http://www.rxlist.comPitocinINDICATIONSElective induction of labor is defined as the initiation of labor in a pregnant individual who has no medical indications for induction. Since the available data are inadequate to evaluate the benefits-to-risks considerations, Pitocin is not indicated for elective induction of labor.

AntepartumPitocin is indicated for the initiation or improvement of uterine contractions, where this is desirable and considered suitable for reasons of fetal or maternal concern, in order to achieve vaginal delivery. It is indicated for (1) induction of labor in patients with a medical indication for the initiation of labor, such as Rh problems, maternal diabetes, preeclampsia at or near term, when delivery is in the best interests of mother and fetus or when membranes are prematurely ruptured and delivery is indicated; (2) stimulation or reinforcement of labor, as in selected cases of uterine inertia; (3) as adjunctive therapy in the management of incomplete or inevitable abortion. In the first trimester, curettage is generally considered primary therapy. In second trimester abortion, oxytocin infusion will often be successful in emptying the uterus. Other means of therapy, however, may be required in such cases.

PostpartumPitocin is indicated to produce uterine contractions during the third stage of labor and to control postpartum bleeding or hemorrhage.

DOSAGE AND ADMINISTRATIONParenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.The dosage of oxytocin is determined by the uterine response and must therefore be individualized and initiated at a very low level. The following dosage information is based upon various regimens and indications in general use.

Induction or Stimulation of LaborIntravenous infusion (drip method) is the only acceptable method of parenteral administration of Pitocin for the induction or stimulation of labor. Accurate control of the rate of infusion is essential and is best accomplished by an infusion pump. It is convenient to piggyback the Pitocin infusion on a physiologic electrolyte solution, permitting the Pitocin infusion to be stopped abruptly without interrupting the electrolyte infusion. This is done in the following way.

Preparationa. The standard solution for infusion of Pitocin is prepared by adding 1 mL (containing 10 units of oxytocin) to 1000 mL of 0.9% aqueous sodium chloride or Ringer's lactate. The combined solution containing 10 milliunits (mU) of oxytocin/mL is rotated in the infusion bottle for thorough mixing.b. Establish the infusion with a separate bottle of physiologic electrolyte solution not containing Pitocin.c. Attach (piggyback) the Pitocin-containing bottle with the infusion pump to the infusion line as close to the infusion site as possible.

AdministrationThe initial dose should be 0.51 mU/min (equal to 36 mL of the dilute oxytocin solution per hour). At 3060 minute intervals the dose should be gradually increased in increments of 12 mU/min until the desired contraction pattern has been established. Once the desired frequency of contractions has been reached and labor has progressed to 56 cm dilation, the dose may be reduced by similar increments.Studies of the concentrations of oxytocin in the maternal plasma during Pitocin infusion have shown that infusion rates up to 6 mU/min give the same oxytocin levels that are found in spontaneous labor. At term, higher infusion rates should be given with great care, and rates exceeding 910 mU/min are rarely required. Before term, when the sensitivity of the uterus is lower because of a lower concentration of oxytocin receptors, a higher infusion rate may be required.

Monitoringa. Electronically monitor the uterine activity and the fetal heart rate throughout the infusion of Pitocin. Attention should be given to tonus, amplitude and frequency of contractions, and to the fetal heart rate in relation to uterine contractions. If uterine contractions become too powerful, the infusion can be abruptly stopped, and oxytocic stimulation of the uterine musculature will soon wane (see PRECAUTIONS section).b. Discontinue the infusion of Pitocin immediately in the event of uterine hyperactivity and/or fetal distress. Administer oxygen to the mother, who preferably should be put in a lateral position. The condition of mother and fetus should immediately be evaluated by the responsible physician and appropriate steps taken.

Control of Postpartum Uterine Bleeding1. Intravenous infusion (drip method). If the patient has an intravenous infusion running, 10 to 40 units of oxytocin may be added to the bottle, depending on the amount of electrolyte or dextrose solution remaining (maximum 40 units to 1000 mL). Adjust the infusion rate to sustain uterine contraction and control uterine atony.2. Intramuscular administration. 1 mL (10 units) of Pitocin can be given after the delivery of the placenta.

Treatment of Incomplete, Inevitable, or Elective AbortionIntravenous infusion of 10 units of Pitocin added to 500 mL of a physiologic saline solution or 5% dextrose-in-water solution may help the uterus contract after a suction or sharp curettage for an incomplete, inevitable, or elective abortion.Subsequent to intra-amniotic injection of hypertonic saline, prostaglandins, urea, etc., for midtrimester elective abortion, the injection-to-abortion time may be shortened by infusion of Pitocin at the rate of 10 to 20 milliunits (20 to 40 drops) per minute. The total dose should not exceed 30 units in a 12-hour period due to the risk of water intoxication.

