Package Insert Mobic
This document is a translation from Japanese into English of the
Enclosed Information (a package insert) of
Meloxicam marketed in 2000 in Japan as Mobic(r)
モービック(r) カプセル５ｍｇ
モービック(r) カプセル１０ｍｇ
www.jouhoukoukai.com
Created: December 2000 (first new version)
Standard Commodity Classification No. of Japan
871149
Storage:
Airtight containers
Expiration Date:
Indicated on the container and the
outer carton
Non-steroidal anti-inflammatory medicine * painkiller
Powerful drug * prescription-only drug
MOBIC(r) Capsules 5 mg
MOBIC(r) Capsules 10 mg
(Meloxicam medication) (r) = registered trademark
Capsules 5 mg
Capsules 10 mg
Approval No.
21200 AMY 00245000
21200 AMY 00244000
Date of the listing in the NHI
(National Health Insurance)
reimbursement price list
February 2001
February 2001
Date of the initial marketing in
Japan
February 2001
February 2001
Date of the international
launch
May 1995
May 1995
【CONTRAINDICATIONS】
(MOBIC IS CONTRAINDICATED FOR THE FOLLOWING PATIENTS)
1. Patients with peptic ulcer (Mobic may worsen a digestive ulcer due
to a reduction of the protecting function of gastric mucosa by
inhibition of prostaglandin synthesis. See paragraph 2 of "Careful
Administration").
2. Patients with severe blood disorder (Mobic may worsen the
disorder).
3. Patients with severe liver disorder (Mobic may worsen the disorder).
4. Patients with severe renal dysfunction (Mobic may worsen the
dysfunction due to reduction of renal blood flow volume, and
disruption of the maintenance of balance of water and sodium,
caused by inhibiting the prostaglandin synthesis).
5. Patients with severe heart failure (Mobic may worsen the heart
failure due to reduction of renal blood flow volume, and disruption
of the maintenance of balance of water and sodium, caused by
inhibiting the prostaglandin synthesis).
6. Patients with severe hypertension (Mobic may increase blood due to
reduction of renal blood flow volume, and disruption of the
maintenance of balance of water and sodium, caused by inhibiting
the prostaglandin synthesis).
7. Patients with, or with history of, hypersensitivity to ingredient of
this product, salicylic acid salts (aspirin etc.) or other NSAIDs.
8. Patients with, or with history of, hypersensitivity to aspirin-triggered
asthma (or induction of asthma attack by NSAIDs etc.). (Mobic
may induce severe asthma attack)
9. Pregnant or expecting pregnancy (see "Use during Pregnancy,
Delivery or Lactation").
【DESCRIPTION】
Trade name
Mobic Capsules 5 mg
Mobic Capsules 10 mg
Ingredients/Contents
1 capsule contains
5 mg meloxicam
1 capsule contains
10 mg meloxicam
Additives
Lauryl sodium sulphate
Lauryl sodium sulphate
Pharmaceutical form
Solid capsules with light
brown-yellow opacity
Solid capsules with light
brown-yellow opacity,
and head with yellow
opacity
Internal content
Powdered or granular
pale yellow substance
Powdered or granular
pale yellow substance
External form
No. 4
No. 4
Length
Approximately. 14 mm
Approximately. 14 mm
Diameters
Approximately 5 mm
Approximately 5 mm
Weight
Approximately 0.185 g
Approximately 0.185 g
Identification Code
M05
M06
【INDICATIONS】
For anti-inflammatory effect and for pain relief in the following diseases
and symptoms:
* Chronic joint rheumatism
* Deformations of the joints (osteoarthrosis)
* Lumbago symptoms
* Periarticular inflammation of the shoulder joint
(scapulohumeral periarthritis)
* Neck-shoulder-arm syndrome (brachialgia,
cervicobrachial syndrom)
【DOSAGE AND ADMINISTRATION】
Usually, the dose of Mobic for adults is 10 mg meloxicam orally,
once a day after meal. In addition to the above, depending on the age
and symptoms, the dose may vary up to 15 mg as the maximum daily
dose.
Caution to DOSAGE AND ADMINISTRATION
There is no safety profile established in this country (Japan) for
doses exceeding 15 mg a day (due to the lack of experience)!
