Arthrotec®
Diclofenac Sodium--Misoprostol
Anti-inflammatory--Analgesic--Mucosal Protective
Agent
Pfizer
http://www.pfizer.com/pfizer/main.jsp
Arthrotec Monograph PDF download here.
CPS:PIS_m066800
Pharmacology
Arthrotec is a combination of a nonsteroidal
anti-inflammatory drug (NSAID) with analgesic properties and a mucosal
protective synthetic analog of prostaglandin E1.
Arthrotec has been
shown to be as effective as diclofenac in reducing the signs and symptoms of
rheumatoid arthritis and osteoarthritis. In addition, Arthrotec has been
associated with a lower incidence of gastroduodenal erosions and ulcers than
diclofenac.
Diclofenac inhibits
prostaglandin synthesis by interfering with the action of prostaglandin
synthetase. This inhibitory effect may partially explain its actions, both
therapeutic and adverse. From a clinical efficacy standpoint, diclofenac
(150 mg daily) is similar in activity to equivalent dosages of 3.6 to
4.8 g daily of ASA. Diclofenac is similar in activity to equivalent
dosages of indomethacin (75 to 150 mg daily). Although diclofenac does not
alter the course of the underlying disease, it has been found to relieve pain,
reduce fever, swelling and tenderness, and increase mobility in patients with
rheumatic disorders of the types listed under Indications.
Studies in healthy
subjects indicate that misoprostol enhances several of the factors implicated
in maintaining gastroduodenal mucosal integrity. Misoprostol has been shown to
inhibit both basal and stimulated gastric acid secretion. In addition,
increases in gastric mucosal blood flow, duodenal bicarbonate secretion and gastric
mucus secretion have all been observed following treatment with misoprostol.
The ability of misoprostol to protect the gastric and duodenal mucosa has been
confirmed in studies in both healthy subjects and patients with rheumatoid
arthritis or osteoarthritis. Endoscopic examination and measurement of fecal
blood loss have shown that coadministration of misoprostol prevents mucosal
injury induced by a variety of NSAIDs, including, ASA, ibuprofen, piroxicam,
naproxen, tolmetin and diclofenac.
Pharmacokinetics
Following administration of a single dose of
Arthrotec 50 to 36 healthy male subjects, the mean Cmax,
AUC (0 to 24) and Tmax for diclofenac were 1.13 µg/mL,
1.63 µg·h/mL and 3.9 h, respectively, while the mean Cmax,
AUC (0 to 24) and Tmax for the principal active metabolite of
misoprostol (misoprostol acid) were 136 pg/mL, 238 pg·h/mL and
0.87 h, respectively.
Following a single dose
of Arthrotec 75 to 35 healthy male and female subjects, the mean Cmax,
AUC (0 to 12) and Tmax for diclofenac were
2.03 µg/mL, 2.77 µg·h/mL and 1.96 h, respectively. The mean Cmax,
AUC (0 to 24) and Tmax for the principal metabolite of
misoprostol (misoprostol acid) were 304 pg/mL, 177 pg·h/mL and
0.26 h, respectively.
Orally administered
diclofenac is rapidly and almost completely absorbed. Forty to 60% of the drug
and its metabolites are eliminated in the urine and the balance in the bile.
Orally administered
misoprostol is also rapidly and extensively absorbed, and undergoes rapid
metabolism to misoprostol acid, which is thereafter quickly eliminated
(elimination half-life of approximately 30 minutes). Approximately 70% of
the dose is excreted in the urine, mainly as biologically inactive metabolites.
Influence of Food: With Arthrotec the effect of
food on the bioavailability of the diclofenac and misoprostol components is
similar to that reported for the individual drugs. The times of peak
concentration (Tmax) for diclofenac and misoprostol are prolonged by
approximately 50 and 100% respectively, while the peak concentrations (Cmax)
are decreased by about 25% for diclofenac and 50% for misoprostol: the AUC for
diclofenac is decreased by approximately 60%, while that of misoprostol is
increased by about 25%.
Clinical Use
In 2 multicentre, double-blind, controlled
clinical trials of 12 weeks duration involving a total of 346 and 339
patients respectively, patient global assessments of the arthritic condition
revealed no statistically significant differences between Arthrotec 50 and
a fixed-combination of diclofenac/placebo.
In 2 multicentre,
double-blind, controlled trials of 4 weeks duration in 455 and 361
patients with osteoarthritis, patient global assessments of the arthritic
condition revealed no overall differences between Arthrotec 50 and
diclofenac/placebo.
