® Patient should therefore be closely monitored.

If abnormal

Mucosta ® findings are observed, the drug should be discontinued and

appropriate measures taken.
3) Hepatic dysfunction (incidence <0.1%) and jaundice (incidence
unknown•):Hepatic dysfunction and jaundice, as indicated by
tablets 100mg increases in AST (GOT), ALT (GPT), y-GTP, and alkaline
phosphatase levels, have been reported in patients receiving
CONTRAINDICATIONS (MUCOSTA Tablets are contraindicated MUCOSTA Tablets. Patient should therefore be closely
in the following patients) monitored. If abnormal laboratory findings are observed, the
Patients with a history of hypersensitivity to any ingredient of drug should be discontinued and appropriate measures taken.
(2) Other adverse reactions
this drug.
*Incidence
<0.1%
Unknown
DESCRIPTION
Hyper- sensitivity Rash, pruritus, drug- Urticaria
Composition (note 1) eruption- like eczema,
MUCOSTA Tablets 100: other symptoms of
Each MUCOSTA Tablet contains 100 mg of rebamipide and the following hypersensitivity
inactive ingredients: Microcrystalline cellulose, Low Substituted Neuro- psychiatric Numbness, dizziness,
Hydroxypropylcellulose, hydroxypropylcellulose, magnesium stearate, sleepiness
hypromellose, macrogol 6000, and titanium oxide. Gastro- intestinal Constipation, feeling of Thirst
abdomen enlarged,
diarrhea, nausea,
PRODUCT DESCRIPTION vomiting, heartburn,
abdominal pain,
Brand name MUCOSTA Tablets 100 mg belching, taste
Description White film-coated tablets abnormality, etc.
Hepatic Increased AST (GOT),
Diameter Thickness Weight (note 2) ALT (GPT), y-GTP,
Appearance Code
(mm) (mm) (mg) alkaline phosphatase
levels
Approx Hematologic Leukopenia, Thrombocytopenia
8.1 3.4 OG33
175 granulocytopenia, etc.
Other Menstrual disorders, Breast swelling and
INDICATIONS increased BUN levels, pain, gynecomastia
 Gastric ulcers edema, feeling of a induction of lactation,
 Treatment of gastric mucosal lesions (erosion, bleeding, redness, foreign body in the palpitations, fever,
and edema) in the following conditions; acute gastritis and acute pharynx facial flushing,
numbness of tongue,
exacerbation of chronic gastritis
cough, respiratory
distress, alopecia
DOSAGE AND ADMINISTRATION
 Gastric ulcers: The usual adult dosage of rebamipide is 100 mg Note
Body1)system/
If such symptoms of hypersensitivity occur, the drug should
(1 MUCOSTA Tablet) taken by the oral route three times daily, be discontinued
frequency
in the morning, in the evening, and before at bedtime. Note 2) If transaminase levels are markedly increased or fever and
rash develop, the drug should be discontinued and appropriate
 Treatment of gastric mucosal lesions (erosion, bleeding, redness,
measures should be taken.
and edema) in the following conditions; acute gastritis and acute * The incidence rates of voluntarily reported adverse reactions are
exacerbation of chronic gastritis: The usual adult dosage of not known.
rebamipide is 100 mg (1 MUCOSTA Tablet) three times daily
taken by the oral route. 2. Use in the Elderly
Special care is required in elderly patients to minimize the risk
PRECAUTIONS of gastrointestinal disorders, because these patients may be
1. Adverse Reactions physiologically more sensitive to this drug than younger patients.
Of 10,047 patients treated, adverse reactions, including
abnormal laboratory findings, were reported in 54 patients 3. Use during Pregnancy, Delivery, or Lactation
(0.54%). Of 3,035 patients aged over 65 years, adverse reactions (1) This drug should be administered to pregnant or possibly
were noted in 18 patients (0.59%). The nature and incidence of pregnant women only if the anticipated therapeutic benefit is
adverse reactions showed no differences between elderly and thought to outweigh any potential risk. (The safety of this drug
younger patients. The following summary of data includes in pregnant women has not been established.)
adverse reactions voluntarily reported after marketing (Figures (2) Nursing should be interrupted when this drug is administered to.
are total cases reported at the time of approval and at the (Rat studies have shown that rebamipide is excreted in the breast
completion of reexamination of MUCOSTA Tablets 100). milk.)
(1) Clinically significant adverse reactions
1) Shock, anaphylactoid reactions (incidence unknown*): Shock or 4. Pediatric Use
anaphylactoid reactions may occur. Patients should therefore be The safety of this drug in low birth weight infants, newborns,
closely monitored. If abnormal findings are observed, the drug suckling infants, infants and children has not been established
should be discontinued and appropriate measures taken. (Clinical experience is insufficient).
2) Leukopenia (incidence <0.1%) and thrombocytopenia (incidence
unknown*): Leukopenia and thrombocytopenia may occur. 5. Precautions for Use
 Patient's Instructions for Use daily dose of 300 mg revealed that recurrence occurred in only 4
Patients should be instructed not to ingest any portion of the patients (approx. 6%).
press-through package (PTP). (There have been reports that the
sharp edges of the sheet can cut or penetrate the esophageal 2. Clinical Efficacy in Acute Gastritis and Acute Exacerbation of
mucosa if accidentally ingested, resulting in mediastinitis or Chronic Gastritis.11,12)
other serious complications.) MUCOSTA Tablets were studied in patients with acute gastritis
or acute exacerbation of chronic gastritis. The drug achieved an
PHARMACOKINETICS 80% (370/461) global efficacy rate in the patients evaluated,
1. Plasma Concentrations 1-4) with 76% (351/461) showing moderate or marked improvement.
The table below shows the pharmacokinetic parameters of The drug's clinical usefulness was found to be reproducible in a
rebamipide following single oral administration of MUCOSTA double-blind study.
Tablets 100 mg at a dose of 100 mg to 27 healthy male subjects
in a fasted state. PHARMACOLOGY