Directions for DispensingPharmacy Bulk PackageNot for Direct Infusion: The pharmacy bulk package is for use in a pharmacy admixture service only in a suitable work area, such as a laminar flow hood. The closure should be penetrated only once utilizing an appropriate sterile transfer device, which allows measured distribution of the contents. The transfer device should be inserted into the Pharmacy Bulk Package using aseptic technique.Contents should be used as soon as possible following initial closure puncture. Discard any unused portion within 24 hours of first entry. Following closure puncture, container should be maintained under labeled storage conditions between 20 to 25C (68 to 77F) under a laminar flow hood until contents are dispensed.

HOW SUPPLIEDPitocin (Oxytocin Injection, USP) Synthetic is available as follows:NDC 42023-130-06 Packages of six 50 mL Pharmacy Bulk Packages, each containing 10 units of oxytocin per mL (total = 500 units of oxytocin per vial).StorageStore between 20 to 25C (68 to 77F). See USP Controlled Room Temperature.

SIDE EFFECTSThe following adverse reactions have been reported in the mother: Anaphylactic reaction Postpartum hemorrhage Cardiac arrhythmia Fatal afibrinogenemia Nausea Vomiting Premature ventricular contractions Pelvic hematoma Subarachnoid hemorrhage Hypertensive episodes Rupture of the uterus Excessive dosage or hypersensitivity to the drug may result in uterine hypertonicity, spasm, tetanic contraction, or rupture of the uterus. The possibility of increased blood loss and afibrinogenemia should be kept in mind when administering the drug. Severe water intoxication with convulsions and coma has occurred, associated with a slow oxytocin infusion over a 24-hour period. Maternal death due to oxytocin-induced water intoxication has been reported.The following adverse reactions have been reported in the fetus or neonate:Due to induced uterine motility Bradycardia Premature ventricular contractions and other arrhythmias Permanent CNS or brain damage Fetal death Neonatal seizures have been reported with the use of Pitocin.Due to use of oxytocin in the mother Low Apgar scores at five minutes Neonatal jaundice Neonatal retinal hemorrhage For medical advice about adverse reactions contact your medical professional. To report SUSPECTED ADVERSE REACTIONS, contact JHP at 1-866-923-2547 or MEDWATCH at 1-800-FDA-1088 (1-800-332-1088) or http://www.fda.gov/medwatch/.

DRUG INTERACTIONSSevere hypertension has been reported when oxytocin was given three to four hours following prophylactic administration of a vasoconstrictor in conjunction with caudal block anesthesia. Cyclopropane anesthesia may modify oxytocin's cardiovascular effects, so as to produce unexpected results such as hypotension. Maternal sinus bradycardia with abnormal atrioventricular rhythms has also been noted when oxytocin was used concomitantly with cyclopropane anesthesia.

WARNINGSPitocin, when given for induction of labor or augmentation of uterine activity, should be administered only by the intravenous route and with adequate medical supervision in a hospital.PRECAUTIONSGeneral1. All patients receiving intravenous oxytocin must be under continuous observation by trained personnel who have a thorough knowledge of the drug and are qualified to identify complications. A physician qualified to manage any complications should be immediately available. Electronic fetal monitoring provides the best means for early detection of overdosage (see OVERDOSAGE section). However, it must be borne in mind that only intrauterine pressure recording can accurately measure the intrauterine pressure during contractions. A fetal scalp electrode provides a more dependable recording of the fetal heart rate than any external monitoring system.2. When properly administered, oxytocin should stimulate uterine contractions comparable to those seen in normal labor. Overstimulation of the uterus by improper administration can be hazardous to both mother and fetus. Even with proper administration and adequate supervision, hypertonic contractions can occur in patients whose uteri are hypersensitive to oxytocin. This fact must be considered by the physician in exercising judgment regarding patient selection.3. Except in unusual circumstances, oxytocin should not be administered in the following conditions: fetal distress, hydramnios, partial placenta previa, prematurity, borderline cephalopelvic disproportion, and any condition in which there is a predisposition for uterine rupture, such as previous major surgery on the cervix or uterus including cesarean section, overdistention of the uterus, grand multiparity, or past history of uterine sepsis or of traumatic delivery. Because of the variability of the combinations of factors which may be present in the conditions listed above, the definition of unusual circumstances must be left to the judgment of the physician. The decision can be made only by carefully weighing the potential benefits which oxytocin can provide in a given case against rare but definite potential for the drug to produce hypertonicity or tetanic spasm.4. Maternal deaths due to hypertensive episodes, subarachnoid hemorrhage, rupture of the uterus, and fetal deaths due to various causes have been reported associated with the use of parenteral oxytocic drugs for induction of labor or for augmentation in the first and second stages of labor.5. Oxytocin has been shown to have an intrinsic antidiuretic effect, acting to increase water reabsorption from the glomerular filtrate. Consideration should, therefore, be given to the possibility of water intoxication, particularly when oxytocin is administered continuously by infusion and the patient is receiving fluids by mouth.6. When oxytocin is used for induction or reinforcement of already existent labor, patients should be carefully selected. Pelvic adequacy must be considered and maternal and fetal conditions evaluated before use of the drug.

