Eisai Co., Ltd.

Revised: January 2017 (6th version) Standard Commodity Classification No. of Japan
873999

- Antirheumatic Agent -

CARERAM Tablets 25 mg
< Iguratimod tablets >
Powerful drug and prescription drug

Storage Approval No. 22400AMX00731000

CARERAM should be stored at room temperature Date of listing in the NHI reimbursement price Aug 2012
Date of initial marketing in Japan Sep 2012
Expiration date International birth date Jun 2012
CARERAM should be used by the expiration date indicated
on the package

Caution: Use only as directed by a physician.

WARNINGS DESCRIPTION
Brand name CARERAM Tablets 25 mg
Overseas clinical studies have reported cases of pancytope-
Ingredient Iguratimod
nia with fatal outcome in patients treated with iguratimod at Content (per tablet) 25 mg
a daily dose of 125 mg. CARERAM should be administered Inactive ingredient Microcrystalline cellulose, carmellose calcium, hy-
by a physician with enough knowledge of this product and droxypropylcellulose, magnesium stearate, hypro-
mellose, polyoxyethylene (105) polyoxypropylene (5)
experience in antirheumatic therapy. Adequate facilities for glycol, talc, titanium oxide, carnauba wax
the treatment of emergencies must be available at the medi- Color/dosage form White film-coated tablets
cal institution where this therapy is administered. Appearance

Size (mm) Approximately 7.6 in diameter,

CONTRAINDICATIONS (CARERAM is contraindi-
cated in the following patients.)
1. Pregnant women and women who may possibly be preg-
nant
[Animal studies (rats) have shown that iguratimod had
teratogenicity, increased early fetal mortality, and caused
vasoconstriction of the fetal ductus arteriosus (See “6. Use
during Pregnancy, Delivery or Lactation” section).]
2. Patients with severe hepatic dysfunction
[Since an adverse reaction of hepatic function disorder
may occur, exacerbation of pre-existing hepatic dysfunc-
tion may result.]
3. Patients with peptic ulcer
[Since an adverse reaction of peptic ulcer may occur, ex-
acerbation of pre-existing peptic ulcer may result.]
4. Patients with a history of hypersensitivity to any of the
ingredients of CARERAM
5. Patients on warfarin therapy
[See “Drug Interactions” section.]
approximately 4.1 in thickness
Weight (mg) Approximately 190.6
INDICATIONS
Rheumatoid arthritis
DOSAGE AND ADMINISTRATION
The usual adult dosage for oral use is 25 mg of iguratimod
once daily after breakfast for 4 weeks or more, after which
the dosage should be increased to one 25 mg tablet taken
twice daily (after breakfast and after supper).
<Precautions>
1. AST (GOT) increased and ALT (GPT) increased were
more frequently observed with the initial daily dose of 50
mg than with that of 25 mg. Therefore, CARERAM should
be administered at a daily dose of 25 mg during the first 4
weeks of treatment.
2. A daily dose should not exceed 50 mg (See “8. Overdos-
age” section).
3. The efficacy of CARERAM is usually observed by 16
weeks of treatment. It is therefore recommended to contin-
ue administration for 16 weeks to assess treatment re-
sponse.
4. Considering the characteristics of CARERAM and the dis-
ease, careful clinical observation should be made during
the treatment period and administration should not be con-
tinued aimlessly.
2 Eisai Co., Ltd.

