MISOPROSTOL

Apotheca, Inc.

MISOPROSTOL 200MCG TABLETS USP Rx Only

FULL PRESCRIBING INFORMATION: CONTENTS*

• WARNINGS
• MISOPROSTOL DESCRIPTION
• CLINICAL PHARMACOLOGY
  • Pharmacodynamics
  • Effects on Gastric Acid Secretion
  • Uterine Effects
  • Other Pharmacologic Effects
  • Clinical Studies
  • Reducing the Risk of Gastric Ulcers Caused by Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
• MISOPROSTOL INDICATIONS AND USAGE
• MISOPROSTOL CONTRAINDICATIONS
• WARNINGS
• PRECAUTIONS
  • Information for Patients
  • Drug interactions
  • Animal toxicology
  • Carcinogenesis, mutagenesis, impairment of fertility
  • Pregnancy: Pregnancy Category X
  • Labor and delivery
  • Nursing mothers
  • Pediatric Use
• MISOPROSTOL ADVERSE REACTIONS
  • Gynecological
  • Elderly
  • Causal Relationship Unknown
• OVERDOSAGE
• MISOPROSTOL DOSAGE AND ADMINISTRATION
• HOW SUPPLIED
• PATIENT INFORMATION
• PRINCIPAL DISPLAY PANEL, Package Label

FULL PRESCRIBING INFORMATION

MISOPROSTOL DESCRIPTION

Misoprostol oral tablets contain either 100 mcg or 200 mcg of misoprostol, a synthetic prostaglandin E₁ analog.

Misoprostol contains approximately equal amounts of the two diastereomers presented below with their enantiomers indicated by (±):

Misoprostol is a water-soluble, viscous liquid.

Pfizer's (manufacture for Greenstone) Inactive ingredients of tablets are hydrogenated castor oil, hypromellose, microcrystalline cellulose, and sodium starch glycolate.

Ivax's (manufacture) Inactive ingredients of tablets are hydrogenated vegetable oil, hypromellose, microcrystalline cellulose, and sodium starch glycolate.

CLINICAL PHARMACOLOGY

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 F analogs.

In normal volunteers, misoprostol is rapidly absorbed after oral administration with a T_max of misoprostol acid of 12 ± 3 minutes and a terminal half-life of 20–40 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 200-400 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.

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 T_1/2, C_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.

Misoprostol does not affect the hepatic mixed function oxidase (cytochrome P-450) enzyme systems in animals.

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.

Pharmacodynamics

Misoprostol 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.

Effects on Gastric Acid Secretion

Uterine Effects

Other Pharmacologic Effects

Clinical Studies

Reducing the Risk of Gastric Ulcers Caused by Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

In these trials there were no significant differences between misoprostol and placebo in relief of day or night abdominal pain. No effect of misoprostol in reducing the risk of duodenal ulcers was demonstrated, but relatively few duodenal lesions were seen.

In another clinical trial, 239 patients receiving aspirin 650–1300 mg q.i.d. for rheumatoid arthritis who had endoscopic evidence of duodenal and/or gastric inflammation were randomized to misoprostol 200 mcg q.i.d. or placebo for 8 weeks while continuing to receive aspirin. The study evaluated the possible interference of misoprostol on the efficacy of aspirin in these patients with rheumatoid arthritis by analyzing joint tenderness, joint swelling, physician’s clinical assessment, patient’s assessment, change in ARA classification, change in handgrip strength, change in duration of morning stiffness, patient’s assessment of pain at rest, movement, interference with daily activity, and ESR. Misoprostol did not interfere with the efficacy of aspirin in these patients with rheumatoid arthritis.

MISOPROSTOL INDICATIONS AND USAGE

MISOPROSTOL CONTRAINDICATIONS

See boxed WARNINGS. Misoprostol should not be taken by pregnant women to reduce the risk of ulcers induced by non-steroidal anti-inflammatory drugs (NSAIDs).

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

WARNINGS

See boxed WARNINGS.

PRECAUTIONS

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 is or 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 abortion (sometimes incomplete), premature labor, or birth defects 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

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: Pregnancy Category X

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.

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 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 hyperstimulation of the uterus 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. Pelvic pain, retained placenta, severe genital bleeding, shock, fetal bradycardia, and fetal and maternal death have been reported.

There may be an increased risk of uterine tachysystole, uterine rupture, meconium passage, meconium staining of amniotic fluid, and Cesarean delivery due to uterine hyperstimulation with the use of higher doses of misoprostol, including the manufactured 100 mcg tablet. The risk of uterine rupture increases with advancing gestational ages and with prior uterine surgery, including Cesarean delivery. Grand multiparity also appears to be a risk factor for uterine rupture.

The effect of misoprostol on the later growth, development, and functional maturation of the child when misoprostol is used for cervical ripening or induction of labor have not been established.