【PRECAUTIONS】
1. Careful Administration (Mobic should be administered with care to the
following patients):
(1) Patients with peptic ulcer (Mobic may worsen a digestive ulcer
due to a reduction of the protective functions of the gastric
mucosa by inhibition of prostaglandin synthesis. See paragraph 2
of "Careful Administration")
(2) Patients with NSAID-induced ulcer and having a concurrent
treatment with misoprostol (Misoprostol has an indication for
ulcer caused by NSAIDs, but there are some cases of ulcer
showing resistance to the misoprostol treatment). Therefore,
patients with, or with a history of, ulcer caused by NSAIDs, and
who require long-term treatment with Mobic, should be carefully
monitored and the drug administer with caution, since not all
patients with such ulcers are cured after misoprostol therapy.
(3) Patients treated with anti-coagulatants (such as warfarin,
etc.).(See "Drug interaction")
(4) Patients with, or with a history of, severe blood disorder (Mobic
may worsen or reoccur the disorder).
(5) Patients with, or with a history of, liver disorder (Mobic may
worsen or reoccur the disorder).
(6) Patients with, or with a history of, renal dysfunction (Mobic may
worsen or reoccur the dysfunction due to reduction of renal
blood flow volume, and due to a disruption - caused by
inhibiting the prostaglandin synthesis, in the maintenance of the
balance of water and sodium).
(7) Patients with heart dysfunction (Mobic may worsen the
dysfunction due to reduction of renal blood flow volume, and
due to a disruption - caused by inhibiting the prostaglandin
synthesis, in the maintenance of the balance of water and
sodium).
(8) Patients with hypertension (Mobic may increase blood pressure
due to reduction of renal blood flow volume, and due to a
disruption - caused by inhibiting the prostaglandin synthesis, in
the maintenance of the balance of water and sodium).
(9) Patients with bronchial asthma (Mobic may induce asthma
attack).
(10) Elderly (See "Use in Elderly").
(11) Patients immediately after a major operation accompanied by a
loss of body fluids (Patients with reduced circulation of body
fluids may have reduction of renal blood flow or renal
dysfunction due to inhibition of prostaglandin synthesis).
2. Important Precautions
(1) Mobic showed stronger inhibition of COX-2 than of COX-1 in in
vitro tests. However, it was not confirmed its higher safety in any
clinical study in Japanese subjects in comparison with NSAIDs
which showed lower selectivity to COX-2. Therefore, especially for
patients with high risk factors for causing a gastric dysfunction
(patients having history of peptic ulcer, etc.), a careful observation is
necessary, and monitoring for incidence of adverse events as well.
(See "Clinical Effects" and "Clinical Pharmacology")
(2) It should be aware that the treatment by Mobic is symptomatic
treatment, but not ethiotropic treatment. Therefore, a consideration
for (appropriate) ethiotropic treatment is necessary.
(3) For long-term treatment by Mobic, regular laboratory tests
(urinalysis, hematology tests, liver function tests, occult bleeding
tests, etc.) should be performed. When abnormality is detected, a
proper treatment such as reduction of the doses or discontinuation
is needed.
(4) The patient condition should be monitored carefully, and it should
be paid a careful attention to the occurrence of side effects. In other
countries, severe adverse reactions in gastro-intestinal system [peptic
ulcer (in some cases perforative ulcer), gastrointestinal hemorrhage
such as hematemesis, melena etc.] are reported. When abnormality
is observed, the dosing should be discontinued, and proper
treatment provided. (See "Adverse Reactions")
(5) Due to the anti-inflammatory effect of meloxicam, an infection may
not be manifested. In this aspect, the monitoring and administration
of the drug should be carefully executed.
(6) It is advised to avoid co-medication with other anti-inflammatory
agents (It is reported that other NSAIDs enhance each others' side
effects). (See "Drug interaction")
(7) Symptoms of a central nervous system dysfunction - such as
abnormal vision accommodation, sleepiness, etc. sometimes
occurred. Enough care should be taken, as operating equipments or
driving a car should be avoided by patients under treatment with
this drug.