Carcinogenesis, Mutagenesis, Impairment of FertilityThere are no animal or human studies on the carcinogenicity and mutagenicity of this drug, nor is there any information on its effect on fertility.

PregnancyTeratogenic EffectsAnimal reproduction studies have not been conducted with oxytocin. There are no known indications for use in the first trimester of pregnancy other than in relation to spontaneous or induced abortion. Based on the wide experience with this drug and its chemical structure and pharmacological properties, it would not be expected to present a risk of fetal abnormalities when used as indicated.

OVERDOSEOverdosage with oxytocin depends essentially on uterine hyperactivity whether or not due to hypersensitivity to this agent. Hyperstimulation with strong (hypertonic) or prolonged (tetanic) contractions, or a resting tone of 15 to 20 mm H2O or more between contractions can lead to tumultuous labor, uterine rupture, cervical and vaginal lacerations, postpartum hemorrhage, uteroplacental hypoperfusion, and variable deceleration of fetal heart, fetal hypoxia, hypercapnia, perinatal hepatic necrosis or death. Water intoxication with convulsions, which is caused by the inherent antidiuretic effect of oxytocin, is a serious complication that may occur if large doses (40 to 50 milliunits/minute) are infused for long periods. Management consists of immediate discontinuation of oxytocin and symptomatic and supportive therapy.

CONTRAINDICATIONSAntepartum use of Pitocin is contraindicated in any of the following circumstances:1. Where there is significant cephalopelvic disproportion;2. In unfavorable fetal positions or presentations, such as transverse lies, which are undeliverable without conversion prior to delivery;3. In obstetrical emergencies where the benefit-to-risk ratio for either the fetus or the mother favors surgical intervention;4. In fetal distress where delivery is not imminent;5. Where adequate uterine activity fails to achieve satisfactory progress;6. Where the uterus is already hyperactive or hypertonic;7. In cases where vaginal delivery is contraindicated, such as invasive cervical carcinoma, active herpes genitalis, total placenta previa, vasa previa, and cord presentation or prolapse of the cord;8. In patients with hypersensitivity to the drug.

CLINICAL PHARMACOLOGYUterine motility depends on the formation of the contractile protein actomyosin under the influence of the Ca2+ -dependent phosphorylating enzyme myosin light-chain kinase. Oxytocin promotes contractions by increasing the intracellular Ca2+. Oxytocin has specific receptors in the myometrium and the receptor concentration increases greatly during pregnancy, reaching a maximum in early labor at term. The response to a given dose of oxytocin is very individualized and depends on the sensitivity of the uterus, which is determined by the oxytocin receptor concentration. However, the physician should be aware of the fact that oxytocin even in its pure form has inherent pressor and antidiuretic properties which may become manifest when large doses are administered. These properties are thought to be due to the fact that oxytocin and vasopressin differ in regard to only two of the eight amino acids (see PRECAUTIONS section).Oxytocin is distributed throughout the extracellular fluid. Small amounts of the drug probably reach the fetal circulation. Oxytocin has a plasma half-life of about 1 to 6 minutes which is decreased in late pregnancy and during lactation. Following intravenous administration of oxytocin, uterine response occurs almost immediately and subsides within 1 hour. Following intramuscular injection of the drug, uterine response occurs within 3 to 5 minutes and persists for 2 to 3 hours. Its rapid removal from plasma is accomplished largely by the kidney and the liver. Only small amounts are excreted in urine unchanged.

REFERENCES1. Seitchik J, Castillo M: Oxytocin augmentation of dysfunctional labor. I. Clinical data. Am J Obstet Gynecol 1982; 144:899905.2. Seitchik J, Castillo M: Oxytocin augmentation of dysfunctional labor. II. Multiparous patients. Am J Obstet Gynecol 1983; 145:777780.3. Fuchs A, Goeschen K, Husslein P, et al: Oxytocin and the initiation of human parturition. III. Plasma concentrations of oxytocin and 13, 14-dihydro-15-keto-prostaglandin F2a in spontaneous and oxytocin-induced labor at term. Am J Obstet Gynecol 1983; 145:497502.4. Seitchik J, Amico J, et al: Oxytocin augmentation of dysfunctional labor. IV. Oxytocin pharmacokinetics. Am J Obstet Gynecol 1984; 150:225228.5. American College of Obstetricians and Gynecologists: ACOG Technical Bulletin Number 110November 1987: Induction and augmentation of labor.Manufactured and Distributed by: JHP Pharmaceuticals, LLC, Rochester, MI 48307. Revised: April 2012.Last reviewed on RxList: 3/22/2013This monograph has been modified to include the generic and brand name in many instances

