میزوپروستول
Misoprostol (Cytotec)
میزوپروستول

نام ژنریک

Misoprostol

شکل دارویی

اشكال دارويي:


Tablet: 100 ,200mcg

موارد مصرف

موارد و مقدار مصرف


پيشگيري از زخم‌هاي معده ناشي از NSAID


بزرگسالان: 200 ميكروگرم خوراكي، 4 بار در روز همراه غذا و موقع خواب، در صورت عدم تحمل بيمار 100 ميكروگرم خوراكي، 4 بار در روز.


زخم معده يا دئودنوم


بزرگسالان: 200-100 ميكروگرم خوراكي، 4 بار در روز همراه غذا و موقع خواب به مدت 8-4 هفته.

موارد منع مصرف

موارد منع مصرف و احتياط


موارد منع مصرف: بارداري، سابقه حساسيت به پروستاگلاندين‌ها.

عوارض جانبی دارو

عوارض جانبي


اعصاب مرکزي: سردرد.


دستگاه گوارش: درد شكم، يبوست، اسهال، سوءهاضمه، نفخ، تهوع، استفراغ.


ادراري ـ تناسلي: كرامپ، ديسمنوره، هايپرمنوره، اختلال قاعدگي، خونريزي پس از يائسگي، لكه بيني.


مسموميت و درمان


تجربه باليني كمي با موارد مصرف بيش از حد دارو وجود دارد. مصرف دوز تجمعي 1600 ميكروگرم با عوارض گوارشي خفيفي همراه بوده است. در صورت بروز مسموميت احتمالات حمايتي توصيه مي‌گردد.

موارد قابل توجه

-

تداخل دارویی

تداخل دارويي


تداخلي گزارش نشده است.

مکانیزم اثر

تداخل دارويي


تداخلي گزارش نشده است.

فارماكوكینتیك

فارماكوكينتيك


جذب: دارو سريعاً بعد از مصرف خوراكي جذب مي‌شود.


پخش: كمتر از 90 درصد دارو به پروتئين‌هاي پلاسما اتصال مي‌يابد.


متابوليسم: دارو سريعاً در اثر شكست پيوند استري به متابوليت فعال تبديل و در نهايت در ساير بافت‌ها تحت واكنش اكسيداسيون قرار مي‌گيرد.


دفع: 15 درصد دوز خوراكي دارو در مدفوع وارد مي‌شود. ولي راه اصلي دفع دارو ادرار است. نيمه‌عمر نهايي دارو 40-20 دقيقه است.

سایر اطلاعات

طبقه‌بندي فارماكولوژيك: آنالوگ پروستاگلاندين E1.


طبقه‌بندي درماني: ضد زخم، محافظ مخاط معده.


طبقه‌بندي مصرف در بارداري: رده X


نام‌هاي تجاري: Cytotec


ملاحظات اختصاصي


توجه: ميزوپروستول با ميفپريستول اشتباه مي‌شود.


1- از تجويز دارو براي خانم‌ها در سنين باروري تا اطمينان از كاربرد يك روش مناسب جلوگيري از بارداري خودداري كنيد. به بيماران در رابطه با خطرات دارو در صورت شكست روش جلوگيري از بارداري به صورت شفاهي و كتبي اطلاع‌رساني نماييد.


دارو بايد در صورت منفي شدن تست بارداري در عرض 2 هفته قبل از شروع دارو درماني و در روز دوم يا سوم پس از قاعدگي طبيعي مصرف شود.


2- عوامل خطر جهت پارگي رحم عبارتند از: ايام پاياني بارداري، مصرف دوز بالا از دارو، سابقه سزارين، جراحي رحم يا 5 و يا بيش از 5 بار سابقه بارداري.


3- اسهال معمولاً وابسته به دوز بوده و در عرض 2 هفته اول درمان به وجود مي‌آيد.