A multicentre,
double-blind, controlled trial of 6 weeks duration involving a total of
572 patients (154 in the diclofenac group, 152 in the Arthrotec 50
group, 175 in the Arthrotec 75 group and 91 in the placebo group) showed
that Arthrotec 50 three times daily and Arthrotec 75 twice daily were
equivalent to diclofenac/placebo in relieving the signs and symptoms of
osteoarthritis.
A multicentre,
double-blind, controlled trial of 12 weeks duration involving a total of
380 patients (107 in the diclofenac group, 107 in the Arthrotec 50 group,
111 in the Arthrotec 75 group and 55 in the placebo group) showed that
Arthrotec 50 three times daily and Arthrotec 75 twice daily were
equivalent to diclofenac/placebo in relieving the signs and symptoms of
rheumatoid arthritis.
Misoprostol has been
compared to placebo in the prevention of clinically significant and serious
gastrointestinal events associated with NSAID use. In a 6-month, double-blind
study of 8843 patients (4404 in the misoprostol group, 4439 in the placebo
group, mean age 68 years) with rheumatoid arthritis, misoprostol
significantly reduced the incidence of serious complications, such as
gastrointestinal bleeding and ulcer perforation, by 40 to 50%.
Arthrotec is associated
with a low incidence of gastroduodenal lesions relative to diclofenac/placebo.
Indications
For acute and chronic use in the relief of the
signs and symptoms of rheumatoid arthritis and osteoarthritis.
Contraindications
The contraindications of Arthrotec are those of
the components of the product. Arthrotec is contraindicated in patients with
active gastrointestinal bleeding.
Pregnancy
Arthrotec is contraindicated in pregnancy.
Arthrotec should not be used in pregnant women because it induces uterine contractions
and therefore has abortifacient potential. Anecdotal reports, primarily from Brazil, of congenital
anomalies and reports of fetal death subsequent to misuse of misoprostol as an
abortifacient have been received. Arthrotec may cause premature closure of the
ductus arteriosis. If pregnancy is suspected, use of the product should be
discontinued, and the pregnancy followed closely. Uterine perforation has been
reported with misuse of misoprostol for cervical ripening or labor induction.
Active peptic ulcer, a
history of recurrent ulceration or active inflammatory disease of the
gastrointestinal system.
Known or suspected
hypersensitivity to misoprostol or other prostaglandins, diclofenac or other
NSAIDs. The potential for cross-reactivity between different NSAIDs must be
kept in mind.
Diclofenac should not
be used in patients with the complete or partial syndrome of nasal polyps, or
in whom asthma, anaphylaxis, urticaria, rhinitis or other allergic
manifestations are precipitated by ASA or other NSAIDs. Fatal anaphylactoid
reactions have occurred in such individuals. As well, individuals with the
above medical problems are at risk of a severe reaction even if they have taken
NSAIDs in the past without any adverse effects.
Significant hepatic
impairment or active liver disease.
Severely impaired or
deteriorating renal function (creatinine clearance <30 mL/min).
Individuals with lesser degrees of renal impairment are at risk of
deterioration of their renal function when prescribed NSAIDs and must be
monitored.
Diclofenac is not
recommended for use with other NSAIDs because of the absence of any evidence
demonstrating synergistic benefits and the potential for additive side effects.
Warnings
Gastrointestinal: The presence of misoprostol in
the product may protect against the mucosal damaging effects of the other
component, diclofenac.
However, serious
gastrointestinal toxicity, such as peptic ulceration, perforation and
gastrointestinal bleeding, sometimes severe and occasionally fatal can
occur at any time, with or without symptoms in patients treated with NSAIDs
including Arthrotec.
Minor upper
gastrointestinal problems, such as dyspepsia, are common, usually developing
early in therapy. Physicians should remain alert for ulceration and bleeding in
patients treated with NSAIDs, even in the absence of previous gastrointestinal
tract symptoms.
In clinical trials,
3549 arthritic patients have been treated with Arthrotec, 506 of whom received
Arthrotec for more than 1 year. A total of 285 patients have been
treated with Arthrotec 75 in clinical trials for a duration of up to
12 weeks.
In patients observed in
clinical trials with Arthrotec, upper gastrointestinal ulcers occurred as
follows: See Table 1.
CPS:Arthrotec_t1Click here for Table 1
Table 1: Arthrotec
Occurrence of Gastrointestinal Ulcers
|
|
A50
b.i.d.
N=391
|
A50
t.i.d.
N=692
|
A50
b.i.d./t.i.d.
N=750
|
D50
b.i.d./t.i.d.
N=754
|
A75
b.i.d.
N=285
|
D75
b.i.d.
N=260
|
|
Upper Gastrointestinal Ulcers
|
0.8
|
1.8
|
0.8
|
2.1
|
3.9
|
9.6
|
Legend:
A50=Arthrotec 50.
