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Standard Commodity Classification No. of Japan - Analgesic/anti-inflammatory agent activated in tissues - Infree  Capsules 100mg
Infree  S Capsules 200mg
<Indometacin farnesil preparation> Cap. 100 mg
S Cap. 200 mg
INFREE should be stored at room temperature. (See “PRECAUTIONS FOR HANDLING” section.) Date of listing in the NHI reimbursement price Expiration date
INFREE should be used before the expiration date Caution : Use only as directed by a physician. CONTRAINDICATIONS (INFREE is contraindicated in
RELATIVE CONTRAINDICATIONS (As a general
the following patients.)
rule, INFREE is contraindicated in the following pa-
1. Patients with peptic ulcer (but, see “Careful Admini- tients. If the use of INFREE is considered essential, it
should be administered with care.)
2. Patients with serious blood dyscrasia [If it is to be used in patients with rheumatoid arthritis, who show no response or are intolerant to other treatment, IN- 3. Patients with serious hepatic function disorders FREE may be used if due caution is exercised. See “Pediat- [Hepatic function disorders may be aggravated.] 4. Patients with serious renal function disorders [Renal function disorders may be aggravated.] DESCRIPTION
5. Patients with serious cardiac dysfunction 1. Composition
[Cardiac dysfunction may be aggravated.] Capsules 100 mg:
Each white, hard capsule contains 100 mg of indometacin It also contains hydrated silicon dioxide, glycin, light an- [It has been reported that acute pancreatitis occurred hydrous silicic acid, microcrystalline cellulose, tartaric with the use of indometacin, the active metabolite of acid, gelatin, talc, tocopherol, macrogol 6000, methylcel- lulose and sodium lauryl sulfate as inactive ingredients. 8. Patients with hypersensitivity to INFREE, indometacin S Capsules 200 mg:
Each light orange, soft capsule contains 200 mg of indo- 9. Patients with aspirin-induced asthma (asthma induced by non-steroidal anti-inflammatory analgesics, etc.) or It also contains L-aspartic acid, yellow ferric oxide, car- nauba wax, hydrogenated oil, titanium oxide, gelatin, [A serious aspirin-induced asthma attack may occur.] D-sorbitol solution, tocopherol, concentrated glycerin, 10. Pregnant women or women suspected of being preg- ethyl parahydroxybenzoate, propyl parahydroxybenzoate, propylene glycol esters of fatty acid and polyoxyethylene [See “Use during Pregnancy, Delivery or Lactation” hydrogenated castor oil 60, glyceryl monooleate as inac- 2. Product description
(9) Patients with a history of hypersensitivity to any drug (10) Patients with a central nervous system diseases, such as [It has been reported that indometacin, the active me- tabolite of INFREE, aggravates these diseases.] (12) Patients with SLE (systemic lupus erythematosus) [It has been reported that an analogue compound (phenylbutazone) aggravated SLE. In addition, acute renal failure has been reported in patients with SLE given indometacin, the active metabolite of INFREE.] ” is printed on the surface of each soft capsule. [It has been reported that indometacin, the active me- INDICATIONS
tabolite of INFREE, aggravated this disease.] Anti-inflammation and analgesia in the following diseases and [It has been reported that indometacin, the active me- Rheumatoid arthritis, osteoarthrosis, low back pain, scapu- tabolite of INFREE, aggravated this disease.] lohumeral periarthritis and neck-shoulder-arm syndrome DOSAGE AND ADMINISTRATION
The usual adult dosage for oral use is 200 mg of indometacin 2. Important Precautions
farnesil twice daily, in the morning and in the evening after (1) Treatment with anti-inflammatory analgesics is gener- ally not causal therapy, but symptomatic therapy. The dosage may be adjusted depending on patient’s age and (2) The patient should be carefully observed for adverse reactions. Symptoms such as an excessive decrease in body temperature, collapse, and coldness of limbs have PRECAUTIONS
been reported in patients receiving indometacin, the ac- 1. Careful Administration (INFREE should be adminis-
tive metabolite of INFREE; hence, INFREE should be tered with care in the following patients.)