با مصرف دارو بعد از غذا و موقع خواب و اجتناب از مصرف آنتاسيدهاي حاوي منيزيم مي‌توان احتمال بروز آن را كاهش داد.


نكات قابل توصيه به بيمار


1- به بيمار توصيه نماييد مصرف دارو را به ديگران پيشنهاد ندهد.


2- به بيمار اطلاع دهيد مصرف دارو در خانم‌هاي باردار باعث سقط مي‌شود.


3- بيمار بايد دارو را براساس دستور پزشك مصرف نمايد.


مصرف در كودكان: ايمني دارو در كودكان به اثبات نرسيده است.


مصرف در شيردهي: در زمان مصرف دارو به دليل احتمال بروز اسهال در نوزاد در شيردهي توصيه نمي‌شود.


مصرف در بارداري: خانم‌هاي باردار نبايد از ميزوپروستول استفاده نمايند.


اثر بر آزمايشهاي تشخيصي


گزارشي وجود ندارد.

Misoprostol (Cytotec)

Cytotec®
(misoprostol) Tablets

WARNING

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.

DRUG DESCRIPTION

Cytotec 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 (±):

Cytotec® (misoprostol) Structural Formula Illustration

Misoprostol is a water-soluble, viscous liquid.

Inactive ingredients of tablets are hydrogenated castor oil, hypromellose, microcrystalline cellulose, and sodium starch glycolate.

What are the possible side effects of misoprostol (Cytotec)?

Stop taking misoprostol and seek emergency medical attention if you experience an allergic reaction (difficulty breathing; closing of the throat; swelling of the lips, tongue, or face; or hives).

Misoprostol may cause mild to moderate diarrhea, stomach cramps, and/or nausea. These problems usually occur during the first few weeks of treatment and stop after about a week. The occurrence of diarrhea may be minimized by taking misoprostol with food. Contact your doctor if these symptoms persist for longer than 8 days or if they are severe.

Other, less serious side effects may also...

Read All Potential Side Effects and See Pictures of Cytotec »

What are the precautions when taking misoprostol (Cytotec)?

Before taking misoprostol, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: stomach/intestinal disease (e.g., inflammatory bowel disease), risk factors for uterine rupture when this drug is used vaginally (e.g., prior Cesarean delivery, uterine surgery, five or more previous pregnancies).

Daily use of alcohol and tobacco may increase your risk for stomach bleeding. Limit alcohol beverages and stop smoking. Consult your doctor or pharmacist for more information.

If you are taking this...

Read All Potential Precautions of Cytotec »

Last reviewed on RxList: 12/7/2012
This monograph has been modified to include the generic and brand name in many instances.

INDICATIONS

Cytotec (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 ADMINISTRATION

The 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 impairment

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

Cytotec 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
0025-1461-60 unit-of-use bottle of 60
0025-1461-31 unit-of-use bottle of 120
0025-1461-34 carton of 100 unit dose

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

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 2012

Last reviewed on RxList: 12/7/2012
This monograph has been modified to include the generic and brand name in many instances.

SIDE EFFECTS

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

Gastrointestinal

In 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 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 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.

Gynecological

Women 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.)

Elderly

There 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 unknown

The 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 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.

Read the Cytotec (misoprostol) Side Effects Center for a complete guide to possible side effects »

DRUG INTERACTIONS

See 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.

Last reviewed on RxList: 12/7/2012
This monograph has been modified to include the generic and brand name in many instances.

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 Cytotec (misoprostol) to patients with pre-existing cardiovascular disease.

Information for patients

Women of childbearing potential using Cytotec to decrease the risk of NSAID-induced ulcers should be told that they must not be pregnant when Cytotec therapy is initiated, and that they must use an effective contraception method while taking Cytotec.

See BOXED WARNINGS.

Cytotec is intended for administration along with nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, to decrease the chance of developing an NSAID-induced gastric ulcer.

Cytotec should be taken only according to the directions given by a physician.