Pharmacokinetic Parameters of Rebamipide 1. Preventive or healing effects in gastric ulcer models13-15)

Rebamipide inhibited gastric mucosal injury in various
tmax Cmax t1/2 AUC24h
experimental rat models of ulcers, including ulcers induced by
(hr) (μg/L) (hr) (μg/L.hr) water-immersion restraint stress, aspirin, indomethacin,
MUCOSTA histamine, serotonin, and pyloric ligation. The drug also
2.4±1.2 216±79 1.9 ± 0.7 874±209 protected the mucosa from injury caused by other ulcerogenic
Tablets 100 mg
conditions that presumably yield reactive oxygen species,
Mean value ± SD, n=27, t1/2 calculated from values up to 12 hr
including mucosal ischemia-reperfusion, administration of
platelet activating factor (PAF) or diethyldithiocarbamate (DOC),
The absorption rate of rebamipide following single oral and administration of indomethacin under stressed conditions.
administration at a dose of 150 mg to 6 healthy male subjects in In a rat acetic acid-induced ulcer model, the drug promoted
a fed state tended to be slower than that in a fasted state. healing of gastric ulcers and was seen to suppress the recurrence
However, food did not affect bioavailability of the drug in and relapse of ulcers 120- 140 days after ulcer induction.
humans 2. Preventive or healing effects in gastritis models16,17)
Pharmacokinetic parameters obtained from patients with renal Rebamipide inhibited the development of taurocholic acid (one
impairment after single oral administration of rebamipide at 100 of the main ingredients of bile acid)-induced gastritis and
mg revealed higher plasma concentrations and a longer promoted healing of the mucosal inflammation associated with
elimination half-life compared with those in healthy subjects. At gastritis in rat experiments.
steady-state, rebamipide plasma concentrations observed in 3. Prostaglandin-increasing effect18,19)
Rebamipide increased the generation of prostaglandin E2 (PGE2)
dialyzed renal patients following repeated administration were
in the gastric mucosa in rats. The drug also increased the
very close to the values simulated from single administration. contents of PGE2, 15-keto-13,14-dihydro-PGE2 (a metabolite of
Therefore, the drug was not considered to accumulate. PGE2) and PGl2 in the gastric juice. In healthy male subjects, the
drug again revealed the increasing effect on the PGE2 content in
2. Metabolism the gastric mucosa and protected the gastric mucosa from injury
caused by ethanol loading.
Rebamipide was primarily excreted as the unchanged compound 4. Cytoprotective effect18,20-22)
in the urine aft.er single oral administration to healthy adult Rebamipide exhibited a gastric cytoprotective effect to inhibit
males at a dose of 600 mg. A metabolite with a hydroxyl group the mucosal injury induced by ethanol, strong acid, or strong
at the 8th position was identified in the urine. However, the base in rats. In in vitro studies, the drug also protected cultured
excretion of this metabolite was only 0.03% of the administered gastric epithelial cells obtained from rabbit fetuses against
dose. The enzyme involved in the formation of the metabolite aspirin- or taurocholic acid (one of the main ingredients of bile
acid)-induced injury.
was CYP3A4.5)
In healthy male subjects, the drug inhibited gastric mucosal
