ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. The following have been reported as adverse events in subjects receiving Misoprostol Tablets:Gastrointestinal: In subjects receiving Misoprostol Tablets 400 or 800 mcg daily in clinical trials, the most frequent gastrointestinal adverse events were diarrhea and abdominal pain. The incidence of diarrhea at 800 mcg in controlled trials in patients on NSAIDs ranged from 14 to 40% and in all studies (over 5,000 patients) averaged 13%. Abdominal pain occurred in 13 to 20% of patients in NSAID trials and about 7% in all studies, but there was no consistent difference from placebo. Diarrhea was dose related and usually developed early in the course of therapy (after 13 days), usually was self-limiting (often resolving after days), but sometimes required discontinuation of Misoprostol Tablets (2% of the patients). Rare instances of profound diarrhea leading to severe dehydration have been reported. Patients with an underlying condition such as inflammatory bowel disease, or those in whom dehydration, were it to occur, would be dangerous, should be monitored carefully if Misoprostol Tablets is prescribed. The incidence of diarrhea can be minimized by administering after meals and at bedtime, and by avoiding coadministration of Misoprostol Tablets with magnesium-containing antacids.Gynecological: Women who received Misoprostol Tablets 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 Misoprostol Tablets administration. If it occurs, diagnostic workup should be undertaken to rule out gynecological pathology. (See boxed WARNINGS.) Elderly: There were no significant differences in the safety profile of Misoprostol Tablets 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 Misoprostol Tablets 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 Misoprostol Tablets and placebo. Causal relationship unknown: The following adverse events were infrequently reported. Causal relationships between Misoprostol Tablets and these events have not been established but cannot be excluded: Body as 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 reaction Metabolic: 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. To report SUSPECTED ADVERSE REACTIONS, contact Novel Laboratories, Inc. at 1-866-403-7592 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

BOXED WARNING SECTION.

WARNING. MISOPROSTOL ADMINISTRATION TO WOMEN WHO ARE PREGNANT CAN CAUSE BIRTH DEFECTS, ABORTION, PREMATURE BIRTH OR UTERINE RUPTURE. UTERINE RUPTURE HAS BEEN REPORTED WHEN MISOPROSTOL TABLETS WERE ADMINISTERED IN PREGNANT WOMEN TO INDUCE LABOR OR TO INDUCE ABORTION. THE RISK OF UTERINE RUPTURE INCREASES WITH ADVANCING GESTATIONAL AGES AND WITH PRIOR UTERINE SURGERY, INCLUDING CESAREAN DELIVERY (see also PRECAUTIONS and LABOR AND DELIVERY). MISOPROSTOL TABLETS 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.Misoprostol Tablets should not be used for reducing the risk of NSAID-induced ulcers in women of childbearing potential unless the patient is at high risk of complications from gastric ulcers associated with use of the NSAID, or is at high risk of developing gastric ulceration. In such patients, Misoprostol Tablets may be prescribed if the patienthas had negative serum pregnancy test within 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 Misoprostol Tablets only on the second or third day of the next normal menstrual period.. has had negative serum pregnancy test within 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 Misoprostol Tablets only on the second or third day of the next normal menstrual period.

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. Pharmacokinetics. Misoprostol is extensively absorbed, and undergoes rapid de-esterification to its free acid, which is responsible for its clinical activity and, unlike the parent compound, is detectable in plasma. The alpha side chain undergoes beta oxidation and the beta side chain undergoes omega oxidation followed by reduction of the ketone to give prostaglandin analogs.In normal volunteers, misoprostol is rapidly absorbed after oral administration with Tmax of misoprostol acid of 12 +- minutes and terminal half-life of 20 to 40 minutes.There is high variability of plasma levels of misoprostol acid between and within studies but mean values after single doses show linear relationship with dose over the range of 200 to 400 mcg. No accumulation of misoprostol acid was noted in multiple dose studies; plasma steady state was achieved within two days.Maximum plasma concentrations of misoprostol acid are diminished when the dose is taken with food and total availability of misoprostol acid is reduced by use of concomitant antacid. Clinical trials were conducted with concomitant antacid, however, so this effect does not appear to be clinically important. Mean +- SD Cmax(pg/ml) AUC(0-4) (pghr/ml) Tmax(min) Fasting 811 +- 317 417 +- 135 14 +- With Antacid 689 +- 315 349 +- 108 20 +- 14 With High Fat Breakfast 303 +- 176 373 +- 111 64 +- 79 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 1/2, max 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 20% decrease in aspirin AUC, not thought to be clinically significant.Pharmacokinetic studies also showed lack of drug interaction with antipyrine and propranolol when these drugs were given with misoprostol. Misoprostol given for week had no effect on the steady state pharmacokinetics of diazepam when the two drugs were administered hours apart.The serum protein binding of misoprostol acid is less than 90% and is concentration-independent in the therapeutic range.After 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 hour after dosing and was 7.6 pg/mL (CV 37%) and 20.9 pg/ml (CV 62%) after single 200 ug and 600 ug misoprostol administration, respectively. The misoprostol acid concentrations in breast milk declined to 1 pg/ml at hours post-dose.. Pharmacodynamics. Misoprostol has both antisecretory (inhibiting gastric acid secretion) and (in animals) mucosal protective properties. NSAIDs inhibit prostaglandin synthesis, and 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 high affinity for misoprostol, for its acid metabolite, and for other type prostaglandins, but not for or 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 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.

