Cytotec

Prostaglandin Antiulcerants

Hazardous Drugs Classification
NIOSH 2016 List: Group 3
NIOSH (Draft) 2020 List: Table 2
Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
ORAL TABLETS/CAPSULES/ORAL LIQUID: Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure and require additional protective equipment. Oral liquid drugs require double chemotherapy gloves and protective gown. Eye/face and respiratory protection may be needed during preparation and administration.
TOPICAL: Use double chemotherapy gloves and protective gown. Eye/face and respiratory protection may be needed during preparation and administration.

Administer tablets orally with meals and at bedtime with food.

NOTE: Misoprostol is not approved by the FDA for sublingual administration.
Sublingual administration for gynecologic and obstetric-related indications (Not FDA-approved):
Consult suggested guidelines for use, dosage and monitoring.
Administer under the supervision of a qualified health care professional with expertise in the field.
Place the required amount of misoprostol tablets for the dose under the tongue.
Frequent examinations should be performed.
Continually monitor maternal vital signs, fetal heart rate or fetal distress, and uterine contractions using established methods and as clinically recommended for the off-label indication for use. Be alert for signs and symptoms or tetanic uterine contractions/uterine hyperstimulation.
Sublingual Administration for misoprostol-only protocol for pregnancy termination (Not FDA-approved):
For each dose, place the required amount of misoprostol tablets for the dose under the tongue and leave them there for 30 minutes; have patient swallow any remnants with water.

NOTE: Misoprostol is not approved by the FDA for vaginal administration.
Vaginal administration for gynecologic and obstetric-related indications (Not FDA-approved):
Consult suggested guidelines for use, dosage and monitoring.
Administration of misoprostol for obstetric use should be done under the supervision of a qualified health care professional with expertise in the field.
Misoprostol tablets have been cut and administered vaginally via digital placement in the posterior vaginal fornix; administer with sterile gloves.
Extemporaneous formulations (e.g., vaginal gels or suppositories) have also been used.
Frequent examinations should be performed.
Continually monitor maternal vital signs, fetal heart rate or fetal distress, and uterine contractions using established methods and as clinically recommended for the off-label indication for use. Be alert for signs and symptoms or tetanic uterine contractions/uterine hyperstimulation.
Vaginal administration for misoprostol-only protocol for pregnancy termination (Not FDA-approved):
For each dose, the patient should moisten the appropriate number of misoprostol tablets for the dose each with a few drops of water before insertion and then place the misoprostol tablets as high up into the vagina as they can reach.
Patient should stay lying down for 30 minutes.
It is okay if pieces of the tablets come out after insertion; pieces of the tablets may remain in the vagina for days.

NOTE: Misoprostol is not approved by the FDA for rectal administration.
Rectal administration has been used as an alternate route for gynecologic and obstetric uses, but is not a preferred route due to inconsistent results. Follow the suggested guidelines for off-label use.
Administer under the supervision of a qualified health care professional with expertise in the field.
Misoprostol tablets have been cut and administered rectally; administer with proper gloving.
Frequent examinations should be performed.
Continually monitor maternal vital signs, fetal heart rate or fetal distress, and uterine contractions using established methods and as clinically recommended for the off-label indication for use. Be alert for signs and symptoms or tetanic uterine contractions/uterine hyperstimulation.

teratogenesis / Delayed / Incidence not known
uterine rupture / Early / Incidence not known
cervical laceration / Early / Incidence not known
fetal death / Delayed / Incidence not known
myocardial infarction / Delayed / Incidence not known
pulmonary embolism / Delayed / Incidence not known
stroke / Early / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known
thrombosis / Delayed / Incidence not known

hyperthermia / Delayed / 30.0-40.0
constipation / Delayed / 1.1-1.1
sinus tachycardia / Rapid / Incidence not known
fetal bradycardia / Delayed / Incidence not known
uterine contractions / Early / Incidence not known
uterine pain / Early / Incidence not known
vaginal bleeding / Delayed / Incidence not known
hypotension / Rapid / Incidence not known
chest pain (unspecified) / Early / Incidence not known
edema / Delayed / Incidence not known
phlebitis / Rapid / Incidence not known
hypertension / Early / Incidence not known