PRECAUTIONS consideration of differential diagnosis of pneumocystis

1. Careful Administration (CARERAM should be admin- pneumonia (e.g. measurement of β-D-glucan levels).
istrated with care in the following patients.) (4) In clinical studies of CARERAM alone, low-weight (<
(1) Lactating women 40 kg) patients had an increased incidence of adverse
[See “6. Use during Pregnancy, Delivery or Lactation” reactions. Such patients should be carefully monitored
section.] during treatment period. If any abnormal findings are
(2) Patients with a current or past history of hepatic dys- observed, appropriate therapeutic measures, such as
function discontinuation of administration, should be taken.
[Hepatic dysfunction may worsen or recur.] CARERAM has not been administered to low-weight
(3) Patients with a current or past history of peptic ulcer patients in clinical studies of the drug in combination
[Peptic ulcer may recur.] with methotrexate; no safety evaluation has been per-
(4) Low-weight patients formed.
[See “2. Important Precautions” section.] (5) The efficacy and safety of CARERAM in combination
(5) Patients with anaemia, leukopenia and thrombocytope- with methotrexate at >8mg/week or with antirheumatic
nia, patients with impaired bone marrow function agents other than methotrexate have not been estab-
[Blood disorder may worsen.] lished. Extreme caution should be exercised when used
(6) Patients with renal dysfunction in these dosing regimens.
[The risk of adverse reactions may increase.]
3. Drug Interactions
2. Important Precautions (1) Contraindications for coadministration (CARE-
(1) Prior to initiating treatment with CARERAM, liver RAM should not be coadministered with the fol-
function tests must be performed. During the lowing drugs.)
treatment period, patients should undergo these Drugs Signs, Symptoms, and Mechanism and
tests periodically, for example, biweekly for the first Treatment Risk Factors
Warfarin There have been reports of The mechanism is un-
2 months of treatment and then monthly, in addi- [WARFARIN, etc.] serious haemorrhage that was known.
tion to careful observation of patient’s clinical con- caused by enhanced effects of
warfarin after administering
dition (See “4. Adverse Reactions” section). CARERAM with warfarin.
It should be noted for liver function that AST (GOT) When patients require warfarin
therapy, they should not be
increased and ALT (GPT) increased were observed at a administered CARERAM, and
high incidence in clinical studies. If any abnormalities should preferentially receive
are found, it should be determined whether administra- warfarin therapy.

tion can be continued or not. In particular, in case of

elevation to 100 IU or higher as a criterion, administra- (2) Precautions for coadministration (CARERAM
tion should be discontinued. should be administered with care when coadminis-
(2) Prior to initiating treatment with CARERAM, exami- tered with the following drugs.)
nations such as blood and renal function tests must be Drugs Signs, Symptoms, and Mechanism and
Treatment Risk Factors
performed. During treatment period, patients should
Nonsteroidal an- Increased incidence of gastro- Both drugs inhibit pros-
undergo these tests periodically, for example, biweekly ti-inflammatory intestinal disorder has been taglandin biosynthesis.
for the first 2 months of treatment and then monthly, in drugs reported. Therefore, in case of
peptic ulcer, in particular, ad-
addition to careful observation of patient’s clinical ministration of CARERAM
condition. should be discontinued and
appropriate therapeutic
If any abnormalities are found, it should be determined measures should be taken (See
whether administration can be continued or not and ap- “4. Adverse Reactions” sec-
tion).
propriate therapeutic measures should be taken. If
Cimetidine Adverse reactions are more The metabolism of
blood disorder, such as erythrocytes decreased, white likely to occur due to the in- CARERAM is inhibited.
blood cell decreased and platelets decreased, is ob- creased plasma concentration
of CARERAM. If any abnor-
served, administration of CARERAM may be discon- mal findings are observed,
tinued or interrupted as needed and appropriate thera- appropriate therapeutic
measures, such as dose reduc-
peutic measures should be taken. tion and interruption of CARE-
(3) Since interstitial pneumonia may occur, caution should RAM,
should be taken.
be exercised against the occurrence of pyrexia, cough,
Phenobarbital The plasma concentration of The metabolism of
dyspnoea and other symptoms while on treatment with CARERAM may be de- CARERAM is promoted.
CARERAM. If any abnormalities are found, chest ra- creased.

diography and clinical laboratory tests including KL-6

and CRP should be conducted immediately, and ad- 4. Adverse Reactions
ministration of CARERAM should be discontinued. Iguratimod monotherapy:
Additionally, appropriate therapeutic measures such as In clinical studies of iguratimod alone conducted before ap-
administration of corticosteroids should be taken in proval, adverse reactions (including changes in laboratory
 Eisai Co., Ltd. 3