If the patient has questions about or problems with Cytotec, the physician should be contacted promptly.

THE PATIENT SHOULD NOT GIVE CYTOTEC TO ANYONE ELSE. Cytotec 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 Cytotec package the patient receives from the pharmacist will include a leaflet containing patient information. The patient should read the leaflet before taking Cytotec and each time the prescription is renewed because the leaflet may have been revised.

Keep Cytotec out of the reach of children.

SPECIAL NOTE FOR WOMEN: Cytotec may cause birth defects, abortion (sometimes incomplete), or premature labor if given to pregnant women.

Cytotec 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.

Carcinogenesis, mutagenesis, impairment of fertility

There was no evidence of an effect of Cytotec 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 Cytotec on tumor occurrence or incidence in mice receiving daily doses up to 1000 times the human dose for 21 months. The mutagenic potential of Cytotec 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

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.

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 delivery

Cytotec 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 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 Cytotec in pediatric patients have not been established.

Last reviewed on RxList: 12/7/2012
This monograph has been modified to include the generic and brand name in many instances.

OVERDOSE

The 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.

CONTRAINDICATIONS

See BOXED WARNINGS.

Cytotec 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.

Last reviewed on RxList: 12/7/2012
This monograph has been modified to include the generic and brand name in many instances.

CLINICAL PHARMACOLOGY

Pharmacokinetics

Misoprostol 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 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.

Mean ± SD Cmax(pg/ml) AUC(0–4) (pg•hr/ml) Tmax(min)
Fasting 811 ± 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 μg and 600 μg misoprostol administration, respectively. The misoprostol acid concentrations in breast milk declined to < 1 pg/ml at 5 hours post-dose.

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

Misoprostol, over the range of 50–200 mcg, inhibits basal and nocturnal gastric acid secretion, and acid secretion in response to a variety of stimuli, including meals, histamine, pentagastrin, and coffee. Activity is apparent 30 minutes after oral administration and persists for at least 3 hours. In general, the effects of 50 mcg were modest and shorter lived, and only the 200-mcg dose had substantial effects on nocturnal secretion or on histamine and meal-stimulated secretion.

Uterine effects

Cytotec has been shown to produce uterine contractions that may endanger pregnancy. (See BOXED WARNINGS.)

Other pharmacologic effects

Cytotec does not produce clinically significant effects on serum levels of prolactin, gonadotropins, thyroid-stimulating hormone, growth hormone, thyroxine, cortisol, gastrointestinal hormones (somatostatin, gastrin, vasoactive intestinal polypeptide, and motilin), creatinine, or uric acid. Gastric emptying, immunologic competence, platelet aggregation, pulmonary function, or the cardiovascular system are not modified by recommended doses of Cytotec.

Clinical studies

In a series of small short-term (about 1 week) placebo-controlled studies in healthy human volunteers, doses of misoprostol were evaluated for their ability to reduce the risk of NSAID-induced mucosal injury. Studies of 200 mcg q.i.d. of misoprostol with tolmetin and naproxen, and of 100 and 200 mcg q.i.d. with ibuprofen, all showed reduction of the rate of significant endoscopic injury from about 70–75% on placebo to 10–30% on misoprostol. Doses of 25–200 mcg q.i.d. reduced aspirin-induced mucosal injury and bleeding.

Reducing the risk of gastric ulcers caused by nonsteroidalanti-inflammatory drugs (NSAIDs)

Two 12-week, randomized, double-blind trials in osteoarthritic patients who had gastrointestinal symptoms but no ulcer on endoscopy while taking an NSAID compared the ability of 200 mcg of Cytotec, 100 mcg of Cytotec, and placebo to reduce the risk of gastric ulcer (GU) formation. Patients were approximately equally divided between ibuprofen, piroxicam, and naproxen, and continued this treatment throughout the 12 weeks. The 200-mcg dose caused a marked, statistically significant reduction in gastric ulcers in both studies. The lower dose was somewhat less effective, with a significant result in only one of the studies.

