Cytotec (Misoprostol)

CYTOTEC®

Searle

Misoprostol

Mucosal Protective Agent

Action And Clinical Pharmacology: Misoprostol is a synthetic analogue of prostaglandin E1. In animals and man, it has both gastric antisecretory and mucosal protective effects. Its antisecretory activity is mediated by a direct action on the parietal cells. Misoprostol exerts a mucosal protective effect by enhancing natural mucosal defense mechanisms. Studies conducted in animals and clinical trials in humans have demonstrated that misoprostol can protect the gastric mucosa against various irritants such as alcohol, ASA, naproxen, sodium taurocholate and tolmetin. In addition, misoprostol has been shown to increase mucus production and to increase bicarbonate secretion in the duodenum. Misoprostol has local and systemic activity.

Following administration of a single 200 µg dose of misoprostol to 6 healthy male subjects, the mean Cmax, AUC (0 to 24) and Tmax of the primary biologically active acid metabolite were: 309 pg/mL, 355 pg.hr/mL and 0.5 hours respectively. After administration of tritiated misoprostol the elimination half-life of misoprostol acid (the active metabolite of misoprostol) was 20.6 minutes, and the elimination half-life of total organic extractable radioactivity was 1.5 to 1.7 hours. The duration of antisecretory activity is greater than 3 but less than 6 hours.

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.

Indications And Clinical Uses: For the treatment and prevention of NSAID-induced gastroduodenal ulcers. Also indicated for the treatment of duodenal ulcers caused by Peptic Ulcer Disease (PUD).

Patients at high risk of developing NSAID-induced complications and who may require protection include: patients with a previous history of ulcer disease or a significant gastrointestinal event; patients over 60 years of age; patients judged to be at risk because of general poor health, severe concomitant medical disease, or patients who are poor surgical risks; patients disabled by joint symptoms (e.g., HAQ Disability Index Score >1.5) or those with severe systemic manifestations of arthritis; patients taking other drugs known to damage or exacerbate damage to the gastrointestinal tract such as corticosteroids or anticoagulants; patients taking a high dosage or multiple NSAIDs, including those available over-the-counter.

The risk of NSAID-induced complications may be highest in the first 3 months of NSAID therapy.

Contra-Indications: Known sensitivity to prostaglandins, prostaglandin analogues or excipients (microcrystalline and hydroxypropyl methylcellulose, sodium starch glycolate and hydrogenated castor oil).

Pregnancy: Contraindicated in pregnancy.

Women should be advised not to become pregnant while taking misoprostol. If pregnancy is suspected, use of the product should be discontinued.

Manufacturers’ Warnings In Clinical States: Pregnancy: Women of childbearing potential should employ adequate contraception (i.e., oral contraceptives or intrauterine devices) while receiving misoprostol (see Contraindications).

Lactation: It is unlikely that misoprostol is excreted in human milk since it is rapidly metabolized throughout the body. However, it is not known if the active metabolite (misoprostol acid) is excreted in human milk. Therefore, misoprostol should not be administered to nursing mothers because the potential excretion of misoprostol acid could cause significant diarrhea in nursing infants.

Children: Safety and effectiveness in patients below the age of 18 have not been established.

Precautions: Selection of Patients: Caution should be used when using symptomatology as the sole diagnostic and follow-up procedure, since misoprostol has not been shown to have an effect on gastrointestinal pain or discomfort.

Before treatment is undertaken, a positive diagnosis of duodenal ulcer or NSAID-induced gastroduodenal ulcer should be made. The general health of the patient should be considered. Misoprostol is rapidly metabolized by most body tissues to inactive metabolites. Nevertheless, caution should be exercised when patients have impairment of renal or hepatic function.

Diarrhea: Rare instances of profound diarrhea leading to severe dehydration have been reported. Patients with an underlying condition such as irritable bowel disease, or those in whom dehydration, were it to occur, would be dangerous, should be monitored carefully if misoprostol is prescribed.

Geriatrics or Renally Impaired: Considerations for Dosage Adjustment: In subjects over 64 years of age or those who are renally impaired the pharmacokinetics may be affected, but not to a clinically significant degree (see Dosage). No routine dosage adjustment is recommended in older patients or those patients with renal impairment. Dosage may need to be reduced if the usual dose is not tolerated. In patients with renal failure, a starting dose in the low range (100 µg q.i.d.) is recommended.

Drug Interactions: The serum protein binding of misoprostol acid (the active metabolite of misoprostol) was not affected by: indomethacin, ranitidine, digoxin, phenylbutazone, warfarin, diazepam, methyldopa, propranolol, triamterene, cimetidine, acetaminophen, ibuprofen, chlorpropamide and hydrochlorothiazide.

Salicylic acid (300 µg/mL) lowered the protein binding of misoprostol from 84 to 52%; this is not considered clinically significant since the binding of misoprostol acid is not extensive and its elimination half-life is very short.

In laboratory studies, misoprostol has shown no significant effect on the cytochrome P450-linked hepatic mixed function oxidase system, and therefore should not affect the metabolism of theophylline, warfarin, benzodiazepines or other drugs normally metabolized by this system.