diarrhea / Early / 14.0-40.0
chills / Rapid / 30.0-40.0
shivering / Rapid / 30.0-40.0
abdominal pain / Early / 7.0-20.0
nausea / Early / 3.2-3.2
vomiting / Early / 3.2-3.2
flatulence / Early / 2.9-2.9
headache / Early / 2.4-2.4
dyspepsia / Early / 2.0-2.0
breakthrough bleeding / Delayed / 0.7-0.7
menstrual irregularity / Delayed / 0.3-0.3
dysmenorrhea / Delayed / 0.1-0.1
vertigo / Early / Incidence not known
lethargy / Early / Incidence not known
infection / Delayed / Incidence not known
weakness / Early / Incidence not known
syncope / Early / Incidence not known
agitation / Early / Incidence not known
leukocytosis / Delayed / Incidence not known
fever / Early / Incidence not known
pelvic pain / Delayed / Incidence not known
diaphoresis / Early / Incidence not known
rash / Early / Incidence not known

Misoprostol is contraindicated during pregnancy for use to reduce the risk of stomach ulcers associated with NSAIDs (the FDA-approved indication). This agent causes reproductive risk, including uterine contractions, miscarriage, and other problems if administered during pregnancy. Drug-induced miscarriages may be result in incomplete abortion, necessitating hospitalization or surgery. Although misoprostol is contraindicated in pregnancy due to its stimulatory effects on uterine contractility, it appears teratogenesis is also a possibility with this drug. Several reports in the literature associate the use of this drug during the first trimester with skull defects, cranial nerve palsies, facial malformations, and limb defects. Misoprostol should be promptly discontinued if pregnancy occurs during treatment with this agent for the approved indication. Misoprostol should not be used for reducing the risk of NSAID-induced ulcers in females 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 1) exhibits a negative serum pregnancy testing within 2 weeks of initiating therapy, 2) follows contraception requirements, using effective and reliable birth control during misoprostol use, 3) receives both oral and written warnings on the potential hazards, and 4) initiates therapy only on the second or third day of the next normal menstrual period. The manufacturer does not contraindicate the use of misoprostol during or following labor and obstetric delivery for off-label uses and recognizes these off-label uses within the special populations information of the label. Misoprostol is widely used off-label in obstetric practice as a cervical ripening agent to induce labor, for term obstetric delivery, for treatment of serious postpartum hemorrhage in the presence of uterine atony, and as part of the FDA-approved regimen for use with mifepristone (RU-486) for termination of pregnancy of 49 days or less. The mifepristone-misoprostol regimen is not effective for treating ectopic pregnancy. Guidelines on the use of misoprostol for obstetric indications, including vaginal administration, have been published. Off-label administration of misoprostol during labor and obstetric delivery for term pregnancy or for labor induction following fetal demise should proceed with caution. Do not use misoprostol or other methods of cervical ripening or labor induction in term pregnancy if contraindications to the induction of labor exist, such as umbilical cord prolapse, active genital herpes infection, vasa previa or complete placenta previa, or if unexplained vaginal bleeding is present during the current pregnancy. Do not use if there are ominous fetal heart rate tracings (acute fetal distress) or abnormal fetal position (e.g., transverse fetal lie). Avoid use of misoprostol in the third trimester in patients with previous caesarean section or uterine surgery because of the increased risk for uterine rupture and other adverse effects; women with multiple gestation (eminent or grand multiparity) or women who have had 6 or more previous pregnancies are also be at increased risk and may not be appropriate candidates for labor induction with prostaglandin analogs. Using a higher dosage of misoprostol than recommended in term pregnancies increases the risk of maternal adverse events. Protocols for labor induction following fetal demise use larger misoprostol doses than those used in term pregnancies, and an increased incidence of maternal adverse effects has not been noted in these cases. As indicated by the clinical situation, monitor maternal vital signs, fetal heart rate (FHR), signs of fetal distress, and uterine contractions. Be alert for signs and symptoms of tetanic uterine contractions/uterine hyperstimulation. Serious adverse events have been reported following off-label use of misoprostol in pregnant women. The manufacturer of misoprostol has not conducted controlled studies of the drug for cervical ripening or labor induction. In addition to the known and unknown acute risks to the mother and fetus, the effect of misoprostol on the later growth, development and functional maturation of the child when the drug is used for induction of labor or cervical ripening has not been established. Information on misoprostol's effect on the need for forceps delivery or other intervention is unknown.