Reduction of Risk of Gastric Ulcers Induced by Ibuprofen, Piroxicam, or Naproxen [No. of patients with ulcer(s) (%)]

Therapy Duration Therapy  
4 weeks 8 weeks 12 weeks
Study No. 1
Cytotec 200 mcg q.i.d. (n=74) 1 (1.4) 0 0 1 (1.4)*
Cytotec 100 mcg q.i.d. (n=77) 3 (3.9) 1 (1.3) 1 (1.3) 5 (6.5)*
Placebo (n=76) 11 (14.5) 4 (5.3) 4 (5.3) 19 (25.0)
Study No. 2
Cytotec 200 mcg q.i.d. (n=65) 1 (1.5) 1 (1.5) 0 2 (3.1)*
Cytotec 100 mcg q.i.d. (n=66) 2 (3.0) 2 (3.0) 1 (1.5) 5 (7.6)
Placebo (n=62) 6 (9.7) 2 (3.2) 3 (4.8) 11 (17.7)
Studies No. 1 & No. 2**
Cytotec 200 mcg q.i.d. (n=139) 2 (1.4) 1 (0.7) 0 3 (2.2)*
Cytotec 100 mcg q.i.d. (n=143) 5 (3.5) 3 (2.1) 2 (1.4) 10 (7.0)*
Placebo (n=138) 17 (12.3) 6 (4.3) 7 (5.1) 30 (21.7)
* Statistically significantly different from placebo at the 5% level.
** Combined data from Study No. 1 and Study No. 2.

In these trials there were no significant differences between Cytotec and placebo in relief of day or night abdominal pain. No effect of Cytotec 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 Cytotec 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. Cytotec did not interfere with the efficacy of aspirin in these patients with rheumatoid arthritis.

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 Cytotec for up to 1 year.

An apparent response of the female mouse to Cytotec 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 Cytotec.

Last reviewed on RxList: 12/7/2012
This monograph has been modified to include the generic and brand name in many instances.

PATIENT INFORMATION

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

Cytotec (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 Cytotec to reduce the risk of NSAID-induced ulcers if you are pregnant. (See BOXED WARNINGS.) Cytotec 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. Cytotec 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 Cytotec therapy, stop taking Cytotec 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 Cytotec and contact your physician immediately.

Cytotec 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 Cytotec 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 Cytotec. If you have prolonged difficulty (more than 8 days), or if you have severe diarrhea, cramping and/or nausea, call your doctor.

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

Do not give Cytotec 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 Cytotec. 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.

This product's label may have been updated. For current full prescribing information, please visit www.pfizer.com.

Last reviewed on RxList: 12/7/2012
This monograph has been modified to include the generic and brand name in many instances.

>

PATIENT INFORMATION

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

Cytotec (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 Cytotec to reduce the risk of NSAID-induced ulcers if you are pregnant. (See BOXED WARNINGS.) Cytotec 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. Cytotec 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 Cytotec therapy, stop taking Cytotec 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 Cytotec and contact your physician immediately.

Cytotec 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 Cytotec 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 Cytotec. If you have prolonged difficulty (more than 8 days), or if you have severe diarrhea, cramping and/or nausea, call your doctor.

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

Do not give Cytotec 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 Cytotec. 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.

This product's label may have been updated. For current full prescribing information, please visit www.pfizer.com.

Last reviewed on RxList: 12/7/2012
This monograph has been modified to include the generic and brand name in many instances.

Disclaimer

Cytotec Consumer

IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

MISOPROSTOL - ORAL

(MYE-soe-PROST-ol)

COMMON BRAND NAME(S): Cytotec

WARNING: Do not take this medication if you think that you may be pregnant. It may cause abortion, premature birth, or birth defects. In rare cases, serious complications (e.g., uterine rupture) have occurred when misoprostol was used to start labor or when used in combination with another drug to cause abortion after the eighth week of pregnancy. These complications have resulted in harm to the unborn baby and mother.