3. Drug Interactions
Table. Cautions for co-medication
Name of
medication
Clinical signs and
symptoms or treatment
Mode of action or
risk factors
Other NSAIDs or
salicylic acid salts
It is reported that
co-medication with other
NSAIDs cause an increase of
the side effects (See
"Important Precautions")
It is considered that
adverse effects are
enhanced because
both medications
inhibit the
prostaglandin
synthesis.
Cumarin type
anticoagulants
(warfarin etc.)
This combination may
increase the risk of bleeding.
When the co-medication
cannot be avoided, blood
coagulation tests should be
conducted, and the effects of
these drugs should be
carefully monitored.
The reason is
considered that both
agents have
anticoagulative effect.
The metabolism by
CYP2C9 may cause
interaction between
this medicine
(meloxicam) and
warfarin.
Heparin
Table (cont.) Cautions for co-medication
Ticlopidine
Risk of increase of the
tendency for bleeding
It is considered that
Ticlopidine has
inhibitory effect on
platelet coagulation.
Anti-thrombotics
This is due to the
anti-thrombotic
effects of both agents.
Cholestyramine
Weakened this drug's effects
It is considered that
the clearance of this
drug (meloxicam) can
be shortened because
cholestyramine
absorbs other drugs.
Oral
anti-hyperglycemics
Weakened this drug's
(meloxicam) effects
Mode of action is
unknown, but
glibenclamide was
reported that it
inhibited this drug's
(meloxicam)
metabolism
(in vitro tests).
Kinidine
Weakened this drug's
(meloxicam) effects
Mode of action is not
known, but kinidine
was reported to
increase this drug's
(meloxicam)
metabolism.
Table (cont.) Cautions for co-medication
Lithium
The lithium concentration in
the blood rises. Because there
are reports that other
NSAIDs lead to lithium
poisoning, when Mobic is
introduced the lithium
concentration in the blood
should be measured, the dose
of Mobic reduced, and
patients carefully observed.
It is considered that
the renal excretion of
lithium is prolonged
due to this drug's
(meloxicam)
inhibitory effect on
the prostaglandin
synthesis.
Methotrexate
This drug (meloxicam) has
the risk of worsening the
blood dysfunction caused by
methotrexate. Hematology
tests are required.
It is considered that
this drug (meloxicam)
reduces the excretion
of methotrexate at
the renal duct due to
inhibitory effect on
the prostaglandin
synthesis.
Diuretics
Patient on diuretics may have
risks of acute renal failure
when co-medicated with
NSAIDs. Co-medication
of this drug (meloxicam)
should be started with special
care on renal function.
The reductions of
renal blood flow
volume, and the
disruption of the
maintenance of
balance of water and
sodium, are
considered to be
caused by the
inhibition of the
prostaglandin
synthesis.
Table (cont.) Cautions for co-medication
Anti-hypotensive
(beta-blockers, ACE
inhibitors, blood
vessel dilating
medicines, diuretics,
etc.)
Other NSAIDs are reported
to reduce anti-hypotensive
drugs' effects.
It is considered that
inhibition of
prostaglandin that
expands blood vessels
weaken the effect of
reduction on the
blood pressure of the
anti-hypotensive
agents.
Cyclosporin
NSAIDs are reported to
enhance the renal toxicity of
cyclosporin. Special care
should be taken on the renal
function.
It is considered that
reduction of renal
blood flow is caused
by inhibition of the
prostaglandin
synthesis.
4. Adverse Reactions
Clinical studies were conducted domestically with patients with chronic
joint rheumatism, osteoarthrosis, lumbago symptoms, scapulohumeral
periarthritis, and cervicobrachial syndrome, and the safety results were
reported. Adverse drug reactions were observed in 183 patients out of 1,128
patients (16.22%). Among these patients, 125 patients (11.08%) showed side
effects in gastro-intestinal system. Major symptoms were gastric or epigastric
discomfort with incidence of 36 cases (3.19%), stomach or epigastric pain in
28 cases (2.48%), exanthem/rash/drug-caused skin eruption in 23 cases
(2.04%), abdomen or upper abdomen pain in 11 cases (0.98%), itchiness in 10
cases (0.89%) and so on. Laboratory tests did not show any tendency of
alterations. (December 1996)
Clinical studies in other countries have been conducted in totally 5,500
subjects - healthy volunteers and patients with chronic joint rheumatism,
osteoarthrosis, and ankylosing spondylitis. Among them, 7.5 mg and 15 mg
meloxicam were administered orally in 3,750 patients. Major adverse drug
reactions were dyspepsia (7.0%), nausea (4.6%), headache (4.0%), diarrhea
(3.5%), rash (2.8%) and so on. (At time of marketing approval application in
Europe)
(1) Serious Adverse Events
1) Peptic ulcer (1% or less) (often with perforation), hematemesis
(incidence is unknown), gastro-intestinal hemorrhage including melena
(1% or less), colitis (less than 0.1%). Careful monitoring should be
performed, and the therapy should be discontinued when abnormality
appears and proper treatment should be administered.