Cytotec

Cytotec(misoprostol) Tablets

CYTOTEC (MISOPROSTOL) ADMINISTRATION TO WOMEN WHO ARE PREGNANT CAN CAUSE BIRTH DEFECTS, ABORTION, OR PREMATURE BIRTH. UTERINE RUPTURE HAS BEEN REPORTED WHEN CYTOTEC WAS ADMINISTERED IN PREGNANT WOMEN TO INDUCE LABOR OR TO INDUCE ABORTION BEYOND THE EIGHTH WEEK OF PREGNANCY (see also PRECAUTIONS and LABOR AND DELIVERY). CYTOTEC SHOULD NOT BE TAKEN BY PREGNANT WOMEN TO REDUCE THE RISK OF ULCERS INDUCED BY NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs) (see CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS).PATIENTS MUST BE ADVISED OF THE ABORTIFACIENT PROPERTY AND WARNED NOT TO GIVE THE DRUG TO OTHERS.

Cytotec 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, Cytotec may be prescribed if the patient has had a negative serum pregnancy test within 2 weeks prior to beginning therapy. is capable of complying with effective contraceptive measures. has received both oral and written warnings of the hazards of misoprostol, the risk of possible contraception failure, and the danger to other women of childbearing potential should the drug be taken by mistake. will begin Cytotec only on the second or third day of the next normal menstrual period.Cytotec oral tablets contain either 100 mcg or 200 mcg of misoprostol, a synthetic prostaglandin E1 analog.

INDICATIONSCytotec (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, e.g., 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. Cytotec has not been shown to reduce the risk of duodenal ulcers in patients taking NSAIDs. Cytotec should be taken for the duration of NSAID therapy. Cytotec 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.

DOSAGE AND ADMINISTRATIONThe recommended adult oral dose of Cytotec 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 CLINICAL PHARMACOLOGY: Clinical studies.) Cytotec should be taken for the duration of NSAID therapy as prescribed by the physician. Cytotec should be taken with a meal, and the last dose of the day should be at bedtime.

Renal impairmentAdjustment of the dosing schedule in renally impaired patients is not routinely needed, but dosage can be reduced if the 200-mcg dose is not tolerated. (See CLINICAL PHARMACOLOGY.)

HOW SUPPLIEDCytotec 100-mcg tablets are white, round, with SEARLE debossed on one side and 1451 on the other side; supplied as:NDC Number Size

0025-1451-60 unit-of-use bottle of 60

0025-1451-20 unit-of-use bottle of 120

0025-1451-34 carton of 100 unit dose

Cytotec 200-mcg tablets are white, hexagonal, with SEARLE debossed above and 1461 debossed below the line on one side and a double stomach debossed on the other side; supplied as:NDC Number Size

0025-1461-60unit-of-use bottle of 60

0025-1461-31unit-of-use bottle of 120

0025-1461-34carton of 100 unit dose

Store at or below 25C (77F), in a dry area.

SIDE EFFECTSThe following have been reported as adverse events in subjects receiving Cytotec:GastrointestinalIn subjects receiving Cytotec 400 or 800 mcg daily in clinical trials, the most frequent gastrointestinal adverse events were diarrhea and abdominal pain. The incidence of diarrhea at 800 mcg in controlled trials in patients on NSAIDs ranged from 1440% and in all studies (over 5,000 patients) averaged 13%. Abdominal pain occurred in 1320% of patients in NSAID trials and about 7% in all studies, but there was no consistent difference from placebo.Diarrhea was dose related and usually developed early in the course of therapy (after 13 days), usually was self-limiting (often resolving after 8 days), but sometimes required discontinuation of Cytotec (2% of the patients). Rare instances of profound diarrhea leading to severe dehydration have been reported. Patients with an underlying condition such as inflammatory bowel disease, or those in whom dehydration, were it to occur, would be dangerous, should be monitored carefully if Cytotec is prescribed. The incidence of diarrhea can be minimized by administering after meals and at bedtime, and by avoiding coadministration of Cytotec with magnesium-containing antacids.GynecologicalWomen who received Cytotec during clinical trials reported the following gynecological disorders: spotting (0.7%), cramps (0.6%), hypermenorrhea (0.5%), menstrual disorder (0.3%) and dysmenorrhea (0.1%). Postmenopausal vaginal bleeding may be related to Cytotec administration. If it occurs, diagnostic workup should be undertaken to rule out gynecological pathology. (See BOXED WARNINGS.)ElderlyThere were no significant differences in the safety profile of Cytotec in approximately 500 ulcer patients who were 65 years of age or older compared with younger patients.Additional adverse events which were reported are categorized as follows:Incidence greater than 1%In clinical trials, the following adverse reactions were reported by more than 1% of the subjects receiving Cytotec and may be causally related to the drug: nausea (3.2%), flatulence (2.9%), headache (2.4%), dyspepsia (2.0%), vomiting (1.3%), and constipation (1.1%). However, there were no significant differences between the incidences of these events for Cytotec and placebo.Causal relationship unknownThe following adverse events were infrequently reported. Causal relationships between Cytotec and these events have not been established but cannot be excluded:Body as a whole: aches/pains, asthenia, fatigue, fever, chills, rigors, weight changes.Skin: rash, dermatitis, alopecia, pallor, breast pain.Special senses: abnormal taste, abnormal vision, conjunctivitis, deafness, tinnitus, earache.Respiratory: upper respiratory tract infection, bronchitis, bronchospasm, dyspnea, pneumonia, epistaxis.Cardiovascular: chest pain, edema, diaphoresis, hypotension, hypertension, arrhythmia, phlebitis, increased cardiac enzymes, syncope, myocardial infarction (some fatal), thromboembolic events (e.g., pulmonary embolism, arterial thrombosis, and CVA).Gastrointestinal: GI bleeding, GI inflammation/infection, rectal disorder, abnormal hepatobiliary function, gingivitis, reflux, dysphagia, amylase increase.Hypersensitivity: anaphylactic reactionMetabolic: glycosuria, gout, increased nitrogen, increased alkaline phosphatase.Genitourinary: polyuria, dysuria, hematuria, urinary tract infection.Nervous system/Psychiatric: anxiety, change in appetite, depression, drowsiness, dizziness, thirst, impotence, loss of libido, sweating increase, neuropathy, neurosis, confusion.Musculoskeletal: arthralgia, myalgia, muscle cramps, stiffness, back pain.Blood/Coagulation: anemia, abnormal differential, thrombocytopenia, purpura, ESR increased.