Information on misoprostol’s effect on the need for forceps delivery or other intervention is unknown.

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

MISOPROSTOL ADVERSE REACTIONS

The following have been reported as adverse events in subjects receiving misoprostol:

In subjects receiving misoprostol 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 14–40% and in all studies (over 5,000 patients) averaged 13%. Abdominal pain occurred in 13–20% 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 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 misoprostol is prescribed. The incidence of diarrhea can be minimized by administering after meals and at bedtime, and by avoiding coadministration of misoprostol with magnesium-containing antacids.

Gynecological

Elderly

There were no significant differences in the safety profile of misoprostol 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:

Causal Relationship Unknown

The following adverse events were infrequently reported. Causal relationships between misoprostol and these events have not been established but cannot be excluded:

Aches/pains, asthenia, fatigue, fever, chills, rigors, weight changes

Rash, dermatitis, alopecia, pallor, breast pain

Abnormal taste, abnormal vision, conjunctivitis, deafness, tinnitus, earache

Upper respiratory tract infection, bronchitis, bronchospasm, dyspnea, pneumonia, epistaxis

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).

GI bleeding, GI inflammation/infection, rectal disorder, abnormal hepatobiliary function, gingivitis, reflux, dysphagia, amylase increase

Anaphylaxis

Glycosuria, gout, increased nitrogen, increased alkaline phosphatase

Polyuria, dysuria, hematuria, urinary tract infection

Anxiety, change in appetite, depression, drowsiness, dizziness, thirst, impotence, loss of libido, sweating increase, neuropathy, neurosis, confusion

Arthralgia, myalgia, muscle cramps, stiffness, back pain

Anemia, abnormal differential, thrombocytopenia, purpura, ESR increased

OVERDOSAGE

The toxic dose of misoprostol 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.

MISOPROSTOL DOSAGE AND ADMINISTRATION

The recommended adult oral dose of misoprostol 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.) Misoprostol should be taken for the duration of NSAID therapy as prescribed by the physician. Misoprostol should be taken with a meal, and the last dose of the day should be at bedtime.

Adjustment 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 SUPPLIED

• NDC 12634-502-91 Blister Pack UD
• NDC 12634-502-92 Bottle of 2
• NDC 12634-502-94 Bottle of 4
• NDC 12634-502-98 Bottle of 8

• 12634-980-91 UD Blister Pack of 1
• 12634-980-94 Bottle of 4
• 12634-980-98 Bottle of 8
• 12634-980-84 Bottle of 14
• 12634-980-78 Bottle of 28
• 12634-980-71 Bottle of 30

PATIENT INFORMATION

Read this leaflet before taking misoprostol and each time your prescription is renewed, because the leaflet may be changed.

Misoprostol is being prescribed by your doctor to decrease the chance of getting stomach ulcers related to the arthritis/pain medication that you take.

Do not take misoprostol to reduce the risk of NSAID induced ulcers if you are pregnant (See boxed WARNINGS). Misoprostol can cause abortion (sometimes incomplete which could lead to dangerous bleeding and require hospitalization and surgery), premature birth, or birth defects. It is also important to avoid pregnancy while taking this medication and for at least one month or through one menstrual cycle after you stop taking it. Misoprostol has been reported to cause the uterus to rupture (tear) when given after the eighth week of pregnancy. Rupture (tearing) of the uterus can result in severe bleeding, hysterectomy, and/or maternal or fetal death.

If you become pregnant during misoprostol therapy, stop taking misoprostol and contact your physician immediately. Remember that even if you are on a means of birth control it is still possible to become pregnant. Should this occur, stop taking misoprostol and contact your physician immediately.

Misoprostol may cause diarrhea, abdominal cramping, and/or nausea in some people. In most cases these problems develop during the first few weeks of therapy and stop after about a week. You can minimize possible diarrhea by making sure you take misoprostol with food.

Because these side effects are usually mild to moderate and usually go away in a matter of days, most patients can continue to take misoprostol. If you have prolonged difficulty (more than 8 days), or if you have severe diarrhea, cramping and/or nausea, call your doctor.

Take misoprostol only according to the directions given by your physician.

Do not give misoprostol to anyone else. It has been prescribed for your specific condition, may not be the correct treatment for another person, and would be dangerous if the other person were pregnant.

This information sheet does not cover all possible side effects of misoprostol. This patient information leaflet does not address the side effects of your arthritis/pain medication. See your doctor if you have questions.

Keep out of reach of children.

Misoprostol 100mcg Manufactured by Ivax Pharmaceuicals in Ireland, for Ivax Pharmceuticals USA
Misoprpstol 200mcg Manufactured by pfizer for Greenstone LLC
Repackaged and Distributed by:
Apotheca Inc.
Phoenix, AZ 85006

PRINCIPAL DISPLAY PANEL, Package Label