortion was induced in 7%. Misoprostol is classified in FDA Pregnancy Category X.

Minor adverse effects include mild nausea, abdominal discomfort, dizziness, and headache; diarrhea has occurred in 14% to 40% of patients.

Following acute misoprostol overdose, sedation, tremor, seizures, dyspnea, abdominal pain, diarrhea, fever, palpitation, hypotension, or bradycardia may occur.

The efficacy and tolerability of mifepristone in combo with misoprostol for termination of early pregnancy (up to 49 days of amenorrhea) are established. We studied the efficacy and tolerability of this combo therapy for termination of pregnancy in women up to 63 days of amenorrhea. We also examined the effect of an additional dose of misoprostol in cases of nonexpulsion within 3 hr after the first dose. The multicenter trial included 1,108 women, mean age 27.9 + or - 6.2 yr. The mean duration of pregnancy was 51.7 + or - 9.2 days. On day 1, the women received an po dose of mifepristone, 600 mg. On day 3, they received an oral dose of misoprostol, 400 ug, and were monitored for up to 3 hr. If they did not expel the conceptus within 3 hr, an additional dose of 200 ug of misoprostol was given and they were monitored for 2 more hours. From days 10-18, the women were followed up with clinical exam, human chorionic gonadotropin measurement, or ultrasound exam. overall, the procedure was successful in 92.9% of women. Efficacy decr with the duration of pregnancy, esp after 56 days of amenorrhea. Up to 42 days of amenorrhea, the success rate was 97.6%; between days 42 and 49, 94.8%; between days 50 and 56, 93.4%; between days 57 and 63, 86.8%; and after day 63, 83.3%. The most common side effects were moderate uterine cramps (80.5) and GI symptoms (34.9), esp vomiting (18.3) and diarrhea (10.5). GI symptoms were generally mild. A second dose of misoprostol was given to 61.6% of the women. In a subgroup analysis, we assessed the efficacy of 600 mg of mifepristone plus 400 or 600 ug of misoprostol (one or two doses) in women with up to 49 days of amenorrhea and compared it with the efficacy in women who received mifepristone plus only 400 ug (one dose) of misoprostol in a previous study. The overall rate of success (termination of pregnancy) was 95.5% in the current study compared with 95.$ in the previous study. The additional dose of misoprostol did not significantly incr the overall rate of success, but did incr the rate of termination within the monitoring period (69.7% versus 64.9% (and within 72 hours after admin of mifepristone (92.7% versus 90.4%). We have confirmed that the combo of mifepristone and misoprostol was effective, safe, and well tolerated for termination of pregnancies at 49 or fewer days of amenorrhea. The efficacy decr slightly between 49 and 56 days, and then decr significantly between 56 and 62 days.

For more Human Toxicity Excerpts (Complete) data for MISOPROSTOL (8 total), please visit the HSDB record page.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Misoprostol

Ambiguous-DILI-concern

3

Adverse reactions

DOI:10.1016/j.drudis.2016.02.015

In animals, overdosage of misoprostol produces diarrhea, GI lesions, emesis, tremors, mydriasis, focal cardiac necrosis, hepatic necrosis, renal tubular necrosis, testicular atrophy, hypertrophy of mucous cells, deepening of gastric pits, respiratory difficulties, reduced motor activity, and CNS depression.

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 gastric mucosa was observed in dogs receiving oral misoprostol dosages of 300 ug/kg daily for 13 weeks.

Prostaglandins appeared protective against acute experimental liver injury of different origin. Misoprostol, stable, orally active, synthetic derivative of PGE1 attenuates several functional alterations in liver mitochondria during ethanol admin. To study its possible hepatoprotective effects on ethanol-induced liver injury in rats we measured: serum activities of alanine aminotransferase (ALT), gamma-glutamyltranspeptidase (GGT) and concn of ammonia in blood and liver tissue. Histopathological evaluation of liver slices was also performed. Activities of both enzymes and ammonia values were elevated after intragastric ethanol admin for 60 days. Treatment for 30 days with misoprostol resulted in their decr. This effect was not observed in the control group. Beneficial results were also obtained in histopathological evaluation of the liver tissue. These results indicate potential therapeutic effects of misoprostol on ethanol-induced liver injury in rats.

The radioprotective nature of misoprostol was extended to examine its ability to influence clonogenic cell survival and induction of oncogenic transformation in Syrian hamster embryo cells exposed to X rays in utero and assayed in vitro. Hamsters in their 12th day of pregnancy were injected sc with misoprostol, and 2 hr later the pregnant hamsters were exposed to graded doses of X rays. Immediately after irradiation, hamsters were euthanized and embryonic tissue was explanted into culture dishes containing complete growth medium. After a 2-wk incubation period, clonogenic cell survival and morphologically transformed foci were determined. Survival of misoprostol-treated SHE cells were incr and yielded a dose reduction factor of 1.5 compared to SHE cells treated with X rays alone. In contrast, radiation-induced oncogenic transformation of misoprostol-treated cells was reduced by a factor of 20 compared to cells treated with X rays alone. These studies suggest that misoprostol not only protects normal tissues in vivo from acute radiation injury, but also protects cells, to a large extent, from injury leading to transforming events.

◉ Summary of Use during Lactation

◈ What is misoprostol?

LD50 Rat oral 81-100 mg/kg

LD50 Mouse oral 27-138 mg/kg

LD50 Rat ip 40-62 mg/kg

LD50 Mouse ip 70-160 mg/kg

Misoprostol

0.009

0.04

The recommended adult oral dose of misoprostol for reducing the risk of NSAID-induced gastric ulcers is 200 ug four times daily with food. If this dose cannot be tolerated, a dose of 100 ug can be used.