values) were observed in 462 (57.89%) of 798 subjects. and appropriate therapeutic measures, such as admin-
The most common adverse reactions include ALT (GPT) istration of corticosteroids, should be taken.
increased in 148 subjects (18.55%), AST (GOT) increased 5) Infection (0.19%): Since infection such as sepsis and
in 132 subjects (16.54%), γ-GTP increased in 86 subjects pyothorax may occur, the patients should be carefully
(of 547 subjects, 15.72%), ALP increased in 119 subjects monitored. If any abnormal findings are observed,
(14.91%), NAG increased in 72 subjects (9.02%), β2 mi- administration should be discontinued and appropri-
croglobulin urine increased in 59 subjects (7.39%), total ate therapeutic measures should be taken.
bile acids increased in 22 subjects (of 385 subjects, 5.71%),
abdominal pain in 44 subjects (5.51%), and rash in 41 sub- (2) Other adverse reactions
jects (5.14%). If any of the following adverse reactions are observed,
Combination with methotrexate (6 to 8 mg/week): appropriate therapeutic measures should be taken ac-
In clinical studies of iguratimod in combination with meth- cording to the severity of symptoms.
otrexate (6 to 8 mg/week) conducted before approval, ad-
verse reactions (including changes in laboratory values) 20% > 10% > 1% > < 0.5%
≥ 10% ≥ 1% ≥ 0.5%
were observed in a total of 136 (58.62%) of 232 subjects Hepatic AST (GOT) Total bile acids Blood bilirubin Urobilinogen
(at Week 52). increased, increased increased urine increased
ALT (GPT)
The most common adverse reactions include AST (GOT) increased,
increased in 27 subjects (11.64%), ALT (GPT) increased in Al-P in-
creased,
27 subjects (11.64%), lymphocyte count decreased in 21 γ-GTP in-
subjects (9.05%), nasopharyngitis in 19 subjects (8.19%), creased
Hemato- - Haemoglobin Anaemia Platelets de-
blood iron decreased in 19 subjects (8.19%), γ-GTP in- logic decreased, creased, plate-
creased in 16 subjects (6.90%), and β2 microglobulin urine haematocrit de- lets increased,
creased, eosin- basophil count
increased in 13 subjects (5.60%). ophil count in- increased, neu-
During this study, adverse reactions (including changes in creased, lym- trophils in-
phocyte count creased, neutro-
laboratory values) were reported in 85 (51.83%) of 164 decreased, white phil count de-
blood cell in- creased, mono-
subjects in the iguratimod + methotrexate group and 29 creased, white cytes increased,
(32.95%) of 88 subjects in the methotrexate monotherapy blood cell de- monocytes de-
creased, eryth- creased, lym-
group (at Week 24). rocytes de- phocyte mor-
creased phology abnor-
mal
(1) Clinically significant adverse reactions Gastro- - Abdominal pain, Gastritis, dys- Constipation,
1) Hepatic function disorder (0.49%), jaundice (0.10%): intestinal stomatitis, oc- pepsia, vomit- abdominal dis-
cult blood posi- ing, decreased tension, glossi-
Since hepatic function disorder with AST (GOT) in- tive, nausea, appetite, tis, oesophagitis,
creased and/or ALT (GPT) increased, etc., and jaun- abdominal dis- cheilitis epigastric dis-
comfort, diar- comfort, gas-
dice may occur, the patients should be carefully mon- rhoea, peptic troenteritis, gas-
ulcer trointestinal dis-
itored, for example, with periodic examinations. If order, periodon-
any abnormal findings are observed, appropriate titis
therapeutic measures, such as discontinuation of ad- Renal - NAG increased, Blood creatinine Pyelonephritis,
β2 microglobulin increased pollakiuria
ministration, should be taken. urine increased,
blood urea in-
2) Pancytopenia (0.10%), agranulocytosis (incidence creased, β2 mi-
unknown), white blood cell decreased (0.10%): Since croglobulin
blood increased,
pancytopenia, agranulocytosis and white blood cell protein urine
decreased may occur, the patients should be carefully present, red
blood cells urine
monitored, for example, with periodic examinations. positive, white
blood cells urine
If any abnormal findings are observed, appropriate positive, urinary
therapeutic measures, such as discontinuation of ad- casts, urinary
sediment present
ministration, should be taken.
Hyper - Rash, pruritus Eczema, urti- Erythema, pho-
3) Peptic ulcer (0.68%): Peptic ulcer possibly resulting sensitivity caria tosensitivity
note)
from inhibition of cyclooxygenase may occur. reaction
Metabolic - Blood iron de- Blood cholines- Glucose urine
Therefore, if any gastrointestinal symptoms such as abnormality creased, BNP terase decreased, present, blood
melena are observed, administration should be dis- increased protein total de- albumin de-
creased creased, iron
continued and appropriate therapeutic measures binding capacity
should be taken. total decreased,
iron binding
4) Interstitial pneumonia (0.29%): Interstitial pneumo- capacity unsatu-
rated increased
nia may occur. Therefore, if pyrexia, cough, dysp-
Psychone- - - Dizziness Headache, in-
noea and other symptoms are observed, examinations urologic somnia, somno-
such as chest radiography should be performed im- lence, feeling
abnormal
mediately, administration should be discontinued,
4 Eisai Co., Ltd.