Avoid pregnancy while taking misoprostol and for at least one month or one completed menstrual cycle after you have stopped treatment. If you become pregnant while taking misoprostol, contact your doctor immediately.

If you are pregnant, do not take this medication to reduce the risk of stomach ulcers due to aspirin or other related drugs (non-steroidal anti-inflammatory drugs-NSAIDs such as ibuprofen). Also, if you are of childbearing age, do not use this drug to reduce the risk of ulcers from NSAIDs unless you are at high risk of having an ulcer or ulcer complications.

Female patients must meet the following four requirements in order to use this drug: 1) test negative for pregnancy within two weeks before starting treatment; 2) use effective birth control to prevent pregnancy; 3) receive oral and written warnings on the dangers of using misoprostol while of childbearing age and the risks of possible birth control failure; 4) start taking misoprostol only on the second or third day of the next normal menstrual period.

This medication must not be shared with others.

USES: This medication is used to prevent stomach ulcers while you take NSAIDs (e.g., aspirin, ibuprofen, naproxen), especially if you are at risk for developing ulcers or have a history of ulcers. Misoprostol helps to decrease your risk of serious ulcer complications such as bleeding. This medication protects your stomach lining by lowering the amount of acid that comes in contact with it.

This medication is also used in combination with another drug (mifepristone) to end a pregnancy (abortion).

OTHER USES: This section contains uses of this drug that are not listed in the approved professional labeling for the drug but that may be prescribed by your health care professional. Use this drug for a condition that is listed in this section only if it has been so prescribed by your health care professional.

This medication may also be used to assist with childbirth only at the time of delivery (e.g., cervical ripening, induction of labor) and for the treatment of severe bleeding after delivery. When misoprostol is used vaginally for these purposes, it works by causing the womb muscles to contract.

HOW TO USE: This medicine comes with a patient information leaflet. Read it carefully. If you have any questions about this drug, ask your doctor, nurse, or pharmacist.

Dosage is based on your medical condition and response to therapy.

If you are taking this drug to prevent stomach ulcers, take it by mouth usually four times a day, after meals and at bedtime to minimize diarrhea, or as directed by your doctor.

If you are taking this medication for abortion, take it by mouth exactly as directed by your doctor.

If you are using this medication to start labor, your healthcare professional will insert it into your vagina.

Avoid taking antacids that contain magnesium while using misoprostol because they may make the diarrhea it causes worse. If you need an antacid, consult your doctor or pharmacist to help you choose a product.

For ulcer prevention, continue to take this drug for as long as you take NSAIDs. Use this medication regularly in order to get the most benefit from it. Remember to use it at the same times each day.

Inform your doctor if your condition persists or worsens.

Disclaimer

Cytotec Consumer (continued)

SIDE EFFECTS: Nausea or stomach cramps may occur. If any of these effects persist or worsen, notify your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Diarrhea is common with misoprostol and usually occurs about two weeks after you start taking it, and lasts for about a week. Be sure to keep up your intake of fluids and minerals/electrolytes to prevent dehydration. Persistent diarrhea may sometimes lead to a large loss of your body's water and minerals. Tell your doctor immediately if you develop any of these serious signs of dehydration and mineral imbalance: severe dizziness, decreased amount of urine, mental/mood changes, muscle weakness, slow/irregular heartbeat.

Tell your doctor immediately if any of these unlikely but serious side effects occur: menstrual problems or irregularities, unusual/heavy vaginal bleeding.

A very serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction may include: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

In the US -

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

Read the Cytotec (misoprostol) Side Effects Center for a complete guide to possible side effects »

PRECAUTIONS: Before taking misoprostol, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: stomach/intestinal disease (e.g., inflammatory bowel disease), risk factors for uterine rupture when this drug is used vaginally (e.g., prior Cesarean delivery, uterine surgery, five or more previous pregnancies).