Data used to generate the benchmarks include the following: Lowest Daily Dose (LDD): 0.4 mg/day, Lowest Therapeutic Dose (LTD): 0.005 mg/kg-day, and Screening Dose: 0.0000017 mg/kg-day.

4-Jun-19

Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).

A02BB01

G - Genito urinary system and sex hormones

A - Alimentary tract and metabolism

QA - Alimentary tract and metabolism

QG - Genito urinary system and sex hormones

G02AD06

Misoprostol is a prostaglandin E1 analog used to reduce the risk of NSAID induced gastric ulcers by reducing secretion of gastric acid from parietal cells. Misoprostol is also used to manage miscarriages and used alone or in combination with mifepristone for first trimester abortions. An oral dose of misoprostol has an 8 minute onset of action and a duration of action of approximately 2 hours, a sublingual dose has an 11 minute onset of action and a duration of action of approximately 3 hours, a vaginal dose has a 20 minute onset of action and a duration of action of approximately 4 hours, and a rectal dose has a 100 minute onset of action and a duration of action of approximately 4 hours.

Misoprostol is a synthetic prostaglandin E1 analog that stimulates prostaglandin E1 receptors on parietal cells in the stomach to reduce gastric acid secretion. Mucus and bicarbonate secretion are also increased along with thickening of the mucosal bilayer so the mucosa can generate new cells. Misoprostol binds to smooth muscle cells in the uterine lining to increase the strength and frequency of contractions as well as degrade collagen and reduce cervical tone.

Misoprostol enhances natural gastromucosal defense mechanisms and healing in acid-related disorders, probably by increasing production of gastric mucus and mucosal secretion of bicarbonate.

Misoprostol inhibits basal and nocturnal gastric acid secretion by direct action on the parietal cells; also inhibits gastric acid secretion stimulated by food, histamine, and pentagastrin. It decreases pepsin secretion under basal, but not histamine stimulation. Misoprostol has no significant effect on fasting or postprandial gastrin or intrinsic factor output.

The half life of an 800µg oral dose is 1.0401±0.5090h, for a sublingual dose is 0.8542±0.1170h, and for a buccal dose is 0.8365±0.1346h.

Terminal - 20-40 minutes

Misoprostol is de-esterified to its active metabolite, misoprostol acid, also known as SC-30695. This metabolite is further reduced to dinor and tetranor metabolites (SC-41411), a prostaglandin F₁ (PGF₁) analog of SC-41411, and a ω-16-carboxylic acid derivative. However, the majority of these metabolites are not well described in the literature.

Rapidly de-esterified to misoprostol acid (primary biologically active metabolite). The de-esterified metabolite undergoes further metabolism by beta and omega oxidation, which can take place in various tissues in the body.

0E43V0BB57

MISOPROSTOL

Established Pharmacologic Class [EPC] - Prostaglandin E1 Analog

Chemical Structure [CS] - Prostaglandins E, Synthetic

Misoprostol is a Prostaglandin E1 Analog.

MISOPROSTOL

Non-steroidal chemical compounds with abortifacient activity.

Various agents with different action mechanisms used to treat or ameliorate PEPTIC ULCER or irritation of the gastrointestinal tract. This has included ANTIBIOTICS to treat HELICOBACTER INFECTIONS; HISTAMINE H2 ANTAGONISTS to reduce GASTRIC ACID secretion; and ANTACIDS for symptomatic relief.

Drugs that stimulate contraction of the myometrium. They are used to induce LABOR, OBSTETRIC at term, to prevent or control postpartum or postabortion hemorrhage, and to assess fetal status in high risk pregnancies. They may also be used alone or with other drugs to induce abortions (ABORTIFACIENTS). Oxytocics used clinically include the neurohypophyseal hormone OXYTOCIN and certain prostaglandins and ergot alkaloids. (From AMA Drug Evaluations, 1994, p1157)

For an 800µg oral dose of misoprostol, the AUC was 2.0192±0.8032h\*ng/mL, the Cmax was 2.6830±1.2161ng/mL, and a tmax of 0.345±0.186h. For a 800µg sublingual dose of misoprostol, the AUC was 3.2094±1.0417h\*ng/mL, the Cmax was 2.4391±1.1567ng/mL, and a tmax of 0.712±0.415h. For a 800µg buccal dose of misoprostol, the AUC was 2.0726±0.3578h\*ng/mL, the Cmax was 1.3611±0.3436ng/mL, and a tmax of 1.308±0.624h.

As much as 73.2±4.6% of a radiolabelled oral dose of misoprostol is recovered in the urine.

Data regarding the volume of distribution of misoprostol is scarce. The apparent volume of distribution of the active metabolite of misoprostol was in subjects with normal renal function was 13.6±8.0L/kg, with mild renal impairment was 17.3±23.0L/kg, with moderate renal impairment was 14.3±6.8L/kg, and with end stage renal disease was 11.0±9.6L/kg.

Because of the rapid de-esterification of misoprostol before or during absorption, it is usually undetectable in plasma. Misoprostol's active metabolite, misoprostol acid, has a total body clearance of 0.286L/kg/min. Subjects with mild renal impairment had a total body clearance of 0.226±0.073L/kg/min, subjects with moderate renal impairment had a total body clearance of 0.270±0.103L/kg/min, and subjects with end stage renal disease had a total body clearance of 0.105±0.052L/kg/min.

Rapidly absorbed following oral administration.

Elimination: Renal (64 to 73% of the oral dose excreted within the first 24 hours). Fecal (15% of the oral dose).

Anti-ulcerative

Use (kg) in USA (2002): 14

Misoprostol contains approximately equal amounts of the two diastereomers

Cytotec oral tablets contain either 100 mcg or 200 mcg of misoprostol