D50=Diclofenac 50 mg.
A75=Arthrotec 75.
D75=Diclofenac 75 mg.
Diclofenac should be
given under close medical supervision to patients prone to gastrointestinal
tract irritation, particularly those with a history of peptic ulcer;
diverticulosis or other inflammatory disease of the gastrointestinal tract such
as ulcerative colitis and Crohn's disease. In these cases the physician must
weigh the benefits of treatment against the possible hazards.
Physicians should
inform patients about the signs and/or symptoms of serious gastrointestinal
toxicity and instruct them to contact a physician immediately if they
experience persistent dyspepsia or other symptoms or signs suggestive of
gastrointestinal ulceration or bleeding.
Because serious
gastrointestinal tract ulceration and bleeding can occur without warning
symptoms, physicians should follow chronically treated patients by checking
their hemoglobin periodically and by being vigilant for the signs and symptoms
of ulceration and bleeding and should inform the patients of the importance of
this followup.
If ulceration is
suspected or confirmed, or if gastrointestinal bleeding occurs, Arthrotec
should be discontinued immediately, appropriate treatment instituted and the
patient monitored closely.
No studies, to date,
have identified any group of patients not at risk of developing ulceration and
bleeding. A prior history of serious gastrointestinal events and other factors
such as excess alcohol intake, smoking, age, female gender and concomitant oral
steroid and anticoagulant use have been associated with increased risk.
Studies to date show
that all NSAIDs can cause gastrointestinal tract adverse events. Although
existing data does not clearly identify differences in risk between various
NSAIDs, this may be shown in the future.
Geriatrics
Patients older than 65 years and frail or
debilitated patients are most susceptible to a variety of adverse reactions
from NSAIDs: the incidence of these adverse reactions increases with dose and
duration of treatment. In addition, these patients are less tolerant to
ulceration and bleeding. Most reports of fatal gastrointestinal events are in
this population. Older patients are also at risk of lower esophageal ulceration
and bleeding.
For such patients,
consideration should be given to a starting dose lower than the one usually
recommended, with individual adjustment when necessary and under close
supervision. See Precautions for further advice.
Cross-sensitivity: Patients sensitive to one of
the NSAIDs may be sensitive to any of the other NSAIDs also.
Aseptic Meningitis: In occasional cases, with
some NSAIDs, the symptoms of aseptic meningitis (stiff neck, severe headaches,
nausea and vomiting, fever or clouding of consciousness) have been observed.
Patients with autoimmune disorders (systemic lupus erythematosus, mixed
connective tissues diseases, etc.) seem to be predisposed. Therefore, in such
patients, the physician must be vigilant to the development of this
complication.
Lactation
It is not recommended that Arthrotec be
administered to nursing mothers. Diclofenac has been found in human milk. It is
unlikely that misoprostol is secreted in human milk since it is rapidly
metabolized throughout the body. It is not known if the active metabolite of
misoprostol (misoprostol acid) is secreted in human milk. However, the
potential presence of misoprostol acid in human milk could cause diarrhea in
nursing infants.
Women of Childbearing Potential
Arthrotec should not be used in women of
childbearing potential unless they use effective contraception (i.e., oral
contraceptives or intrauterine devices) and have been advised of the risks of
taking Arthrotec if pregnant. If pregnancy is suspected, use of Arthrotec should
be discontinued.
Children
The safety and effectiveness of Arthrotec in
children below the age of 18 years have not been established.
Precautions
Renal Function: Long-term administration of
NSAIDs to animals has resulted in renal papillary necrosis and other abnormal
renal pathology. In humans, there have been reports of acute interstitial
nephritis with hematuria, proteinuria, and occasionally nephrotic syndrome.
A second form of renal
toxicity has been seen in patients with prerenal conditions leading to the
reduction in renal blood flow or blood volume, where the renal prostaglandins
have a supportive role in the maintenance of renal perfusion. In these
patients, administration of a NSAID may cause a dose dependent reduction in
prostaglandin formation and may precipitate overt renal decompensation.
Patients at greatest risk of this reaction are those with impaired renal
function, heart failure, liver dysfunction, those taking diuretics, and the
elderly. Discontinuation of nonsteroidal anti-inflammatory therapy is usually
followed by recovery to the pretreatment state.
Diclofenac and its
metabolites are eliminated primarily by the kidneys, therefore the drug should
be used with great caution in patients with impaired renal function. In these
cases, utilization of lower doses of diclofenac should be considered and
patients carefully monitored.
During long-term
therapy kidney function should be monitored periodically.