2) Asthma (less than 0.1%). Careful monitoring should be performed,
and the therapy should be discontinued when abnormality appears and
proper treatment should be administered.
3) Acute renal failure (incidence is unknown). Careful monitoring should
be performed, and the therapy should be discontinued when
abnormality appears and proper treatment should be administered.
4) Agranulocytosis (incidence unknown), thrombocytopenia (1% or less).
Careful monitoring should be conducted and hematology tests should
be carried out regularly and when needed. The therapy should be
discontinued when abnormality appears and proper treatment should
be administered. Special care is required for co-medication with agents
that reduce bone marrow function, such as methotrexate. (See "Drug
Interaction")
5) Muco-cutaneo-ocular syndrome (Stevens-Johnson syndrome)
(incidence unknown), epidermal toxic necrolysis (Lyell syndrome)
(incidence unknown), blisters (incidence unknown) and erythema
multiforme (incidence unknown). Careful monitoring should be
performed, and the therapy should be discontinued when abnormality
appears and proper treatment should be administered.
6) Anaphylaxis, anaphylactoid reaction (less than 0.1%). Careful
monitoring should be performed and the therapy should be
discontinued when abnormality appears and proper treatment should
be administered.
7) Hepatitis (incidence unknown), severe lever dysfunction (1% or less)
Careful monitoring should be conducted and laboratory tests should
be carried out regularly and when needed. The therapy should be
discontinued when abnormality appears and proper treatment should
be administered.
Note: The incidence figures cited here are taken from the results
of the clinical studies conducted outside Japan. The
incidence marked as "unknown" is based on the
voluntary reports of PMS studies from overseas.
(2) Serious Adverse Events (observed with the same class medicines)
Shock, aplastic anemia, bone marrow depression, nephrolysis syndromes
have been observed with other NSAIDs. Physicians should carefully monitor,
conduct regular laboratory tests as well as when needed, discontinue and
provide proper treatment when abnormality occurs.
(3) Other Adverse Events
Table. Other Adverse Events
More than
5% *Note 1
In range of
0.1-5% Note 1
Less than
0.1% Note 1
Negligible
frequency
Note 2
Circulatory
organs
Increase of
blood
pressure
Hypotension,
heart
throbbing
Digestive
organs
Stomachache
Occult
bleeding,
gastric ulcer,
vomiting,
nausea /
feeling like
vomiting,
anorexia,
indigestion,
mouth
drying,
stomatitis,
angular
stomatitis,
eructation,
diarrhea,
flatulence
crepitus Note 3,
gullet flame
Note 3
Abdominal
fullness,
constipation
Gastritis
Table (cont.) Other Adverse Events
More than
5% *Note 1
In range of
0.1-5% Note 1
Less than
0.1% Note 1
Negligible
frequency
Note 2
Central
Nervous
System
Headache,
taste
abnormality
Sensory
disturbance,
sleepiness,
vertigo
Confusion,
disorientation
Erethism,
Hyper-
sensitivity
Rashes, skin
itchiness,
urticaria
Contact
dermatitis,
photosensitivity
Note 3
Sense
organs
Strange
sensation in
eye, eyeball
sclera
congestion,
tinnitus
Conjunctivitis,
abnormal
vision (sight
obstacles),
blurred vision
Liver
Increase of
AST (GOT),
ALT (GTP),
LDH, A1-P in
liver
functional
disorders, rise
of total
bilirubin
value,
urobilinogen
Table (cont.) Other Adverse Events
More than
5% *Note 1
In range of
0.1-5% Note 1
Less than
0.1% Note 1
Negligible
frequency
Note 2
Kidney
BUN, creatinine,
and uric acid
values increase,
total proteins,
decrease of
albumins, urine
protein, urine
glucose
Decrease of
the volume of
urine
Blood
Increase of a
white blood cells,
decrease of red
blood cells, white
blood cells,
hemoglobin,
hematocrit value
and lymphocytes,
increase of
neutrophils,
eosinophils,
basophils and
monocytes,
anemia 3)
Table (cont.). Other Adverse Events
More than
5% *Note 1
In range of
0.1-5% Note 1
Less than 0.1%