DRUG INTERACTIONSSee CLINICAL PHARMACOLOGY. Cytotec has not been shown to interfere with the beneficial effects of aspirin on signs and symptoms of rheumatoid arthritis. Cytotec does not exert clinically significant effects on the absorption, blood levels, and antiplatelet effects of therapeutic doses of aspirin. Cytotec has no clinically significant effect on the kinetics of diclofenac or ibuprofen.Prostaglandins such as Cytotec may augment the activity of oxytocic agents, especially when given less than 4 hours prior to initiating oxytocin treatment. Concomitant use is not recommended

PregnancyPregnancy Category XTeratogenic effects: See BOXED WARNINGS. Congenital anomalies sometimes associated with fetal death have been reported subsequent to the unsuccessful use of misoprostol as an abortifacient, but the drug's teratogenic mechanism has not been demonstrated. Several reports in the literature associate the use of misoprostol during the first trimester of pregnancy with skull defects, cranial nerve palsies, facial malformations, and limb defects.Cytotec is not fetotoxic or teratogenic in rats and rabbits at doses 625 and 63 times the human dose, respectively.Nonteratogenic effects: See BOXED WARNINGS. Cytotec may endanger pregnancy (may cause abortion) and thereby cause harm to the fetus when administered to a pregnant woman. Cytotec may produce uterine contractions, uterine bleeding, and expulsion of the products of conception. Abortions caused by Cytotec may be incomplete. If a woman is or becomes pregnant while taking this drug to reduce the risk of NSAID-induced ulcers, the drug should be discontinued and the patient apprised of the potential hazard to the fetus.

Labor and deliveryCytotec can induce or augment uterine contractions. Vaginal administration of Cytotec, 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 Cytotec is uterine tachysystole 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 and lead to adverse fetal heart changes. Uterine activity and fetal status should be monitored by trained obstetrical personnel in a hospital setting.The risk of uterine rupture increases with advancing gestational ages and prior uterine surgery, including Cesarean delivery. Grand multiparity also appears to be a risk factor for uterine rupture.The use of Cytotec outside of its approved indication may also be associated with meconium passage, meconium staining of amniotic fluid, and Cesarean delivery. Maternal shock, maternal death, fetal bradycardia, and fetal death have also been reported with the use of misoprostol.Cytotec should not be used in the third trimester in women with a history of Cesarean section or major uterine surgery because of an increased risk of uterine rupture. Cytotec should not be used in cases where uterotonic drugs are generally contraindicated or where hyperstimulation of the uterus is considered inappropriate, such as cephalopelvic disproportion, grand multiparity, hypertonic or hyperactive uterine patterns, or fetal distress where delivery is not imminent, or when surgical intervention is more appropriate.The effect of Cytotec on later growth, development, and functional maturation of the child when Cytotec is used for cervical ripening or induction of labor has not been established. Information on Cytotec's effect on the need for forceps delivery or other intervention is unknown.Nursing mothersMisoprostol is rapidly metabolized in the mother to misoprostol acid, which is biologically active and is excreted in breast milk. There are no published reports of adverse effects of misoprostol in breast-feeding infants of mothers taking misoprostol. Caution should be exercised when misoprostol is administered to a nursing woman.Pediatric useSafety and effectiveness of Cytotec in pediatric patients have not been established.