(Note) The usual dosage in adults is 100 mg three times daily. injury induced by aspirin, ethanol, or HCl-ethanol loading.
5. Mucus-increasing effect23-25)
3. Excretion Rebamipide promoted gastric enzyme activity to synthesize high
Approximately 10% of the administered dose was excreted in molecular weight glycoproteins, thickened the superficial
the urine when rebamipide was administered as a single oral mucous layer of gastric mucosa, and increased the amount of
gastric soluble mucus in rats. Endogenous PGs were not
dose to healthy adult males at 100 mg.
involved in the increase in soluble mucus.
6. Mucosal blood flow-increasing effect22)
4. Protein Binding6) Rebamipide increased gastric mucosal blood flow and improved
Rebamipide at 0.05 - 5 µg/mL was added to human plasma in impaired hemodynamics after blood loss in rats.
vitro, and 98.4% - 98.6% of the drug was bound to plasma 7. Effect on mucosal barrier 26)
proteins. Rebamipide did not ordinarily affect the gastric transmucosal
potential difference in rats, but did inhibit lowering of the
CLINICAL STUDIES potential difference by ethanol.
1. Clinical Efficacy in Gastric Ulcer.7-10) 8. Effect on gastric alkaline secretion 27)
MUCOSTA Tablets were studied in patients with gastric ulcer, Rebamipide promoted gastric alkaline secretion in rats.
using endoscopy for objective drug evaluation. In the final 9. Effect on mucosal cell turnover
endoscopic assessment, the drug achieved complete healing in Rebamipide activated gastric mucosal cell proliferation and
60% (200/335) of the patients studied and near-complete healing increased the number of covering epithelial cells in rats.
in 67% (224/335). The clinical usefulness of this drug, based on 10. Effect on gastric mucosal repair28,29)
efficacy and safety was demonstrated in a double-blind study. Rebamipide restored the bile acid- or hydrogen peroxide-
Six-month follow-up of 67 patients who showed healing at a induced retardation of artificial wound-repair in cultured rabbit
 gastric epithelial cells. PHARMACEUTICAL PRECAUTIONS
11. Effect on gastric secretion30)
Rebamipide did not alter either basal secretion of gastric juice or Store below 30°C.
secretagogue-stimulated acid secretion. Keep all medicines out of the reach of children.
12. Effects on reactive oxygen species31-35) To be sold on the prescription of a registered medical practitioner only.
Rebamipide scavenged hydroxyl radicals directly and
suppressed superoxide production by polymorphonuclear
leukocytes. The drug inhibited the gastric mucosal cell injury
caused by reactive oxygen species released from neutrophils
stimulated by Helicobacter pylori in vitro. The drug reduced the
content of lipid peroxide in the gastric mucosa of rats treated
with indomethacin under stressed conditions and inhibited the
mucosal injury.
13. Effect on inflammatory cell infiltration in the gastric
mucosa16,36,37)
Rebamipide prevented inflammatory cell infiltration in rat
models of taurocholic acid (one of the main ingredients of bile
acid)-induced gastritis and NSAID-induced or
ischemia-reperfusion-induced gastric mucosal damage.
14. Effect on inflammatory cytokine release (interleukin-8) in the
PACKAGING
gastric mucosa38,39)
Mucosta tablets are round, white, film coated tablets, with a code OG33
Rebamipide, taken by the oral route, suppressed the increased