20% > 10% > 1% > < 0.5% 9. Precautions concerning Use
≥ 10% ≥ 1% ≥ 0.5%
Others - Blood pressure Pyrexia, alope- Herpes zoster,
Precautions regarding dispensing: For drugs that are dis-
increased, na- cia, dysgeusia, malaise, tinnitus, pensed in a press-through package (PTP), instruct the pa-
sopharyngitis, upper respirato- cough, menstru-
KL-6 increased ry tract inflam- al disorder, can- tient to remove the drug from the package prior to use. (It
mation, oedema didiasis, bron- has been reported that, if the PTP sheet is swallowed, the
chitis,
paronychia, sharp corners of the sheet may puncture the esophageal
pharyngitis, dry mucosa, resulting in serious complications such as medias-
skin, palpita-
tions, oropha- tinitis).
ryngeal pain,
back pain, mus-
cle spasms, 10. Other Precautions
chills, cystitis,
mycosis (1) In vitro studies have demonstrated the inhibitory effect
Note) In case of such symptoms, administration should be dis- of iguratimod on cyclooxygenase-2. This drug has also
continued. suppressed the production of prostaglandin E2 in the
mouse cultured fibroblasts and rat inflammatory exu-
5. Use in the Elderly date.
Clinical pharmacology studies in healthy male adults have (2) Decreases in count corpora lutea, implantation sites,
shown that the plasma concentration of CARERAM was and number of live fetuses have been reported in a
slightly higher in elderly adults than in nonelderly adults. study of fertility and early embryonic development to
In clinical studies of CARERAM alone, no difference in implantation in rats.1)
the efficacy and incidence of adverse reactions was ob- (3) In a 2-year, oral-dose, carcinogenicity study in mice,
served, whereas elderly adults had more adverse reactions the incidence of malignant lymphoma increased at a
than nonelderly adults in studies of CARERAM + metho- dose of ≥ 70 mg/kg and renal cell adenoma developed
trexate. The elderly often have reduced physiological func- in male mice at 700 mg/kg. However, neither carcino-
tion and may be at an increased risk of adverse reactions. genicity in rats nor genotoxicity of iguratimod and its
Therefore, CARERAM should be administered to elderly metabolites have been observed.
adults while closely monitoring the patient’s condition. (4) In a phototoxicity study in guinea pigs, iguratimod as a
single oral dose showed phototoxicity at a dose of ≥
6. Use during Pregnancy, Delivery or Lactation 3.75 mg/kg.
(1) CARERAM should not be used in pregnant women and
women who may possibly be pregnant. PHARMACOKINETICS
[A study for effects on embryo-fetal development in 1. Plasma concentration
rats have shown that iguratimod had teratogenicity (1) Single dose 3)
(cardiac/macrovascular abnormalities) and increased The plasma concentration over the first 72 hours after
early fetal mortality.1) Vasoconstriction of the fetal single oral administration of iguratimod 25 mg to elderly
ductus arteriosus has also been reported in a study to and nonelderly, healthy male adults in fed conditions was
evaluate the effect on the fetal ductus arteriosus of rats evaluated. The concentration-time profile is shown in
in late pregnancy.2)] Figure 1. The maximum plasma concentration was
(2) Nursing mothers should avoid breast feeding during achieved at approximately 4 hours post-dose with the
treatment. level being slightly higher in elderly adults compared to
[Animal studies (rats) have reported that iguratimod is nonelderly adults over time.
excreted in breast milk.]
Plas ma concentrations (ng/mL)

Elderly group
7. Pediatric Use
Nonelderly group
The safety of CARERAM in children has not been estab-
lished (no clinical experience).