OVERDOSEThe toxic dose of Cytotec 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.

CONTRAINDICATIONSCytotec should not be taken by pregnant women to reduce the risk of ulcers induced by nonsteroidal anti-inflammatory drugs (NSAIDs). Cytotec should not be taken by anyone with a history of allergy to prostaglandins.

CLINICAL PHARMACOLOGYPharmacokineticsMisoprostol is extensively absorbed, and undergoes rapid deesterification to its free acid, which is responsible for its clinical activity and, unlike the parent compound, is detectable in plasma. The alpha side chain undergoes beta oxidation and the beta side chain undergoes omega oxidation followed by reduction of the ketone to give prostaglandin F analogs.In normal volunteers, Cytotec (misoprostol) is rapidly absorbed after oral administration with a Tmax of misoprostol acid of 12 3 minutes and a terminal half-life of 2040 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 200400 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.Mean SD Cmax(pg/ml) AUC(04) (pghr/ml) Tmax(min)

Fasting811 317 417 135 14 8

With Antacid 689 315 349 108* 20 14

With High Fat Breakfast 303 176* 373 111 64 79*

* Comparisons with fasting results statistically significant, p < 0.05.

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 T1/2, Cmax, and AUC compared to normals, but no clear correlation between the degree of impairment and AUC. In subjects over 64 years of age, the AUC for misoprostol acid is increased. No routine dosage adjustment is recommended in older patients or patients with renal impairment, but dosage may need to be reduced if the usual dose is not tolerated.Drug interaction studies between misoprostol and several nonsteroidal anti-inflammatory drugs showed no effect on the kinetics of ibuprofen or diclofenac, and a 20% decrease in aspirin AUC, not thought to be clinically significant.Pharmacokinetic studies also showed a lack of drug interaction with antipyrine and propranolol when these drugs were given with misoprostol. Misoprostol given for 1 week had no effect on the steady state pharmacokinetics of diazepam when the two drugs were administered 2 hours apart.The serum protein binding of misoprostol acid is less than 90% and is concentration-independent in the therapeutic range.After a single oral dose of misoprostol to nursing mothers, misoprostol acid was excreted in breast milk. The maximum concentration of misoprostol acid in expressed breast milk was achieved within 1 hour after dosing and was 7.6 pg/ml (CV 37%) and 20.9 pg/ml (CV 62%) after single 200 g and 600 g misoprostol administration, respectively. The misoprostol acid concentrations in breast milk declined to < 1 pg/ml at 5 hours post-dose.

PharmacodynamicsMisoprostol has both antisecretory (inhibiting gastric acid secretion) and (in animals) mucosal protective properties. NSAIDs inhibit prostaglandin synthesis, and a deficiency of prostaglandins within the gastric mucosa may lead to diminishing bicarbonate and mucus secretion and may contribute to the mucosal damage caused by these agents. Misoprostol can increase bicarbonate and mucus production, but in man this has been shown at doses 200 mcg and above that are also antisecretory. It is therefore not possible to tell whether the ability of misoprostol to reduce the risk of gastric ulcer is the result of its antisecretory effect, its mucosal protective effect, or both.In vitro studies on canine parietal cells using tritiated misoprostol acid as the ligand have led to the identification and characterization of specific prostaglandin receptors. Receptor binding is saturable, reversible, and stereospecific. The sites have a high affinity for misoprostol, for its acid metabolite, and for other E type prostaglandins, but not for F or I prostaglandins and other unrelated compounds, such as histamine or cimetidine. Receptor-site affinity for misoprostol correlates well with an indirect index of antisecretory activity. It is likely that these specific receptors allow misoprostol taken with food to be effective topically, despite the lower serum concentrations attained.Misoprostol produces a moderate decrease in pepsin concentration during basal conditions, but not during histamine stimulation. It has no significant effect on fasting or postprandial gastrin nor on intrinsic factor output.

This product's label may have been updated. For current full prescribing information, please visit www.pfizer.com.Distributed by: G.D. Searle Division of Pfizer Inc, NY, NY 10017. Revised November 2012Last reviewed on RxList: 12/7/2012This monograph has been modified to include the generic and brand name in many instances.

Methergine (methylergonovine maleate) Tablets, USP (methylergonovine maleate) Injection, USP

DRUG DESCRIPTIONMethergine (methylergonovine maleate) is a semi-synthetic ergot alkaloid used for the prevention and control of postpartum hemorrhage.Methergine is available in sterile ampuls of 1 mL, containing 0.2 mg methylergonovine maleate for intramuscular or intravenous injection and in tablets for oral ingestion containing 0.2 mg methylergonovine maleate.