Daily use of alcohol and tobacco may increase your risk for stomach bleeding. Limit alcohol beverages and stop smoking. Consult your doctor or pharmacist for more information.

If you are taking this medication in combination with mifepristone to end a pregnancy, an incomplete abortion may rarely occur. It is very important for you to be closely monitored by your doctor and to keep your scheduled appointments to follow your progress. Be sure to have clear instructions from your doctor about who to call and what to do in case of an emergency. Expect vaginal bleeding after you take the combined medicine, however tell your doctor immediately if you develop any unlikely symptoms such as severe/prolonged vaginal bleeding, signs of infection (e.g., fever, chills), or fainting.

This drug must not be used during pregnancy to prevent stomach ulcers because of possible harm to an unborn baby (see also Warnings). If you are of childbearing age, use effective birth control methods while taking misoprostol and for at least one month or one completed menstrual cycle after you stop taking it. If you become pregnant or think you may be pregnant, inform your doctor immediately.

This medication passes into breast milk. However, this drug is unlikely to harm a nursing infant. Consult your doctor before breast-feeding.

Disclaimer

Cytotec Consumer (continued)

DRUG INTERACTIONS: See also the How to Use section.

Your healthcare professionals (e.g., doctor or pharmacist) may already be aware of any possible drug interactions and may be monitoring you for it. Do not start, stop or change the dosage of any medicine before checking with them first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use.

Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly. Symptoms of overdose may include: severe drowsiness, seizures, severe dizziness, slow/irregular heartbeats.

NOTES: Do not share this medication with others.

MISSED DOSE: If you miss a dose, use it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at or below 77 degrees F (25 degrees C) in a dry place away from light and moisture. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised May 2010. Copyright(c) 2010 First Databank, Inc.

Cytotec Patient Information Including Side Effects

Brand Names: Cytotec

Generic Name: misoprostol (Pronunciation: mye so PRAH stole)

What is misoprostol (Cytotec)?

Misoprostol reduces stomach acid and replaces protective substances in the stomach that are inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin.

Misoprostol is used to prevent the formation of ulcers in the stomach during treatment with aspirin or an NSAID such as ibuprofen (Motrin, Advil, Nuprin, others), ketoprofen (Orudis, Orudis KT, Oruvail), naproxen (Naprosyn, Aleve, Anaprox, Naprelan), oxaprozin (Daypro), indomethacin (Indocin), diclofenac (Voltaren, Cataflam), etodolac (Lodine), piroxicam (Feldene), meloxicam (Mobic), tolmetin (Tolectin), nabumetone (Relafen), and fenoprofen (Nalfon). NSAIDs and aspirin are used to treat pain, fever, arthritis, and inflammatory conditions.

Misoprostol may also be used for purposes other than those listed in this medication guide.

Cytotec 100 mcg

round, white, imprinted with SEARLE, 1451

Cytotec 200 mcg

hexagonal, white, imprinted with LOGO STOMACH, SEARLE 1461

Misoprostol 100 mcg-GRE

round, white, imprinted with G 5007

Misoprostol 100 mcg-IVA

round, white, imprinted with LOGO 100, 4430

Misoprostol 200 mcg-GRE

hexagonal, white, imprinted with G 5008

Misoprostol 200 mcg-IVA

round, white, imprinted with 4431, LOGO 200

What are the possible side effects of misoprostol (Cytotec)?

Stop taking misoprostol and seek emergency medical attention if you experience an allergic reaction (difficulty breathing; closing of the throat; swelling of the lips, tongue, or face; or hives).

Misoprostol may cause mild to moderate diarrhea, stomach cramps, and/or nausea. These problems usually occur during the first few weeks of treatment and stop after about a week. The occurrence of diarrhea may be minimized by taking misoprostol with food. Contact your doctor if these symptoms persist for longer than 8 days or if they are severe.