Note 1
Negligible
frequency Note 2
Others
Oedema,
fatigue, feeling
bad, increase
of urine
sediment, urine
occult
bleeding,
decrease of
serum iron, rise
of potassium
Coughing, pain
of the axilla or
breast, rigors,
hot flushes,
fever, weakness
in the lower
extremities
5. Use in Elderly
Elderly tend to suffer from adverse effects more often. The
administration to elderly of this drug (meloxicam) should start with a careful
monitoring of the patient's condition, for example, starting with low dose (5
mg once a day). In general, gastro-intestinal bleeding, ulcer and ulcer
perforation in elderly will have more severe outcome, and in rare cases are
reported as fatal digestive organ disorders. These events can happen at any
treatment stage with or without history of serous digestive organ disorders.
Physicians should carefully monitor patients (for digestive organ disorders
especially gastro-intestinal bleeding), and when an abnormality is detected, to
discontinue the administration and to provide appropriate treatment.
6. Use during Pregnancy, Delivery or Lactation
(1) This drug should not be administered to women with pregnancy or
expecting pregnancy since the following is found in animal studies
(in rats and rabbits):
1） In studies with administration prior or at early stage of
pregnancy in rats, it was observed a decrease of numbers of
corpus lutea, implantations, survived fetuses and implantation
rate, and an increase of death rate after implantation.
2） In studies with administration during the period of
organogenesis in rats, it was observed a prolongation of
pregnancy duration and an increase of the stillborns.
3） In studies with administration during the period of
organogenesis in rabbits, an increase of death rate after
implantation was observed, although not significant.
4） In studies with administration during the perinatal and lactation
periods, extension of pregnancy duration, extension of birth
delivery, an increase of stillbirths and mortality within the first
four days after the birth were observed.
(2) Dosing of lactating woman should be avoided. If the administration
cannot be avoided, the lactation should be discontinued. [This drug
is known to be excreted into milk in the pre-clinical animal tests (in
rats)].
7. Pediatric Use
Safety in newborns with low body weight, neonates, babies and infants is
not established due to lack of experience.
8. Overdosage
(1) Symptoms
Overdose is rarely reported, and therefore the typical symptoms and
treatment are not described.
(2) Treatment
When overdosed, according to general treatment, physician should
wash stomach, and provide support treatment and symptomatic
therapy. Cholestyramine is reported to shorten the effect of this
drug 1).
9. Precautions Concerning the Use
Taking the medicine
It is necessary to explain to patients to take out the tablets from PTP
sheets for the drug in PTP package. (It is reported that if swallowed by a
mistake, the hard edge of PTP sheets may perforate the mucous membrane
of the esophagus, thus leading to mediastinitis and other severe
complications)
10. Other Precautions
There is reported that other NSAIDs reduce contraception effects of the
intrauterine devices.
【PHARMACOKINETICS】
1) Adsorption
When 14C-meloxicam 30 mg Note)* was administered orally to healthy
volunteers, absorption rate was estimated to be approximately 100 % 2).
2) Blood Concentration
(1) Single dosage
When meloxicam 5, 10, or 20 mg Note) were administered orally to
healthy volunteers at after fasting, Cmax was observed at about 7 hours after
dosing, as the peaks of the blood drug concentration showed two phases.
Based on those findings, it is considered that this compound shows
enteroenteric circulation from intestine to intestine, thus the drug is
re-absorbed at the intestines after being excreted to intestines, or as a result of
the intestine-liver circulation. Cmax and AUC showed a dose correlation.