TabletsActive Ingredient: methylergonovine maleate, USP, 0.2 mg.Inactive Ingredients: acacia, carnauba wax, D&C Red #7, FD&C Blue #1, gelatin special, lactose, maleic acid, mixed parabens, povidone, sodium benzoate, sodium hydroxide, starch, stearic acid, sucrose, talc, and titanium dioxide.Ampuls: 1 mL, clear, colorless solution.Active Ingredient: methylergonovine maleate, USP, 0.2 mg.Inactive Ingredients: maleic acid, 0.10 mg; sodium chloride, 7.0 mg; water for injection, qs to 1 mL.

INDICATIONSFollowing delivery of the placenta, for routine management of uterine atony, hemorrhage and subinvolution of the uterus. For control of uterine hemorrhage in the second stage of labor following delivery of the anterior shoulder.

DOSAGE AND ADMINISTRATIONParenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.Intramuscularly1 mL, 0.2 mg, after delivery of the anterior shoulder, after delivery of the placenta, or during the puerperium. May be repeated as required, at intervals of 2-4 hours.Intravenously1 mL, 0.2 mg, administered slowly over a period of no less than 60 seconds (See WARNINGS.)OrallyOne tablet, 0.2 mg, 3 or 4 times daily in the puerperium for a maximum of 1 week.

HOW SUPPLIEDTablets0.2 mg round, coated, orchid, branded 78-54 one side, SANDOZ other side.Bottles of 100..NDC 0078-0054-05Ampuls1 mL sizeBoxes of 20.NDC 0078-0053-03Store and DispenseTablets: Store below 25C (77F); in tight, light-resistant container.Ampuls: Store in refrigerator, 2C-8C (36F-46F). Protect from light. Administer only if solution is clear and colorless.

SIDE EFFECTSThe most common adverse reaction is hypertension associated in several cases with seizure and/or headache. Hypotension has also been reported. Abdominal pain (caused by uterine contractions), nausea and vomiting have occurred occasionally. Rarely observed reactions have included: acute myocardial infarction, transient chest pains, vasoconstriction, vasospasm, coronary arterial spasm, bradycardia, tachycardia, dyspnea, hematuria, thrombophlebitis, water intoxication, hallucinations, leg cramps, dizziness, tinnitus, nasal congestion, diarrhea, diaphoresis, palpitation, rash, and foul taste.1There have been rare isolated reports of anaphylaxis, without a proven causal relationship to the drug product.

Postmarketing ExperienceThe following adverse drug reactions have been derived from post-marketing experience with Methergine via spontaneous case reports. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorized as not known.Nervous system disordersCerebrovascular accident, paraesthesiaCardiac disordersVentricular fibrillation, ventricular tachycardia, angina pectoris, atrioventricular blockDrug Abuse And DependenceMethergine (methylergonovine maleate) has not been associated with drug abuse or dependence of either a physical or psychological nature.Read the Methergine (methylergonovine maleate) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONSCYP 3A4 Inhibitors (e.g., Macrolide Antibiotics and Protease Inhibitors)There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g., dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine.CYP3A4 inducersDrugs (e.g. nevirapine, rifampicin) that are strong inducers of CYP3A4 are likely to decrease the pharmacological action of Methergine.Beta-blockersCaution should be exercised when Methergine is used concurrently with beta-blockers. Concomitant administration with beta-blockers may enhance the vasoconstrictive action of ergot alkaloids.AnestheticsAnesthetics like halothan and methoxyfluran may reduce the oxytocic potency of Methergine.Glyceryl trinitrate and other antianginal drugsMethylergonovine maleate produces vasoconstriction and can be expected to reduce the effect of glyceryl trinitrate and other antianginal drugs.No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known.Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors, ergot alkaloids, or prostaglandins.

WARNINGSGeneralThis drug should not be administered I.V. routinely because of the possibility of inducing sudden hypertensive and cerebrovascular accidents. If I.V. administration is considered essential as a lifesaving measure, Methergine (methylergonovine maleate) should be given slowly over a period of no less than 60 seconds with careful monitoring of blood pressure. Intra-arterial or periarterial injection should be strictly avoided.Caution should be exercised in the presence of impaired hepatic or renal function.Breast-feedingMothers should not breast-feed during treatment with Methergine. Milk secreted during this period should be discarded. Methergine may produce adverse effects in the breast-feeding infant. Methergine may also reduce the yield of breast milk. Mothers should wait at least 12 hours after administration of the last dose of Methergine before initiating or resuming breast feedingCoronary artery diseasePatients with coronary artery disease or risk factors for coronary artery disease (e.g., smoking, obesity, diabetes, high cholesterol) may be more susceptible to developing myocardial ischemia and infarction associated with methylergonovine-induced vasospasm.Medication errorsInadvertent administration of Methergine to newborn infants has been reported. In these cases of inadvertent neonatal exposure, symptoms such as respiratory depression, convulsions, cyanosis and oliguria have been reported. Usual treatment is symptomatic. However, in severe cases, respiratory and cardiovascular support is required.Methergine has been administered instead of vitamin K and Hepatitis B vaccine, medications which are routinely administered to the newborn . Due to the potential for accidental neonatal exposure, Methergine injection should be stored separately from medications intended for neonatal administration.