8. Overdosage
In case of overdosage, the patients should be carefully
Time (hr)
monitored. If any abnormal findings are observed, appro-
priate therapeutic measures should be taken. (Mean ± standard deviat ion, n=7)
(1) Clinical studies have revealed that laboratory abnor- Figure 1
malities were more frequently observed in the 75 Time-Course Changes in Plasma Concentration Follow-
ing Single Dose
mg/day group than in the 50 mg/day group.
(2) Japanese and overseas clinical studies reported 1 case
(2) Multiple doses 3)
each of pancytopenia at a daily dose of ≥ 100 mg, of
Following multiple oral doses of iguratimod (at a dose of
which 1 in the overseas study was fatal.
25 mg, twice daily for 14 days) to elderly and nonelderly,
healthy male adults, the plasma concentrations reached a
 Eisai Co., Ltd. 5

steady state after Day 4 for iguratimod and Day 10 for 2. Long-term study 7)
the metabolites, M1 (3-amino metabolite of iguratimod) ACR20 response rate at Week 52 was 41.0% (59/144 pa-
and M2 (3-acetylamino metabolite of iguratimod). These tients) in patients with rheumatoid arthritis who initiated
plasma concentrations remained slightly higher in elderly iguratimod treatment at a dose of 25 mg once daily, which
adults than in nonelderly adults. Pharmacokinetic param- was increased 4 weeks later to 25 mg twice daily for 48
eters obtained from analysis of the plasma concentrations weeks.
over 168 hours after last dosing are shown in Table 1.
Elderly adults had slightly increased levels of both Cmax 3. Study in combination with methotrexate
and AUC compared to nonelderly adults. (6 to 8 mg/week)
Table 3 shows ACR20 response rate at Week 24 in a dou-
Table 1 Pharmacokinetic Parameters Following Multiple Doses ble-blind, placebo-controlled study of iguratimod (initial
Cmax tmax AUC0→12 t1/2
Subjects
(µg/mL) (hr) (µg·hr/mL) (hr) dose of 25 mg once daily, which was increased 4 weeks
igurat- Nonelderly 1.60±0.34 3.3±1.0 12.2±2.8 73.3±15.6 later to 25 mg twice daily for 20 weeks) in combination
imod Elderly 1.72±0.46 3.9±0.7 14.3±3.8 61.8±17.9 with methotrexate (6 to 8 mg/week) in patients with rheu-
Nonelderly 0.537±0.185 3.3±1.5 5.58±1.76 43.5±13.1 matoid arthritis inadequately responsive to methotrexate
M1
Elderly 0.637±0.181 0.6±1.5 6.52±1.82 43.4±10.6 treatment. The response rate with iguratimod was signifi-
Nonelderly 2.97±1.10 3.3±1.5 33.0±12.5 52.8±11.5 cantly greater than that with placebo (p < 0.001).
M2
Elderly 3.43±1.50 0.6±1.5 37.6±16.8 55.2±12.2
(Mean ± standard deviation, n=7) Table 3 ACR20 Response Rate
Iguratimod + meth- Placebo + metho-
otrexate group trexate group
2. Protein binding rate 4)
ACR20 response rate (%)
Iguratimod was bound to human serum protein at a range [No. of responders/No. of subjects
69.5 30.7
[114/165] [27/88]
of 93.0% to 93.2% in vitro (determined by centrifugal ul- evaluated for efficacy]
trafiltration at the drug level of 0.3 to 30 µg/mL).
PHARMACOLOGY
3. Metabolism 5) 1. Effects in an arthritis model 8)9)
After multiple oral doses of iguratimod (at a dose of 25 mg, Prophylactic and therapeutic administration of iguratimod
twice daily for 14 days) to healthy male adults, the follow- reduced joint swelling and delayed the progression of bone
ing metabolites were detected in the plasma: M1, M2, M3 lesions in adjuvant arthritis, a chronic arthritis model in rats.
(6-phenoxy-hydroxylated metabolite of M2), M4 (6- phe- In addition, iguratimod inhibited the progression of arthritis
noxy-hydroxylated metabolite of iguratimod), and M5 swelling in a mouse model of collagen-induced arthritis
(6-phenoxy-hydroxylated metabolite of M1), of which M1 dose-dependently as well as histologically improved the
and M2 were found to be active metabolites. synovial and osteochondral lesions in the joints of the hind
limbs in MRL/lpr mice, a model of spontaneous arthritis.
4. Excretion 3)
Following multiple oral doses of iguratimod (at a dose of 2. Effects in a cell-mediated immunity-related inflam-
25 mg, twice daily for 14 days) to elderly and nonelderly, mation model 10)11)
healthy male adults, the 24-hour urinary excretion rate at Iguratimod suppressed the development of paralytic symp-
steady state was approximately 20%, with M3 and M4 toms in a rat model of autoimmune encephalomyelitis and
primarily detected as compared to < 1% for iguratimod and suppressed murine delayed foot-pad oedema.
active metabolites, M1 and M2.
3. Effects on immunoglobulin production 8)12)13)
CLINICAL STUDIES In culture experiments using murine and human B-cells,
1. Double-blind, controlled study 6) iguratimod inhibited immunoglobulin (IgG and IgM) pro-
Table 2 shows the response rate according to criteria de- duction. It also decreased human IgG levels detected in the
veloped by the American College of Rheumatology serum in severe combined immunodeficiency mice (SCID
(ACR20) at Week 28 in a double-blind, placebo-controlled mice) recipients of the synovial tissue derived from rheu-
study of iguratimod (initial dose of 25 mg once daily, matoid arthritis patients. Furthermore, it improved hyper-
which was increased 4 weeks later to 25 mg twice daily for gammaglobulinemia in rat adjuvant arthritis and MRL/
24 weeks) in patients with rheumatoid arthritis. The re- lpr-mouse spontaneous arthritis models.
sponse rate with iguratimod was significantly greater than
that with placebo (p < 0.001). 4. Effects on cytokine production 14)
Culture experiments using monocytic cells and rheumatoid
Table 2 ACR20 Response Rate arthritis patient-derived synovial cells have shown that
Iguratimod group Placebo group
iguratimod inhibited the cell-stimulated production of in-
ACR20 response rate (%)
53.8 17.2 flammatory cytokines (TNFα, IL-1β, IL-6, IL-8, and
[No. of responders/No. of subjects
[71/132] [11/64]
evaluated for efficacy] MCP-1). It also showed dose-dependent suppression in the
following levels: serum TNFα in a mouse model of conca-
6 Eisai Co., Ltd.