No clinically significant drug interactions attributable to misoprostol have been observed to date.

Some prostaglandins and prostaglandin analogues have the capacity to produce hypotension through peripheral vasodilation. The results of clinical trials to date indicate that misoprostol has not produced hypotension at dosages effective in promoting the healing of ulcers. Nevertheless, misoprostol should be used with caution in the presence of disease states where hypotension might precipitate severe complications, e.g., cerebral vascular disease or coronary artery disease.

Epileptic seizures have been reported with prostaglandins and prostaglandin analogues administered by routes other than oral. Therefore, misoprostol tablets should be used in known epileptics only when their epilepsy is adequately controlled and then only when expected benefits outweigh potential risks.

Symptomatic responses to misoprostol do not preclude the presence of gastric malignancy.

Adverse Reactions: Gastrointestinal: In 18 985 subjects receiving misoprostol daily in clinical trials, the most frequent gastrointestinal adverse events were diarrhea (10.7%), abdominal pain (7.3%), nausea (4.2%), flatulence (3.3%), and dyspepsia (3.2%). The incidence of diarrhea was 7.8% when the total daily dose was 400 µg. In patients receiving placebo, the incidence of diarrhea was 3.6%. The events were usually transient and mild to moderate in severity.

Diarrhea, when it occurred, usually developed early in the course of therapy, was self-limiting and required discontinuation of misoprostol in less than 2% of the patients. The incidence of diarrhea can be minimized by adjusting the dose of misoprostol, by administering after food, and by avoiding coadministration of misoprostol with magnesium-containing antacids.

Gynecological: Women who received misoprostol during clinical trials reported the following gynecological disorders: spotting (0.7%), cramps (0.3%), hypermenorrhea (0.4%), menstrual disorder (0.3%) and dysmenorrhea (0.1%).

Geriatrics: 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.

Confusion has been reported in a small number of patients in postmarketing surveillance of misoprostol.

Incidence greater than 1%: In clinical trials, the following adverse reactions were reported by more than 1% of the subjects receiving misoprostol and may be causally related to the drug: headache (2.5%), vomiting (1.4%) and constipation (1.4%). However, there were no clinically significant differences between the incidences of these events for misoprostol and placebo.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: The toxic dose of misoprostol in human beings has not been determined. Cumulative total daily doses of 1 600 µg have been tolerated with only symptoms of gastrointestinal discomfort being reported. In animals, the acute toxic effects are similar to those reported for other prostaglandins and prostaglandin analogues: relaxation of smooth muscle, respiratory difficulties and depression of the CNS. Possible clinical signs that may indicate an overdose may include: sedation, tremor, fever, convulsions, dyspnea, abdominal pain, diarrhea, palpitations, hypotension or bradycardia. Treatment should be symptomatic and supportive.

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.

Dosage And Administration: Treatment and Prevention of NSAID-Induced Gastroduodenal Ulcers: The recommended adult oral dosage for the prevention and treatment of NSAID-induced gastroduodenal ulcer is 400 to 800 µg a day in divided doses. NSAIDs should be taken according to the schedule prescribed by the physician. When appropriate, misoprostol and NSAIDs are to be taken simultaneously. Misoprostol should be taken after food.

Treatment of Duodenal Ulcer: The recommended adult oral dosage of misoprostol for duodenal ulcer is 800 µg/day for 4 weeks in 2 or 4 equally divided doses (i.e., 200 µg q.i.d. or 400 µg b.i.d.). The last dose should be taken at bedtime with food. Antacids (aluminum based) may be used as needed for relief of pain. Treatment should be continued for a total of 4 weeks unless healing in less time has been documented by endoscopic examination. In the small number of patients who may not have fully healed after 4 weeks, therapy with misoprostol may be continued for a further 4 weeks.

Geriatrics and Renally Impaired: Consideration for Dosage Adjustment: Pharmacokinetic studies in patients with varying degrees of renal impairment showed an approximate doubling of T1/2, Cmax and AUC compared to normals. There was no clear correlation between degree of impairment and AUC. In subjects over 64 years of age the pharmacokinetics may be affected. In both patient groups the pharmacokinetic changes are not clinically significant. No routine dosage adjustment is recommended in older patients or those patients with renal impairment. Dosage may need to be reduced if the usual dose is not tolerated. In patients with renal failure, a starting dose in the low range (100 µg q.i.d.) is recommended.

Availability And Storage: 100 µg: Each white to off-white, round tablet, with SEARLE engraved on one side and CYTOTEC on the other, contains: misoprostol 100 µg. Nonmedicinal ingredients: cellulose, hydrogenated castor oil, hydroxypropyl methylcellulose and sodium starch glycolate. Bottles of 100. Store below 30°C.

200 µg: Each white to off-white, scored, hexagonal tablet, with SEARLE 1461 engraved on one side, contains: misoprostol 200 µg. Nonmedicinal ingredients: cellulose, hydrogenated castor oil, hydroxypropyl methylcellulose and sodium starch glycolate. Bottles of 120 and 500. Store below 30°C.

Pharmacist: Dispense with Patient Insert. (Shown in Product Recognition Section)

CYTOTEC® Searle Misoprostol Mucosal Protective Agent

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