MISOPROSTOL: 3,539 Adverse Event Reports & Safety Profile

DESCRIPTION Misoprostol oral tablets contain either 100 mcg or 200 mcg of misoprostol, a synthetic prostaglandin E 1 analog. Misoprostol contains approximately equal amounts of the two diastereomers presented below with their enantiomers indicated by (±): C 22 H 38 O 5 M.W. = 382.5 (±) methyl 11α, 16-dihydroxy-16-methyl-9-oxoprost-13E-en-1-oate Misoprostol is a water-soluble, viscous liquid. Inactive ingredients of tablets are hydrogenated castor oil, hypromellose, microcrystalline cellulose, and sodium starch glycolate.

Chemical

Structure

INDICATIONS AND USAGE Misoprostol tablets are 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. Misoprostol tablets has not been shown to reduce the risk of duodenal ulcers in patients taking NSAIDs. Misoprostol tablets should be taken for the duration of NSAID therapy. Misoprostol tablets 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.

Directions ■ Before using it, clean the affected area with soap and soak the nail with warm water to soften it. ■ For toe fungus, scrape off the dirt on the nail, and gently file the thickened part of the fungal nail with a nail file until it’s flat. (be careful not to hurt the nail bed) You can use a nail file every 2-3 days to polish the surface of the affected area. Apply the liquid with a thin layer over the affected area, the skin under the nail, and around the cuticle area. ■ For athlete’s foot, pay special attention to spaces between toes. ■ Use it twice in the morning and evening for at least 8 weeks to see the effect. And if you want complete improvement, we recommend using it for 3-6 months. ■ You can use this product preventively for fungus in hot and humid conditions.

CONTRAINDICATIONS See boxed WARNINGS .

Misoprostol

Tablets should not be taken by pregnant women to reduce the risk of ulcers induced by nonsteroidal anti-inflammatory drugs (NSAIDs).

Misoprostol

Tablets should not be taken by anyone with a history of allergy to prostaglandins.

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 8 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 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 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 Lupin Pharmaceuticlas, Inc. at 1-866-403-7592 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

WARNINGS See boxed WARNINGS . For hospital use only if misoprostol were to be used for cervical ripening, induction of labor, or for the treatment of serious post-partum hemorrhage, which are outside of the approved indication.

PRECAUTIONS Caution should be employed when administering misoprostol to patients with pre-existing cardiovascular disease. Information for patients: Women of childbearing potential using misoprostol to decrease the risk of NSAID-induced ulcers should be told that they must not be pregnant when misoprostol therapy is initiated, and that they must use an effective contraception method while taking misoprostol. See boxed WARNINGS . Misoprostol 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 should be taken only according to the directions given by a physician. If the patient has questions about or problems with misoprostol, the physician should be contacted promptly. THE PATIENT SHOULD NOT GIVE MISOPROSTOL TO ANYONE ELSE. Misoprostol has been prescribed for the patient’s 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 package the patient receives from the pharmacist will include a leaflet containing patient information. The patient should read the leaflet before taking misoprostol and each time the prescription is renewed because the leaflet may have been revised. Keep misoprostol out of the reach of children. SPECIAL NOTE FOR WOMEN: Misoprostol may cause birth defects, abortion (sometimes incomplete), premature labor or rupture of the uterus if given to pregnant women. Misoprostol is available only as a unit-of-use package that includes a leaflet containing patient information.

See Patient

Information at the end of this labeling. Drug interactions: See Clinical Pharmacology . Misoprostol has not been shown to interfere with the beneficial effects of aspirin on signs and symptoms of rheumatoid arthritis. Misoprostol does not exert clinically significant effects on the absorption, blood levels, and antiplatelet effects of therapeutic doses of aspirin. Misoprostol has no clinically significant effect on the kinetics of diclofenac or ibuprofen. Prostaglandins such as misoprostol may augment the activity of oxytocic agents, especially when given less than 4 hours prior to initiating oxytocin treatment. Concomitant use is not recommended. Animal toxicology: A reversible increase in the number of normal surface gastric epithelial cells occurred in the dog, rat, and mouse. No such increase has been observed in humans administered misoprostol for up to 1 year. An apparent response of the female mouse to misoprostol in long-term studies at 100 to 1000 times the human dose was hyperostosis, mainly of the medulla of sternebrae. Hyperostosis did not occur in long-term studies in the dog and rat and has not been seen in humans treated with misoprostol. Carcinogenesis, mutagenesis, impairment of fertility: There was no evidence of an effect of misoprostol on tumor occurrence or incidence in rats receiving daily doses up to 150 times the human dose for 24 months. Similarly, there was no effect of misoprostol on tumor occurrence or incidence in mice receiving daily doses up to 1000 times the human dose for 21 months. The mutagenic potential of misoprostol was tested in several in vitro assays, all of which were negative. Misoprostol, when administered to breeding male and female rats at doses 6.25 times to 625 times the maximum recommended human therapeutic dose, produced dose-related pre- and post-implantation losses and a significant decrease in the number of live pups born at the highest dose. These findings suggest the possibility of a general adverse effect on fertility in males and females. Pregnancy: Teratogenic 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. Misoprostol is not fetotoxic or teratogenic in rats and rabbits at doses 625 and 63 times the human dose, respectively. Nonteratogenic effects: See boxed WARNINGS . Misoprostol may endanger pregnancy (may cause abortion) and thereby cause harm to the fetus when administered to a pregnant woman. Misoprostol may produce uterine contractions, uterine bleeding, and expulsion of the products of conception. Abortions caused by misoprostol 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 delivery: Misoprostol can induce or augment uterine contractions. Vaginal administration of misoprostol, 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 misoprostol 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 associated with misoprostol use in pregnancy 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 misoprostol 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. Misoprostol 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. Misoprostol 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 on later growth, development, and functional maturation of the child when misoprostol is used for cervical ripening or induction of labor has not been established. Information on misoprostol's effect on the need for forceps delivery or other intervention is unknown. The use of misoprostol 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 patient’s clinical presentation. Nursing mothers: Misoprostol 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 use: Safety and effectiveness of misoprostol in pediatric patients have not been established.

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 4 hours prior to initiating oxytocin treatment. Concomitant use is not recommended.

Active Ingredient Undecylenic acid 10%

Inactive ingredients Mineral oil, Apricot Kernel Oil, Tea Tree Oil, Tocopherol, Peppermint Oil, Camphor Oil, Jojoba Oil, Bergamot Oil, Lavender Oil