Cytotec

Rx

Synthetic, oral prostaglandin E1 (PGE1) analog approved for prevention of gastric ulcers secondary to use of nonsteroidal antiinflammatory drugs (NSAIDs); taken for the duration of NSAID therapy
Boxed warning regarding the abortifacient effects and reproductive risk; females of childbearing age must use adequate contraception with oral product use for NSAID-induced ulcer prevention
Used off-label in obstetrics for cervical ripening and labor induction; also a recognized component of the FDA-approved mifepristone-regimen for termination of early pregnancy

200 mcg PO 4 times daily, with meals and at bedtime. May reduce to 100 mcg PO four times daily in those who do not tolerate 200 mcg dose. A dosage of 50 to 100 mcg PO four times daily was as effective as the 200 mcg PO regimen in the prevention of gastric injury, and, for prevention of duodenal injury, doses of 100 mcg PO four times daily were equivalent to 200 mcg PO four times daily. In a 12-week, double-blind, placebo-controlled study of arthritis patients receiving NSAIDs, the protective effect of misoprostol appeared to be dose-related and plateaued between 200 mcg PO two to three times per day. The authors concluded that lower doses (e.g., 200 mcg PO either two or three times per day) be considered for prophylaxis of either gastric or duodenal ulcerations. Continue for the duration of NSAID therapy.

A dose of 100—200 mcg PO four times per day, with meals and at bedtime for 4—8 weeks or until healing occurs; however, the use of misoprostol for the treatment of peptic ulcer unrelated to NSAIDs is controversial. Misoprostol in doses of 200 mcg PO four times per day has been effective for both gastric and duodenal ulcer but the efficacy is roughly equivalent to H2-receptor antagonists. Because adverse reactions are greater with misoprostol than with H2-antagonists, misoprostol is considered a second-line agent.

Misoprostol 200 mcg PO four times per day for the first 12 weeks after transplantation was utilized in one study. The number of patients experiencing acute rejection was significantly lower in the misoprostol group (26% vs 51%). Although it was not statistically significant, the number of patients who developed cyclosporine nephrotoxicity was higher in the misoprostol group.

On day 1, administer one 200 mg mifepristone tablet PO as a single dose. Between 24 to 48 hours later, administer misoprostol 800 mcg buccally; the patient should place two 200 mcg misoprostol tablets in each cheek pouch for 30 minutes and then swallow any remnants with water or another liquid. The duration of pregnancy may be determined from menstrual history and clinical examination. If the duration of pregnancy is uncertain or ectopic pregnancy is suspected, assess by ultrasonographic scan. Intrauterine devices (IUDs) should be removed prior to mifepristone treatment. Discuss an appropriate location for the patient to be when she takes misoprostol; expulsion could begin within 2 hours of administration, and typically occurs within 24 hours. Patients should be given emergency contact numbers for healthcare providers and instructed what to do if significant discomfort, excessive bleeding, or other adverse events occur. Follow-up assessment to confirm complete pregnancy termination and evaluate bleeding should occur approximately 7 to 14 days after mifepristone administration. If complete expulsion has not occurred, but the pregnancy is not ongoing, women may be treated with another dose of misoprostol 800 mcg buccally; a follow-up visit approximately 7 days later should occur to assess for complete termination.

Consult specialized literature. In one study, 178 gravid adult women (of less than 63 days gestation) received methotrexate 50 mg/m2 IM as a single dose, followed by misoprostol 800 mcg vaginally 5 to 7 days later. Seven days after the first dose of misoprostol, patients were offered a second misoprostol dose or vacuum aspiration if there was evidence of a persistent gestational sac. Ninety-six percent of women had a successful medical abortion after the first or second dose of misoprostol. Seventy-six percent of women successfully aborted within 12 hours after insertion of misoprostol.

Consult specialized literature. A dose of 200 mcg (2 x 100 mcg tablets) inserted vaginally (placed into the posterior vaginal fornix) every 12 hours until successful abortion was used in one study of pregnant women between 12 and 22 weeks gestation who were undergoing termination of pregnancy for either intrauterine fetal death (n=37) or medical or genetic reasons (n=18). Approximately 89% of the second trimester patients receiving vaginal misoprostol aborted within 24 hours; all patients aborted within 38 hours.

Consult specialized literature. The following protocol is not FDA-approved but has been endorsed by the Society of Family Planning: 800 mcg sublingually or vaginally every 3 hours for at least 3 to 4 doses. Either route can be used for each dose. An additional dose should be provided in case of need. The patient should take the extra dose if no more than scant bleeding occurs, if the patient is not sure that the pregnancy has passed, or if instructed to do so by their clinician. Determine the duration of pregnancy from menstrual history and clinical examination. The patient should receive the patient instruction sheet, emergency contact numbers for health care providers, at least 1 high sensitivity pregnancy test, and other supportive medications that might be needed. A follow-up assessment to confirm complete pregnancy termination and evaluate bleeding should occur approximately 7 to 14 days after administration.