PRECAUTIONSGeneralCaution should be exercised in the presence of sepsis, obliterative vascular disease. Also use with caution during the second stage of labor. The necessity for manual removal of a retained placenta should occur only rarely with proper technique and adequate allowance of time for its spontaneous separation.Carcinogenesis, Mutagenesis, Impairment of FertilityNo long-term studies have been performed in animals to evaluate carcinogenic potential. The effect of the drug on mutagenesis or fertility has not been determined.PregnancyCategory C. Animal reproductive studies have not been conducted with Methergine. It is also not known whether methylergonovine maleate can cause fetal harm or can affect reproductive capacity. Use of Methergine is contraindicated during pregnancy because of its uterotonic effects. (See INDICATIONS AND USAGE.)Labor and DeliveryThe uterotonic effect of Methergine is utilized after delivery to assist involution and decrease hemorrhage, shortening the third stage of labor.Nursing MothersMothers should not breast-feed during treatment with Methergine and at least 12 hours after administration of the last dose. Milk secreted during this period should be discarded.Pediatric UseSafety and effectiveness in pediatric patients have not been established.Geriatric UseClinical studies of Methergine did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in response between the elderly and younger patients. In general dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

OVERDOSESymptoms of acute overdose may include: nausea, vomiting, oliquria, abdominal pain, numbness, tingling of the extremities, rise in blood pressure, in severe cases followed by hypotension, respiratory depression, hypothermia, convulsions, and coma.Because reports of overdosage with Methergine (methylergonovine maleate) are infrequent, the lethal dose in humans has not been established. The oral LD50 (in mg/kg) for the mouse is 187, the rat 93, and the rabbit 4.5.2 Several cases of accidental Methergine injection in newborn infants have been reported, and in such cases 0.2 mg represents an overdose of great magnitude. However, recovery occurred in all but one case following a period of respiratory depression, hypothermia, hypertonicity with jerking movements, and convulsions.Also, several children 1-3 years of age have accidentally ingested up to 10 tablets (2 mg) with no apparent ill effects. A postpartum patient took 4 tablets at one time in error and reported paresthesias and clamminess as her only symptoms.Treatment of acute overdosage is symptomatic and includes the usual procedures of:1. removal of offending drug by inducing emesis, gastric lavage, catharsis, and supportive diuresis.2. maintenance of adequate pulmonary ventilation, especially if convulsions or coma develop.3. correction of hypotension with pressor drugs as needed.4. control of convulsions with standard anticonvulsant agents.5. control of peripheral vasospasm with warmth to the extremities if needed.3

CONTRAINDICATIONSHypertension; toxemia; pregnancy; and hypersensitivity.

CLINICAL PHARMACOLOGYMethergine (methylergonovine maleate) acts directly on the smooth muscle of the uterus and increases the tone, rate, and amplitude of rhythmic contractions. Thus, it induces a rapid and sustained tetanic uterotonic effect which shortens the third stage of labor and reduces blood loss. The onset of action after I.V. administration is immediate; after I.M. administration, 2-5 minutes, and after oral administration, 510 minutes.Pharmacokinetic studies following an I.V. injection have shown that methylergonovine is rapidly distributed from plasma to peripheral tissues within 2-3 minutes or less. The bioavailability after oral administration was reported to be about 60% with no accumulation after repeated doses. During delivery, with intramuscular injection, bioavailability increased to 78%. Ergot alkaloids are mostly eliminated by hepatic metabolism and excretion, and the decrease in bioavailability following oral administration is probably a result of first-pass metabolism in the liver.Bioavailability studies conducted in fasting healthy female volunteers have shown that oral absorption of a 0.2 mg methylergonovine tablet was fairly rapid with a mean peak plasma concentration of 3243 1308 pg/mL observed at 1.12 0.82 hours. For a 0.2 mg intramuscular injection, a mean peak plasma concentration of 5918 1952 pg/mL was observed at 0.41 0.21 hours. The extent of absorption of the tablet, based upon methylergonovine plasma concentrations, was found to be equivalent to that of the I.M. solution given orally, and the extent of oral absorption of the I.M. solution was proportional to the dose following administration of 0.1, 0.2, and 0.4 mg. When given intramuscularly, the extent of absorption of Methergine solution was about 25% greater than the tablet. The volume of distribution (Vdss/F) of methylergonovine was calculated to be 56.1 17.0 liters, and the plasma clearance (CLp/F) was calculated to be 14.4 4.5 liters per hour. The plasma level decline was biphasic with a mean elimination half-life of 3.39 hours (range 1.5 to 12.7 hours). A delayed gastrointestinal absorption (Tmax about 3 hours) of Methergine tablet might be observed in postpartum women during continuous treatment with this oxytocic agent.