INFORMATION FOR PATIENTS SECTION.

Information for Patients. Women of childbearing potential using Misoprostol Tablets to decrease the risk of NSAID-induced ulcers should be told that they must not be pregnant when Misoprostol Tablets therapy is initiated, and that they must use an effective contraception method while taking Misoprostol Tablets.See boxed WARNINGS. Misoprostol Tablets is intended for administration along with nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, to decrease the chance of developing an NSAID-induced gastric ulcer.Misoprostol Tablets should be taken only according to the directions given by physician.If the patient has questions about or problems with Misoprostol Tablets, the physician should be contacted promptly.THE PATIENT SHOULD NOT GIVE MISOPROSTOL TABLETS TO ANYONE ELSE. Misoprostol Tablets has been prescribed for the patients specific condition, may not be the correct treatment for another person, and may be dangerous to the other person if she were to become pregnant. The Misoprostol Tablets package the patient receives from the pharmacist will include leaflet containing patient information. The patient should read the leaflet before taking Misoprostol Tablets and each time the prescription is renewed because the leaflet may have been revised.Keep Misoprostol Tablets out of the reach of children.SPECIAL NOTE FOR WOMEN: Misoprostol Tablets may cause birth defects, abortion (sometimes incomplete), premature labor or rupture of the uterus if given to pregnant women.Misoprostol Tablets is available only as unit-of-use package that includes leaflet containing patient information. See Patient Information at the end of this labeling.

LABOR & DELIVERY SECTION.

Labor and Delivery. Misoprostol Tablets can induce or augment uterine contractions. Vaginal administration of Misoprostol Tablets, outside of its approved indication, has been used as cervical ripening agent, for the induction of labor and for treatment of serious postpartum hemorrhage in the presence of uterine atony. major adverse effect of the obstetrical use of Misoprostol Tablets 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 hospital setting.The risk of uterine rupture associated with misoprostol use in pregnancy increases with advancing gestational ages and prior uterine surgery, including Cesarean delivery. Grand multiparity also appears to be risk factor for uterine rupture.The use of Misoprostol Tablets 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 reportedwith the use of misoprostol.Misoprostol Tablets should not be used in the third trimester in women with history of Cesarean section or major uterine surgery because of an increased risk of uterine rupture. Misoprostol Tablets 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 Misoprostol Tablets on later growth, development, and functional maturation of the child when Misoprostol Tablets is used for cervical ripening or induction of labor has not been established. Information on Misoprostol Tablets effect on the need for forceps delivery or other intervention is unknown.The use of Misoprostol Tablets for the management of postpartum hemorrhage has been associated with reports of high fevers (greater than 40 degrees Celsius or 104 degrees Fahrenheit), accompanied by autonomic and central nervous system effects, such as tachycardia, disorientation, agitation, and convulsions. These fevers were transient in nature. Supportive therapy should be dictated by the patients clinical presentation.

OVERDOSAGE SECTION.

OVERDOSAGE. The toxic dose of Misoprostol Tablets 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 fatty acid, it is unlikely that dialysis would be appropriate treatment for overdosage.

PHARMACODYNAMICS SECTION.