Table. Changes in the pharmacokinetic parameters after a single oral
dose of meloxicam (administered after fasting) 3)
Pharmacokinetic
parameters
5 mg
10 mg
20 mg *Note)
Cmax (?g/mL)
0.26 + 0.06
0.72+ 0.20
1.06+0.15
Tmax (h)
7.00+2.76
7.00+ 3.29
8.33+3.67
T1/2 (h)
-
27.6+ 7.30
25.4+8.70
AUC 0-168 (?g *h/mL)
7.87+2.13
22.8+ 3.61
42.2+15.1
Cl tot (L/h)
-
0.35+ 0.05
0.49+0.15
Vd (L)
-
13.7+ 3.70
16.8+4.14
(Mean + S.D., n=6)
(- For the assay limit, the calculation of pharmacokinetic
parameters was impossible)
Graph. Plasma concentration (?g/mL) of meloxicam after
administration of various doses
Time (hours)
(2) Multiple dosage
When meloxicam 10 mg was repeatedly administered to healthy
volunteers 30 minutes after meal, T1/2 was approximately 17-22 hours. 4)
(3) Effects of food
Meloxicam was administered to healthy volunteers at a dose of 10 mg
between meals (starving condition) or after meal, and the pharmacokinetic
parameters were compared. As the results, Cmax was higher in groups dosed
after meal and the AUCs were not differed between the groups. It was
concluded that food did not affect the absorption of meloxicam.
Table. Changes in the pharmacokinetic parameters after a single oral
dose of meloxicam (administered before and after meal) 5)
Pharmacokinetic
parameters
Cmax
(?g/mL)
Tmax (h)
T1/2 (h)
AUC 0-168
(?g
*h/mL)
Before meal
0.741±0.101
8.0±8.0
28.7±5.6
26.6±5.0
After meal
0.851±0.139
5.0±1.0
23.7±5.3
26.9±5.1
(Mean + S.D., n=12)
3) Distribution (a reference)
When 14C-meloxicam 1 mg/kg was orally administered, its levels were
high in blood, liver, kidney, lung, thymus, as well as in the intestines, but it was
almost not detected at any level in the brain (in rats 6)). It was excreted in milk
(in rats 7)).
4) Protein binding rate
(1) In vivo studies
When 14C-meloxicam 30 mg *Note) was orally administered in healthy
volunteer, its biding rate to the serum proteins was more than 99% 2).
(2) In vitro studies
The biding rate of meloxicam to the human serum proteins was more
than 99% 8), as the main binding protein was found to be the albumin 9).
5) Metabolism
When 14C-meloxicam 30 mg Note) was orally administered in healthy
volunteers, the major form in the plasma was the unchanged parent
compound (meloxicam), as metabolites were rarely detected 2). The unchanged
compound was not found in urine. The major metabolites were
5'-hydroxymethyl meloxicam, 5'-carboxy meloxicam and an oxamic acid
compound that resulted from the oxydative opening of the thiazine ring. The
metabolism of meloxicam suggested that CYP2C9 of the liver cytochrome
P-450 was mostly involved, and partially the CYP3A 10).
6) Excretion
When 14C-meloxicam 30 mg Note) was orally administered in healthy
volunteers, the summarily level of the unchanged parent compound and its
metabolites was approximately 43% in the urine at 168 hours after dosing, and
approximately 47% in faces at 180 hours after dosing 2).
【CLINICAL STUDIES】
1. Clinical Effects
Results of double-blind comparison studies in patients with chronic
joint rheumatism, osteoarthrosis, lumbago symptoms, scapulohumeral
periarthritis and cervicobrachial syndrome revealed the effectiveness of
Mobic.
Among the total 955 patients at 280 sites, including those in domestic
double-blind comparison studies, the trial results from 636 patients with the
approved indications and doses are shown below.