25 mcg intravaginally every 3 to 6 hours. 50 mcg intravaginally every 6 hours may be appropriate in some situations, although an increased risk of complications (e.g., uterine hyperstimulation and fetal heart rate changes) has been reported.

25 mcg PO every 2 hours. Vaginal administration produces greater clinical efficacy than the oral route; however, oral misoprostol use is associated with fewer abnormal fetal heart rate (FHR) patterns and episodes of uterine tachysystole with FHR deceleration when compared with vaginal administration. Oral use may result in fewer vaginal births within the first 24 hours vs. vaginal regimens; overall rates of vaginal birth appear similar.

200 to 400 mcg intravaginally every 4 to 12 hours in persons less than 28 weeks gestation with intrauterine fetal demise.

25 mcg PO every 2 hours.

600 mcg PO as a single dose. Oxytocin plus misoprostol appears to be no more effective than oxytocin used alone for prophylaxis of postpartum hemorrhage, so standard protocols (e.g., use of oxytocin administration, uterine massage, and umbilical cord traction) are recommended in persons at risk. If there is inadequate uterine response and ongoing postpartum hemorrhage, then various uterotonics, including misoprostol, may be given in rapid succession if there are no contraindications. Consider misoprostol only for persons with asthma and hypertension.

800 mcg SL as a single dose. Oxytocin plus misoprostol appears to be no more effective than oxytocin used alone for prophylaxis of postpartum hemorrhage, so standard protocols (e.g., use of oxytocin administration, uterine massage, and umbilical cord traction) are recommended in persons at risk. If there is inadequate uterine response and ongoing postpartum hemorrhage, then various uterotonics, including misoprostol, may be given in rapid succession if there are no contraindications. Consider misoprostol only for persons with asthma and hypertension.

600 to 1,000 mcg PR as a single dose. However, some guidelines no longer recommend rectal administration due to late onset of action. Oxytocin plus misoprostol appears to be no more effective than oxytocin used alone for prophylaxis of postpartum hemorrhage, so standard protocols (e.g., use of oxytocin administration, uterine massage, and umbilical cord traction) are recommended in persons at risk. If there is inadequate uterine response and ongoing postpartum hemorrhage, then various uterotonics, including misoprostol, may be given in rapid succession if there are no contraindications.

As an alternative to traditional management, such as surgical or expectant management, misoprostol has shown efficacy and safety in women <= 13 weeks gestation with indicators of pregnancy failure. The dosage regimen was 800 mcg intravaginally (placed into the posterior vaginal fornix) on day 1, followed by a repeat dose on day 3 if expulsion was incomplete. The regimen was followed by vacuum aspiration on day 8 if expulsion was still incomplete.

†Indicates off-label use

Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Specific guidelines for dosage adjustments in renal impairment are not available. No routine dosage adjustment is recommended; however, the dose can be reduced if the usual dose is not tolerated (manufacturer information).
 
Intermittent hemodialysis
Because misoprostol is metabolized like a fatty acid, it is unlikely that hemodialysis enhances drug clearance.

Aluminum Hydroxide; Magnesium Hydroxide: (Major) Avoid concomitant use of magnesium-containing antacids, such as magnesium hydroxide, and misoprostol in order to minimize misoprostol-associated diarrhea.
Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Major) Avoid concomitant use of magnesium-containing antacids, such as magnesium hydroxide, and misoprostol in order to minimize misoprostol-associated diarrhea.
Magnesium Hydroxide: (Major) Avoid concomitant use of magnesium-containing antacids, such as magnesium hydroxide, and misoprostol in order to minimize misoprostol-associated diarrhea.
Oxytocin: (Major) In certain cases, oxytocin can be used in combination with other oxytocics for therapeutic purposes. However, in the augmentation of labor, oxytocin administration is usually withheld until after the last dose of intravaginal misoprostol. There is a risk of severe uterine hypertony occurring, with possible uterine rupture or cervical laceration when misoprostol and oxytocin are used at the same time. These products should be used concomitantly only under adequate supervision, with particular attention to ensure adequate cervical dilation has occurred.

Cytotec/Misoprostol Oral Tab: 100mcg, 200mcg

800 mcg/day PO.

800 mcg/day PO.

Safe and effective use has not been established.

Safe and effective use has not been established.