administered with great care in the elderly with fever or (1) Patients with a history of peptic ulcer (3) When INFREE is used for the treatment of a chronic (2) Patients with peptic ulcer due to long-term administra- disease (rheumatoid arthritis, osteoarthrosis, etc.), the tion of non-steroidal anti-inflammatory analgesics, who need to take INFREE for a long time and are being 1) When INFREE must be used in long-term therapy, laboratory tests (e.g. urinalysis, hematological test, [Although an indication of misoprostol is peptic ulcer hepatic function tests, and ophthalmologic examina- due to administration of non-steroidal anti-inflam- tion, etc.) should be performed periodically during matory analgesics, some peptic ulcers are resistant to treatment. If abnormal findings are observed, appro- misoprostol therapy. Therefore, if INFREE is adminis- priate measures, such as reduction in dosage or tem- tered continuously, the patient’s condition should be porary discontinuation of the medication, should be closely observed and INFREE administered with care.] (3) Patients with blood dyscrasia or its history 2) Alternatives to drug therapy should also be consid- [Blood dyscrasia may be aggravated or recur.] (4) Patients with hepatic function disorder or their history (4) INFREE may mask the signs and symptoms of infec- [Hepatic function disorder may be aggravated or recur.] tions. Therefore, an appropriate antibiotic should be (5) Patients with renal function disorder or their history used in combination to treat inflammation, and the pa- [Renal function disorder may be aggravated or recur.] tient should be closely monitored and INFREE admin- [Cardiac dysfunction may be aggravated.] (5) It is recommended to avoid the concomitant use of other anti-inflammatory analgesics with INFREE. (6) Since drowsiness and dizziness may occur with the use of INFREE, patients should be cautioned against en- [It has been reported that acute pancreatitis occurred gaging in potentially hazardous activities requiring with the use of idometacin, the active metabolite of alertness, such as operating machinery or driving a car. 3. Drug Interactions
Signs, Symptoms,
Mechanism and
(1) Contraindications for coadministration (INFREE
and Treatment
Risk Factors
should not be coadministered with the following
metacin, the active me-tabolite of INFREE, aspi- Signs, Symptoms,
Mechanism and
and Treatment
Risk Factors
It has been reported that when It is considered that the acute renal failure occurs increases to compensate administered indometacin, brought about by decrease potentiates its effect. Caution thesis by indometacin. (2) Precautions for coadministration (INFREE should
be administered with care when coadministered with
the following drugs.)
Signs, Symptoms,
Mechanism and
losporin, Indometacin, the contributing factor. and Treatment
Risk Factors
active metabolite of IN-FREE, may cause an in- increase, because the effects suppressed due to the in- of these agents are enhanced hibition of prostaglandin by the concomitant use with biosynthesis by indo- 4. Adverse Reactions
Adverse reactions were reported in 682 of 13,564 patients (5.03%). (At the end of the reexamination period) (1) Clinically significant adverse reactions
1) Shock and anaphylactoid reaction
Shock (incidence unknown) may occur. Patients should be carefully observed, treatment should be discontinued and appropriate measures taken in the products, indometacin, the tion is increased as a result. event of symptoms such as cold sweat, facial pallor, dyspnea or decrease in blood pressure, etc. 2) Perforation of the digestive tract, hemorrhage of
the digestive tract, ulcer of the digestive tract,
hemorrhagic colitis, constriction and obstruction
of the intestinal tract, and ulcerative colitis
Perforation of the digestive tract, hemorrhage of the digestive tract, ulcer of the digestive tract, hemor- metacin, the active metabo- hibited by probenecid, and lite of INFREE, probenecid the blood indometacin rhagic colitis, constriction and obstruction of the in- may potentiate the effect of concentration is increased testinal tract (incidence unknown) may occur. In the event of such symptoms, treatment should be discon- tinued and appropriate measures taken. It also has been reported that ulcerative colitis (incidence un- known) occurred with the use of indometacin which 3) Blood dyscrasia
Symptoms of hematological dyscrasia such as aplas- tic anemia (incidence unknown), hemolytic anemia A-II receptor antago- metacin, the active me- (incidence unknown), leucocytopenia (<0.1%) or tabolite of INFREE, these crease in the humoral cir- thrombocytopenia (incidence unknown) may occur. Patients should be carefully monitored through blood examinations. In the event of such abnormal findings, treatment should be discontinued and appropriate 4) Dermatologic disorders