Table. Clinical effectiveness
Target indications
Number of
effective
cases/Number of
evaluated cases
Efficacy rate (more
than gradual
improvement)
Chronic joint rheumatism
102/306
33.3 %
Deformations of the joints
(osteoarthrosis)
20/166
72.3 %
Lumbago symptoms
48/57
84.2 %
Periarticular inflammation
of the shoulder joint
(scapulohumeral
periarthritis)
37/55
67.3 %
Neck-shoulder-arm
syndrome (brachialgia,
cervicobrachial syndrom)
42/52
80.8 %
2. Safety (results of double-blind comparison study)
1. The results of double-blind comparison studies in patients
with chronic joint rheumatism comparing Mobic with piroxicam
capsules 20 mg (administered one per day) demonstrated
equivalency in the overall safety ratings between Meloxicam and
piroxicam 11).
2. The results of double-blind comparison studies in patents
with osteoarthrosis comparing Mobic with diclofenac tablets 25
mg (administered 3 times per day) proved the significant
superiority of meloxicam in overall safety ratings against
diclofenac tablets 12).
3. The double-blind comparison studies with indomethacin
capsules 25 mg (3 times dosing per day) in patients with lumbago
symptoms, scapulohumeral periarthritis, or cervicobrachial
syndrome showed equivalency in overall safety ratings between
the two medicines 13).
【PHARMACOLOGY】
1. Anti-inflammatory effects
Meloxicam showed almost equivalent to the indomethacin
anti-inflammatory effect in caoline-induced foot oedema (in rats). In adjuvant
arthritis (in rats 14, 15)), meloxicam in some cases exerted stronger effects
compared to indomethacin, piroxicam or diclofenac. Meloxicam demonstrated
anti-inflammatory effects in carrageenen-induced foot oedema model (in rats
16)), in cotton-ball-induced granulation model (in rats 14)) and in
carrageenen-induced pleurisy model (in rats 14, 17)).
2. Analgesia
Meloxicam demonstrated an effect equivalent to indomethacin or
piroxicam in foot oedema with inflammatory pain test (in rats 14)
Randall-Selitto method), in pain in adjuvant arthritis models (in rats 16)), and in
acetic acid writhing test (in mice 16)).
3. Effects on gastrointestinal tract
Meloxicam showed weaker effects than piroxicam or indomethacin in
gastric mucosa dysfunction effect (in rats 11, 17)), and in intestinal ulcer induced
effects (in rats 16)). Piroxicam caused significant enhancement of HCl-induced
gastric mucosa damage (in rats), while meloxicam did not produced any
enhancement 18).
4. Inhibition activity on Cyclooxygenase (COX)-1 and COX-2
Meloxicam has shown stronger inhibition activity for COX-2 than
COX-1 in enzyme assay 17) and cell assay 19).
Table. Inhibition ratio of COX-2 vs. COX-1 in in vitro assays 17, 19)
Enzyme assay 17)
Cell assay 19)
IC50（COX-2/COX-1）
0.0825
0.33
5. Mode of action
Based on the results, it is considered that meloxicam inhibits the
cyclooxygenase (COX) activity (in vitro 17, 19)), inhibits the local synthesis of
prostaglandin in focal inflammation (in rats, mice 20)), and shows
anti-inflammatory and analgesic effects.
【PHYSICOCHEMISTRY】
Nonproprietary name: Merokishikamu* (JAN)
Meloxicam (JAN)
Chemical name: 4-hydroxy -2-methyl -N -(5-methyl
-2-thiazolyl)-2 H -1,2- benzothiazine
-3-carboxamide 1,1-dioxide
Structural formula
Molecular formula: C14H13N3O4S2
Molecular weight: 351.41
Description: It is a pale yellow, odorless powder. It is
highly soluble in strong acids and bases,
slightly soluble in methanol or ethanol
(95%), and practically insoluble in water or
diethyl ether.