navalin A-induced hepatitis, an immunoreactive liver dis- Eisai Co., Ltd.

order model; MCP-1 in the exudates of an air pouch in-
flammation model; and serum IL-6 in a collagen-induced Manufactured and marketed by:
arthritis model. Eisai Co., Ltd.
6-10, Koishikawa 4-chome, Bunkyo-ku, Tokyo, 112-8088
PHYSICOCHEMISTRY
Nonproprietary name: Iguratimod
Chemical name:
N-[7-[(Methanesulfonyl)amino]-4-oxo-6-
phenoxy-4H-1-benzopyran-3-yl]formamide
Molecular formula: C17H14N2O6S
Molecular weight: 374.37
Structural formula:

Description:
Iguratimod occurs as white crystalline powder. It is slightly
soluble in acetonitrile, very slightly soluble in ethanol
(99.5), and practically insoluble in water. It is hygroscopic.
Melting point: 238 °C to 242 °C

PACKAGING
CARERAM Tablets 25 mg:
Boxes of 100 tablets in press-through packages

REFERENCES
1) Internal document (Reproduction toxicity studies)
2) Internal document (Effects on the fetal ductus arterio-
sus in rats)
3) Internal document (Pharmacokinetics in the elderly)
4) Internal document (Protein binding)
5) Internal document (Pharmacologic action)
6) Hara M. et al.: Mod. Rheumatol., 17: 1, 2007
7) Hara M. et al.: Mod. Rheumatol., 17: 10, 2007
8) Urata N. et al.: Japanese Pharmacology &
Therapeutics, 35: 571, 2007
9) Tanaka K. et al.: Int. J. Immunother., 9: 69, 1993
10) Aikawa Y. et al.: J. Neuroimmunol., 89: 35, 1998
11) Internal document (Inhibitory effects on delayed
foot-pad oedema in mice)
12) Yamamoto T. et al.: Japanese Pharmacology & Thera-
peutics, 35: 561, 2007
13) Tanaka K. et al.: Rheumatology, 42: 1365, 2003
14) Yamamoto M. et al.: Japanese Pharmacology & Thera-
peutics, 35: 551, 2007

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cited in the REFERENCES to the following company:

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