Oculo-muco-cutaneous syndrome (Stevens-Johnson syndrome) (incidence unknown) or toxic epidermal necrolysis (Lyell syndrome) (incidence unknown) may occur. In the event of such symptoms, treatment should be discontinued and appropriate measures taken. 5) Asthmatic attack
5% > ≥0.1% <0.1% Incidence
Acute respiratory disorders such as asthmatic attack (incidence unknown) may occur. In the event of such symptoms, treatment should be discontinued and ap- uria, fever, chest diaphoresis pain and hypo- 6) Renal function disorders
Renal function disorders such as acute renal failure 1) In the event of such symptoms, treatment should be discon- (incidence unknown) or nephrotic syndorome (inci- dence unknown), or hyperkalemia (<0.1%) may oc- 2) It has been reported that indometacin, the active metabolite cur. In the event of such symptoms, treatment should be discontinued and appropriate measures taken. It 3) It has been reported that corneal opacity and retinal disor- also has been reported that hypoalbuminemia (inci- ders occurred with the use of indometacin, the active me- dence unknown) occured with the use of indo- tabolite of INFREE in patients with rheumatoid arthritis or metacin, the active metabolite of INFREE. other diseases during long-term therapy. If any prodromal 7) Hepatic function disorders and jaundice
syndromes (such as blurred vision) occur, treatment should Hepatic function disorders (5%> ≥0.1%) or jaundice (incidence unknown) may occur. In the event of such symptoms, treatment should be discontinued and ap- 5. Use in the Elderly
Adverse reactions may occur frequently in the elderly. The 8) Coma and confusion
patients should be closely observed and administration It has been reported that coma (incidence unknown) should be performed with care, such as initiating at lowest and confusion (incidence unknown) occured with the use of indometacin, the active metabolite of INFREE. 9) Genital bleeding
6. Use during Pregnancy, Delivery or Lactation
It has been reported that genital bleeding (incidence (1) INFREE should not be used in pregnant women or unknown) occured with the use of indometacin, the 1) It has been reported that persistent fetal circulation (2) Other adverse reactions
(PFC), contraction of arteries in the fetus, patent 5% > ≥0.1% <0.1% Incidence
ductus arteriosus, renal failure in the fetus, entero- brosis in the fetus and oligoamnios occurred when indometacin, the active metabolite of INFREE, was administered during the late stage of pregnancy. In addition, when indometacin was administered during the late stage of pregnancy, increases in the incidence rates of necrotizing colitis, perforation of the diges- tive tract, and intracranial hemorrhage were reported 2) It has been reported that indometacin, the active me- tabolite of INFREE, exhibited a teratogenic action in an animal study (in mice) and that INFREE induced a reduction in the rate of implantation and an increase in the frequency of dead and resorbed fetuses in rats. 3) In an experiment with rats administered INFREE at the late stage of pregnancy, contraction of arteries in (2) Nursing mothers should discontinue breast feeding dur- [It has been reported that INFREE is excreted in breast 7. Pediatric Use
The safety in children has not been established (no clinical 8. Precautions concerning Use
1) In patients with biliary stasis or reduced biliary secre- tion, the absorption of INFREE is considered to be decreased. Therefore, INFREE should not be admin- A study in 5 healthy adult male volunteers given repeated oral administration of the drug (INFREE two 100 mg hard 2) The absorption rate of INFREE decreases as the dose capsules b.i.d., 11 times) indicated that the plasma concen- is increased. Clinical benefits should be evaluated, tration of the unchanged drug does not accumulate in the when the total daily dose exceeds 400 mg. When two 100 mg hard capsules or one 200 mg soft cap- Since the absorption of INFREE may decrease when it sule of INFREE were administered orally to 24 healthy is administered during fasting, it should be adminis- adult male volunteers in a single dose after a meal in a cross-over design trial, the differences in the mean values until 24 hr of the area under the plasma concentration-time For drugs that are dispensed in a press-through package curve and Cmax of the unchanged drug were within approx. (PTP), instruct the patient to remove the drug from the package prior to use. [It has been reported that, if the PTP sheet is swallowed, the sharp corners of the sheet may puncture the esophageal mucosa, causing perfora-tion and resulting in serious complications such as me-diastinitis.]
9. Other Precautions
(1) It has been reported that peptic ulcer and perforation of the digestive tract occurred when indometacin, the ac-tive metabolite of INFREE was coadministered with lentinan in an animal study (in mice.) (2) Reversible infertility has been reported in women re- ceiving non-steroidal anti-inflammatory analgesics for long periods.