and supplied as 100mg tablets in packs of 100 tablets (blister strips of 10
production of interleukin-8 in the mucosa of patients with
x 10).
Helicobacter pylori. The drug also inhibited the activation of
NF-κB, the expression of interleukin-8 mRNA, and the REFERENCES
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(10), 1667-1671, 1995.
Chemical name: 5) Koyama, N. et al.: XENOBIOTICA, 32(7), 573-586, 2002.
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(2RS)-2-(4-Chlorobenzoylamino)-3-(2-oxo-1,2- 7) Takemoto, T. et al.: Rinsho Seijinbyo (J. Adult Dis.) 19 (4), 539-551,
dihydroquinolin-4-yl) propanoic acid 1989.
8) Takemoto, T. et al.: Rinsho Seijinbyo (J. Adult Dis.) 19 (5), 739-751,
Molecular formula: 1989.
C19H15CIN2O4 9) Takemoto, T. et al.: Rinsho Seijinbyo (J. Adult Dis.) 19 (5), 753-775,
1989.
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370.79 1989.
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259-277, 1992.
18) Yamasaki, K. et al.: Eur. J. Pharmacol. 142 (1), 23-29, 1987.
and enantiomer 19) Kleine, A. et al.: Dig. Dis. Sci., 38 (8), 1441-1449, 1993.
20) Nakamura, H. et al.: Rinsho Seijinbyo (J. Adult Dis.) 19 (6), 1109-1114,
1989.
Description: 21) Dammann, H.G.: Eur. J. Gastroenterol. Hepatol. 6 (10), 911-915, 1994.
Rebamipide occurs as a white crystalline powder. It has a bitter taste. It is soluble in 22) Kawano, S. et al.: Folia Pharmacologica Japonica (Jpn. J. Pharmacol.) 97
N.N-dimethylformamide, very slightly soluble in methanol and ethanol (99.5), and (6), 371-380, 1991.
practically insoluble in water. Its N.N-dimethylformamide solution (1→20) shows 23) lshiyama, H. et al.: Yakuri to Chiryo (Jpn. Pharmacol. Ther.) 16 (10),
no optical rotation. 4103-4109, 1988.
Melting point: About 291°C (decomposition) 24) lshiyama, H. et al.: Yakuri to Chiryo (Jpn. Pharmacol. Ther.) 16 (10),
4111-4118, 1988.
Drug Reg. No.: 078129 25) Ishihara, K. et al.: Arzneim.-Forsch./Drug Res. 42 (II), 1462-1466, 1992.
26) Yamasaki, K. et al.: Yakuri to Chiryo (Jpn. Pharmacol. Ther.) 18 (9),
3395-3400, 1990.
27) Yamasaki, K. et al.: Yakuri to Chiryo (Jpn. Pharmacol. Ther.) 18 (10),
3765-3772, 1990.
28) Watanabe, S. et al.: Aliment. Pharmacol. Ther. 10 (6), 927-932, 1996.
29) Watanabe, S. et al.: Dig. Dis. Sci. 43 (9), 107S-112S, 1998.
30) Yamasaki, K. et al.: Yakuri to Chiryo (Jpn. Pharmacol. Ther.) 16 (6),
2487-2495, 1988.
31) Yoshikawa, T. et al.: Arzneim.-Forsch./Drug Res. 43 (I), 363-366, 1993.
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 33) Ogino, K. et al.: Eur. J. Pharmacol. 212 (1), 9-13, 1992.
34) Suzuki, M. et al.: Gut 35 (10), 1375-1378, 1994. Manufactured By:
35) Yamasaki, K. et al.: Pathophysilogy 1 (4), 251-257, 1994
36) Murakami, K. et al.: Dig. Dis. Sci. 42 (2), 319-325, 1997.
37) Kim, C.D. et al.: J. Pharmacol. Exp. Ther. 275 (1), 340-344, 1995.
38) Mihara, M. et al.: Shokakika (Dept. Gastroenterol.) 24 (6), 681-688, Korea Otsuka Pharmaceutical Co., Ltd.
1997. Gyeonggi-do, Korea
39) Aihara, M. et al.: Dig. Dis. Sci. 43 (9), 174S-180S, 1998.
Under Authority of:

For more scientific information contact:

Otsuka Pakistan Limited
30-B, Sindhi Muslim Cooperative Housing Society, Otsuka Pharmaceutical Co., Ltd., Japan
Karachi-74400
Marketed By:

Otsuka Pakistan Limited

(A company of Otsuka Group Japan)