Other, less serious side effects may also occur. Continue to take misoprostol and talk to your doctor if you experience

  • vomiting;
  • flatulence;
  • constipation;
  • headache; or
  • menstrual cramps, spotting, or increased or irregular menstruation.

Side effects other than those listed here may also occur. Talk to your doctor about any side effect that seems unusual or that is especially bothersome. You may report side effects to FDA at 1-800-FDA-1088.

Read the Cytotec (misoprostol) Side Effects Center for a complete guide to possible side effects »

What is the most important information I should know about misoprostol (Cytotec)?

Do not share this medication with anyone else. Misoprostol 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.

Side Effects Centers

Cytotec Patient Information including How Should I Take

What should I discuss with my healthcare provider before taking misoprostol (Cytotec)?

Before taking misoprostol, tell your doctor if you have inflammatory bowel disease, irritable bowel syndrome, or other intestinal problems. You may need a dosage adjustment or special monitoring during treatment with misoprostol.

It is not known whether misoprostol passes into breast milk. Do not take misoprostol without first talking to your doctor if you are breast-feeding a baby.

How should I take misoprostol (Cytotec)?

Take misoprostol exactly as directed by your doctor. If you do not understand these directions, ask your pharmacist, nurse, or doctor to explain them to you.

Take each dose with a full glass of water.

Misoprostol is usually taken four times a day, with meals and at bedtime. Follow your doctor's instructions.

Misoprostol may cause mild to moderate diarrhea, stomach cramps, and/or nausea. These problems usually occur during the first few weeks of treatment and stop after about a week. The occurrence of diarrhea may be minimized by taking misoprostol with food. Contact your doctor if these symptoms persist for longer than 8 days or if they are severe.

Take misoprostol for the full amount of time prescribed by your doctor. Treatment usually continues for as long as aspirin or an NSAID is taken.

Do not share this medication with anyone else. Misoprostol 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.

Store misoprostol at room temperature away from moisture and heat.

Side Effects Centers

Cytotec Patient Information including If I Miss a Dose

What happens if I miss a dose (Cytotec)?

Take the missed dose as soon as you remember. However, if it is almost time for the next dose, skip the missed dose and take only the next regularly scheduled dose. Do not take a double dose of this medication.

What happens if I overdose (Cytotec)?

Seek emergency medical attention.

The symptoms of a misoprostol overdose are not well known but might include stomach upset, stomach pain, diarrhea, drowsiness, tremor, seizures, difficulty breathing, fever, low blood pressure, and an irregular heart beat.

What should I avoid while taking misoprostol (Cytotec)?

Do not share this medication with anyone else. Misoprostol 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.

The incidence of diarrhea may be reduced by avoiding antacids that contain magnesium. If an antacid is needed, one that contains aluminum or calcium may be a more appropriate choice.

There are no restrictions on food, beverages, or activities during treatment with misoprostol unless otherwise directed by your doctor.

What other drugs will affect misoprostol (Cytotec)?

The incidence of diarrhea may be reduced by avoiding antacids that contain magnesium. If an antacid is needed, one that contains aluminum or calcium may be a more appropriate choice.

Drugs other than those listed here may also interact with misoprostol. Talk to your doctor and pharmacist before taking any prescription or over-the-counter medicines, including herbal products.

Where can I get more information?

Your pharmacist has more information about misoprostol written for health professionals that you may read.


Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

Copyright 1996-2012 Cerner Multum, Inc. Version: 7.03. Revision date: 12/15/2010.

Your use of the content provided in this service indicates that you have read,understood and agree to the End-User License Agreement,which can be accessed by clicking on this link.

Healthwise

Side Effects Centers

توزیع کنندگان این دارو
شرکت های تولید کننده یا وارد کننده دارو

دارونـــما
نوآوری برای سلامت

طراحی و اجرا M.Ramezani
ارتباط با ما Info@darunama.com