PHARMACOKINETICS
1. Blood concentration (absorption)
Changes in plasma indometacin farnesil concentration after
INFREE was administered orally to 5 healthy adult male oral administration of INFREE two 100 mg Capsules and
volunteers at a single dose of two 100 mg hard capsules INFREE S one 200 mg Capsule
after a meal. The time to reach peak plasma concentration (tmax) and the peak plasma concentration (Cmax) of the un- 2. Effect of meal
changed drug was about 5 to 6 hr and 2.01µg/mL, respec- The absorption of unchanged drug was markedly decreased tively. It disappeared from the plasma in 24 hrs after ad- when a 150 mg hard capsule of indometacin farnesil was administered to 8 healthy adult male volunteers after 12 hr of fasting in a cross-over design trial, but INFREE was well absorbed following an ordinary meal (containing about 10 g of fat). 2)
3. Metabolism and excretion
When INFREE was administered orally to 5 healthy adult male volunteers at a single dose of two 100 mg hard cap-sules, no unchanged drug was detected in their urine; des-benzoylindometacin (5.5% of the dose), indometacin (2.9% of the dose), and desmethylindometacin (1.9% of the dose) were detected. 1)
CLINICAL STUDIES
Changes in plasma concentration of unchanged indometacin
Clinical efficacy
farnesil and indometacin derived from INFREE
The clinical efficacy of INFREE was determined in 1,751 pa- tients with the diseases indicated below in clinical trials, in- cluding double-blind clinical trials. The following improve- Pharmacokinetic parameters of unchanged indometacin farnesil
after single oral administration of INFREE
Description:
Indometacin farnesil occurs as a yellow, clear, oily liquid. It has a slight characteristic odor. It is very soluble in ace- tonitrile, in acetone, in chloroform and in diethyl ether, freely soluble in ethanol (99.5), sparingly soluble in methanol, and practically insoluble in water. PHARMACOLOGY
PRECAUTIONS FOR HANDLING
1. Anti-inflammatory action
1. PTP packages of INFREE Capsules 100mg should be pro- Indometacin farnesil exhibited a definite anti-inflammatory tected from moisture after opening aluminum bag. (IN- action after oral administration in experimental rat models, FREE Capsules 100mg may change in color by light. Col- including acute or chronic experimental by induced in- ored film is used for Press-through package.) flammations, such as carrageenin podedema, kaolin pode- 2. Bottle packages of INFREE Capsules 100mg should be dema, carrageenin bullosis, adjuvant arthritis, and type II protected from light and moisture after opening cap. 3. PTP packages of INFREE S Capsules 200mg should be pro- tected from high temperature and moisture after opening alu- 2. Analgesic action
minum bag. Bottle packages should be protected from high Indometacin farnesil exhibited a definite analgesic action af- temperature and moisture after opening cap. (Softening, and ter oral administration to adjuvant arthritis rats with inflam- adherence to the inside of press through package may occur in matory pain induced by extension stimuli and to dogs with pain induced by intra-arthral injection of carrageenin. 11, 12) PACKAGING
3. Mechanism of action
INFREE Capsules 100 mg:
It is presumed that the anti-inflammatory and analgesic ac- Boxes of 100, 140 (14Caps. × 10), 700 (14Caps. × 50), tions exhibited by indometacin farnesil occur by a mecha- 1,000 and 1,400 (14Caps. × 100) in press-through pack- nism in which indometacin is first released in its active moiety from indometacin farnesil; this indometacin inhibits INFREE S capsules 200 mg:
prostaglandin biosynthesis by inhibiting cyclooxygenase. Boxes of 100, 140 (14Caps. × 10), 700 (14Caps. × 50), When indometacin farnesil is administered orally, it is ab- 1,000 and 1,400 (14Caps. × 100) in press-through pack- sorbed as unchanged drug, and is only mildly injurious to the gastrointestinal tract. A major fraction of the drug ad- ministered to dogs or humans is detected as unchanged REFERENCES
drug in the blood; Unchanged drug is metabolized to in- 1) Ikenouchi H. et al.: Jpn. J. Clin. Exp. Med., 66, 2360, 1989.
dometacin, the active moiety, in the liver and kidney, and 2) Ogawa M. et al.: ibid., 66, 3023, 1989.
released into the blood. It has been demonstrated by in vivo 3) Shiokawa Y. et al.: Med. Consult. New Remed., 26, 546, 1989.
and in vitro studies that the unchanged drug is metabolized 4) Yamamoto M. et al.: Jpn. Pharmacol. Ther., 17, 1653, 1989.
releasing active indometacin in inflammatory tissue (in rat) 5) Onomura T. et al.: ibid., 17, 2261, 1989.
or inflammatory target cells (in human or rat synovial 6) Shiokawa Y. et al.: ibid., 17, 3245, 1989.
7) Nobunaga M. et al.: Med. Consult. New Remed., 30, 1309, 1993.
8) Murota K. et al.: Jpn. Pharmacol. Ther., 21, 2739, 1993.
PHYSICOCHEMISTRY
9) Kobayashi S. et al.: Pharmacometrics, 36, 91, 1988.
Nonproprietary name: Indometacin Farnesil (JAN, INN)
10) Kumakura S. et al.: Agents Actions, 29, 286, 1990.
Chemical name:
11) Ozaki S. et al.: Pharmacometrics, 37, 439, 1989.
7:3 (2E: 2Z) geometric mixture of (6E)-3,7,11-trimethyl- 12) Mishima M. et al.: Xenob. Metab. Dispos., 6, 615, 1991.
2,6,10-dodecatrienyl 1-(p-chlorobenzoyl)-5-methoxy-2- 13) Kobayashi S. et al.: Drug Exp. Clin. Res., 10, 845, 1984.
14) Mishima M. et al.: Xenobiotica, 20, 135, 1990.
Molecular formula: C34H40ClNO4
15) Mishima M. et al.: Xenob. Metab. Dispos., 4, 419, 1989.
Molecular weight: 562.15
16) Mishima M. et al.: ibid., 4, 447, 1989.
Structural formula:
17) Mishima M. et al.: Res. Commun. Chem. Pathol. Pharmacol., 72, 183, 1991.
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Dialon (Indonesia)

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