Mechanism of Action: Misoprostol inhibits basal and nocturnal gastric acid secretion through a direct action on the parietal cell. Parietal cells contain receptors that have high affinity for prostaglandins of the E series. Misoprostol can inhibit gastric acid secretion secondary to stimulation from food, alcohol, NSAIDs, histamine, pentagastrin, or caffeine, and this effect appears to be more pronounced with increasing doses. H2-antagonists, however, appear to be more potent than misoprostol in the ability to inhibit gastric acid output, especially at night.Misoprostol also exerts a mucosal protectant effect that may contribute to its effectiveness in treating ulcers. It has been suggested that the cytoprotective effect is secondary to mucus and bicarbonate secretion, prevention of mucus bilayer disruption, reduction of backflow of hydrogen ions, regulation of mucosal blood flow, and protection of the mucosal capacity to produce cells. Misoprostol reduces pepsin concentrations under basal conditions; however, histamine-stimulated secretion is not affected.Because prostaglandins can affect many tissues, other actions of misoprostol have been identified. Misoprostol may increase the frequency of uterine contractions, which is responsible for its abortifacient capability and ability to promote labor and cervical ripening. Increases in the amplitude and frequency of uterine contractions reduces cervical tone, which produces cervical dilation. In addition, misoprostol has been shown to improve renal function in renal transplant patients treated with cyclosporine and prednisone; misoprostol may offset cyclosporine-induced intrarenal vasoconstriction.

Misoprostol is administered orally, and is administered 'off-label' by the vaginal route.  
 
After systemic absorption, misoprostol undergoes rapid de-esterification to misoprostol acid, which is responsible for the drug's clinical activity and, unlike the parent compound, is detectable in plasma. Animal data suggest that a portion of this metabolism occurs in the parietal cell. 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. The metabolism is similar to that of other fatty acids. The serum protein binding of misoprostol acid is < 90% and is concentration-independent. Misoprostol distribution has not been fully elucidated. It is unknown whether this agent crosses the placenta or is distributed into breast milk, but because misoprostol can stimulate uterine contractions, it should not be used during pregnancy (see Contraindications). Misoprostol does not affect the hepatic cytochrome P450 enzyme system. Less than 1% of a dose is excreted in the urine as unchanged drug. After administration of a radiolabeled dosage, roughly 80% of the total radioactivity is detected in the urine.

When given orally, misoprostol is absorbed rapidly (Tmax 12 +/- 3 minutes) and extensively (88%). Mean plasma concentration values for misoprostol acid after single doses show a linear relationship within a dosage range of 200—400 mcg. Inhibition of gastric acid secretion occurs approximately 30 minutes following a single oral dose, reaching a maximum effect within 60—90 minutes. No accumulation of misoprostol acid occurs with continued dosing; plasma steady state levels are achieved within 2 days. Maximum plasma concentrations of misoprostol acid are diminished when an oral dose is taken with food and total availability of misoprostol acid is reduced by the concomitant use of antacid. Clinical trials were conducted with concurrent antacid, however, so this effect does not appear to be clinically relevant. The effect of food on misoprostol's activity is also clinically insignificant and the drug should be given with food. The duration and intensity of gastric acid inhibition is dose-related, with a probable ceiling effect at 400 mcg.

Vaginal Route
Misoprostol is also well absorbed by the intravaginal route.

According to the manufacturer, caution is advised if misoprostol is administered to a breast-feeding woman. Because misoprostol is quickly metabolized in the body to misoprostol acid, it is unlikely that misoprostol itself would be distributed into breast milk. However, biologically active misoprostol acid has been shown to be excreted in breast milk after a single oral dose of misoprostol. Misoprostol concentrations in breast milk appear to be low following singular doses or short-dosing periods, such as might occur in off-label use for cervical ripening or off-label for post-partum hemorrhage; breast-feeding may be acceptable in these scenarios following a waiting period to avoid peak milk concentrations. In clinical evaluation, maximum misoprostol acid concentrations were achieved in breast milk within 1 hour after dosing and were 7.6 pg/mL and 20.9 pg/mL after single 200 mg and 600 mg misoprostol doses, respectively. Concentrations of misoprostol acid in expressed breast milk declined to 1 pg/mL at 5 hours post-dose. Although there are no published reports of adverse effects from misoprostol in breast-feeding infants, the ingestion of misoprostol acid may cause significant diarrhea in a nursing infant. Potential alternatives to consider for lactating patients when considering longer-term treatment or prophylaxis for GI ulcers include famotidine , which is considered to be compatible with breast-feeding. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated maternal condition.