Pharmacodynamics. Misoprostol has both antisecretory (inhibiting gastric acid secretion) and (in animals) mucosal protective properties. NSAIDs inhibit prostaglandin synthesis, and 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 high affinity for misoprostol, for its acid metabolite, and for other type prostaglandins, but not for or 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 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.

PHARMACOKINETICS SECTION.

Pharmacokinetics. Misoprostol is extensively absorbed, and undergoes rapid de-esterification to its free acid, which is responsible for its clinical activity and, unlike the parent compound, is detectable in plasma. The alpha side chain undergoes beta oxidation and the beta side chain undergoes omega oxidation followed by reduction of the ketone to give prostaglandin analogs.In normal volunteers, misoprostol is rapidly absorbed after oral administration with Tmax of misoprostol acid of 12 +- minutes and terminal half-life of 20 to 40 minutes.There is high variability of plasma levels of misoprostol acid between and within studies but mean values after single doses show linear relationship with dose over the range of 200 to 400 mcg. No accumulation of misoprostol acid was noted in multiple dose studies; plasma steady state was achieved within two days.Maximum plasma concentrations of misoprostol acid are diminished when the dose is taken with food and total availability of misoprostol acid is reduced by use of concomitant antacid. Clinical trials were conducted with concomitant antacid, however, so this effect does not appear to be clinically important. Mean +- SD Cmax(pg/ml) AUC(0-4) (pghr/ml) Tmax(min) Fasting 811 +- 317 417 +- 135 14 +- With Antacid 689 +- 315 349 +- 108 20 +- 14 With High Fat Breakfast 303 +- 176 373 +- 111 64 +- 79 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 1/2, max 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 20% decrease in aspirin AUC, not thought to be clinically significant.Pharmacokinetic studies also showed lack of drug interaction with antipyrine and propranolol when these drugs were given with misoprostol. Misoprostol given for week had no effect on the steady state pharmacokinetics of diazepam when the two drugs were administered hours apart.The serum protein binding of misoprostol acid is less than 90% and is concentration-independent in the therapeutic range.After 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 hour after dosing and was 7.6 pg/mL (CV 37%) and 20.9 pg/ml (CV 62%) after single 200 ug and 600 ug misoprostol administration, respectively. The misoprostol acid concentrations in breast milk declined to 1 pg/ml at hours post-dose.

PRECAUTIONS SECTION.

PRECAUTIONS. Caution should be employed when administering misoprostol to patients with pre-existing cardiovascular disease.. Information for Patients. Women of childbearing potential using Misoprostol Tablets to decrease the risk of NSAID-induced ulcers should be told that they must not be pregnant when Misoprostol Tablets therapy is initiated, and that they must use an effective contraception method while taking Misoprostol Tablets.See boxed WARNINGS. Misoprostol Tablets is intended for administration along with nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, to decrease the chance of developing an NSAID-induced gastric ulcer.Misoprostol Tablets should be taken only according to the directions given by physician.If the patient has questions about or problems with Misoprostol Tablets, the physician should be contacted promptly.THE PATIENT SHOULD NOT GIVE MISOPROSTOL TABLETS TO ANYONE ELSE. Misoprostol Tablets has been prescribed for the patients specific condition, may not be the correct treatment for another person, and may be dangerous to the other person if she were to become pregnant. The Misoprostol Tablets package the patient receives from the pharmacist will include leaflet containing patient information. The patient should read the leaflet before taking Misoprostol Tablets and each time the prescription is renewed because the leaflet may have been revised.Keep Misoprostol Tablets out of the reach of children.SPECIAL NOTE FOR WOMEN: Misoprostol Tablets may cause birth defects, abortion (sometimes incomplete), premature labor or rupture of the uterus if given to pregnant women.Misoprostol Tablets is available only as unit-of-use package that includes leaflet containing patient information. See Patient Information at the end of this labeling. Drug Interactions. See Clinical Pharmacology. Misoprostol Tablets has not been shown to interfere with the beneficial effects of aspirin on signs and symptoms of rheumatoid arthritis. Misoprostol Tablets does not exert clinically significant effects on the absorption, blood levels, and antiplatelet effects of therapeutic doses of aspirin. Misoprostol Tablets has no clinically significant effect on the kinetics of diclofenac or ibuprofen. Prostaglandins such as Misoprostol Tablets may augment the activity of oxytocic agents, especially when given less than hours prior to initiating oxytocin treatment. Concomitantuse is not recommended.