Melting point: 241 Co (resolution)
【PACKAGING】
Capsules 5 mg: 100 capsules (10 capsules x 10) PTP
700 capsules (14 capsules x 50) PTP
1000 capsules (10 capsules x 100) PTP
250 capsules in bottle
Capsules 10 mg: 100 capsules (10 capsules x 10) PTP
700 capsules (14 capsules x 50) PTP
1000 capsules (10 capsules x 100) PTP
250 capsules in bottle
【REFERENCES】
1) Busch U et al: Eur J Clin Pharmacol 48: 269, 1995
2) Schmid J et al: Drug Metab Dispos 23: 1206, 1995
3) Azuma J et al: Clinical Reports 30 (12): 3189, 1996
4) Azuma J et al: Clinical Reports 30 (12): 3211, 1996
5) Irie Sh et al: Clinical Reports 30 (12): 3249, 1996
6) Ooiwa Youko et al: Drug Metabolism 12 (2): 108, 1997
7) Busch U: Drug Metab Dispos 26 (6): 576, 1998
8) Busch U: Internal communication
9) Turck D et al: Arzneim-Forsch 47 (1): 253, 1997
10) Chesne C et al: Xenobiotica 28 (1): 1, 1998
11) Mizushima Y et al: Clinical Reports 31 (3): 1115, 1997
12) Aoki T et al : J. Clin Therapeutics & Medicine 13 (4): 973, 1997
13) Sakurai M et al: Clinical Reports 31 (3): 1201, 1997
14) Engelhardt G et al: Inflamm Res 44: 423, 1995
15) Engelhardt G et al: Inflamm Res 44: 548, 1995
16) Yoshida M et al: Adv Drug Reactions 53: 351, 1997
17) Ogino K et al: Pharmacology 55 (1): 44, 1997
18) Schierok H J: Internal communication
19) Engelhardt G et al: Biochem Pharmacol 51: 21, 1996
20) Engelhardt G et al: Biochem Pharmacol 51: 29, 1996
【REQUESTS FOR INFORMATION】
Nippon Boehringer Ingelheim Co., Ltd.
Scientific Information Department
3-10-1 Yato, Kawanishi-shi, Hyogo, Japan 666-0193
【INFORMATION ABOUT LONG TERM ADMINISTRATION】
This medicine (meloxicam) has been categorized as a "Drug with New
Active Ingredient" (Ministry of Health and Welfare Notification No. 73
(dated March 17, 2000) and it is not permitted to be prescribed to the patients
for a treatment period exceeding 30 days per prescription. This restriction
shall be effective for one year after the date of listing the product (for
reimbursement) in the National Health Insurance tariff list.
【NAME AND ADDRESS OF THE MANUFACTURER AND DISTRIBUTOR】
Manufacturer
Nippon Boehringer Ingelheim Co., Ltd.
3-10-1 Yato, Kawanishi-shi, Hyogo-ken, Japan 666-0193
Co-distributor (co-marketer)
Dai-Ichi Pharmaceutical Co., Ltd.
3-14-10 Nihonbashi, Chuo-ku, Tokyo
* Note 1 Incidence figures are taken from domestic clinical test results.
Note 2 The incidence marked as "unknown" is based on the voluntary
reports of PMS studies from overseas (those adverse drug effects
were not observed in domestic clinical studies).
Note 3 On the basis of foreign clinical test results (those adverse effects
that were not observed in domestic clinical trials).
* Note 1 Incidence figures are taken from domestic clinical test results.
Note 2 The incidence marked as "unknown" is based on the voluntary
reports of PMS studies from overseas (those adverse drug
effects were not observed in domestic clinical studies).
Note 3 On the basis of foreign clinical test results (those adverse effects
that were not observed in domestic clinical trials).
* Note 1 Incidence figures are taken from domestic clinical test results.
Note 2 The incidence marked as "unknown" is based on the voluntary
reports of PMS studies from overseas (those adverse drug effects
were not observed in domestic clinical studies).
Note 3 On the basis of foreign clinical test results (those adverse effects
that were not observed in domestic clinical trials).
* Note 1 Incidence figures are taken from domestic clinical test results.
Note 2 The incidence marked as "unknown" is based on the voluntary
reports of PMS studies from overseas (those adverse drug effects
were not observed in domestic clinical studies).
Note 3 On the basis of foreign clinical test results (those adverse effects
that were not observed in domestic clinical trials).
* Reference 2) - from foreign data
Note): Approved dose and dosages of this product is 10 mg as
meloxicam, taken orally once per day after meal.
* Note): Approved dose and dosages of this product is 10 mg as
meloxicam, taken orally once per day after meal.
* Note): Approved dose and dosages of this product is 10 mg as
meloxicam, taken orally once per day after meal.
* Japanese phonetic transcription
Mobic
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