Genitourinary Tract: Some NSAIDs are known to
cause persistent urinary symptoms (bladder pain, dysuria, urinary frequency),
hematuria or cystitis. The onset of these symptoms may occur at any time after
the initiation of therapy with an NSAID. Some cases have become severe on
continued treatment. Should urinary symptoms occur, treatment with Arthrotec must
be stopped immediately to obtain recovery. This should be done before any
urological investigations or treatments are carried out.
Hepatic Function: As with other NSAIDs,
borderline elevations of one or more liver function tests may occur in up to
15% of patients. These abnormalities may progress, may remain essentially
unchanged, or may be transient with continued therapy. In clinical trials of 4
to 12 weeks duration, clinically significant (≥ 3 times the upper limit
of normal) elevations of ALT and/or AST, were observed in 1.6% or less of
patients who received diclofenac/misoprostol or diclofenac/placebo.
A patient with symptoms
and/or signs suggesting liver dysfunction, or in whom an abnormal liver test
has occurred, should be evaluated for evidence of the development of more
severe hepatic reaction while on therapy with this drug. Severe hepatic
reactions including jaundice and cases of fatal hepatitis have been reported
with NSAIDs.
Although such reactions
are rare, if abnormal liver tests persist or worsen, if clinical signs and
symptoms consistent with liver disease develop, or if systemic manifestations
occur (e.g., eosinophilia, rash, etc.), this drug should be discontinued.
During long-term
therapy, liver function tests should be monitored periodically. If there is a
need to prescribe this drug in the presence of impaired liver function, it must
be done under strict observation.
Fluid and Electrolyte Balance: Fluid retention
and edema have been observed in patients treated with Arthrotec. Therefore, as
with many other NSAIDs, the possibility of precipitating congestive heart
failure in elderly patients or those with compromised cardiac function should
be borne in mind. Arthrotec should be used with caution in patients with heart
failure, hypertension or other conditions predisposing to fluid retention.
With NSAID treatment,
there is a potential risk of hyperkalemia particularly in patients with
conditions such as diabetes mellitus or renal failure; elderly patients; or in
patients receiving concomitant therapy with beta-adrenergic blockers,
angiotensin converting enzyme inhibitors or some diuretics. Serum electrolytes
should be monitored periodically during long-term therapy, especially in those
patients who are at risk.
Hematology: Drugs inhibiting prostaglandin
biosynthesis do interfere with platelet function to varying degrees; therefore,
patients who may be adversely affected by such an action should be carefully
observed when Arthrotec is administered.
The addition of
misoprostol does not exacerbate the effect of diclofenac on platelet function.
In clinical trials, there has been no evidence that Arthrotec affects
hemostasis.
Blood dyscrasias (such
as neutropenia, leukopenia, thrombocytopenia, aplastic anemia and
agranulocytosis) associated with the use of NSAIDs are rare, but could occur
with severe consequences.
Infection: In common with other
anti-inflammatory drugs, Arthrotec may mask the usual signs of infection.
Ophthalmology: Blurred and/or diminished vision
has been reported with the use of Arthrotec and other NSAIDs. If such symptoms
develop, this drug should be discontinued and an ophthalmologic examination
performed; ophthalmic examination should be carried out at periodic intervals
in any patient receiving this drug for an extended period of time.
Central Nervous System: Some patients may
experience drowsiness, dizziness, vertigo, insomnia or depression with the use
of diclofenac. If patients experience these side effects, they should exercise
caution in carrying out activities that require alertness.
Allergies: Allergic reactions, including
anaphylaxis, have been reported in individuals without prior exposure to
diclofenac.
Drug Interactions
No drug-drug interactions for Arthrotec have been
observed. However, the following information is known for the components.
Misoprostol has been
used concomitantly with at least 44 different classes of drugs, including
more than 150 drugs. There were no reports of any clinically significant
drug interactions.
In laboratory studies,
misoprostol has shown no significant effect on the cytochrome P450-linked
hepatic mixed function oxidase system, and therefore should not affect the
metabolism of theophylline, warfarin, benzodiazepines or other drugs normally
metabolized by this system.
ASA or Other NSAIDs: When diclofenac and ASA are
taken simultaneously, the bioavailability of each is reduced. Concomitant
administration of Arthrotec and ASA is not recommended because diclofenac
is displaced from its binding sites by ASA, resulting in lower plasma
concentrations, peak plasma levels and AUC values. Misoprostol does not affect
the kinetics of other NSAIDs (e.g., ibuprofen, indomethacin and piroxicam). The
use of Arthrotec in addition to any other NSAIDs, including those
over-the-counter ones (such as ASA and ibuprofen) is not recommended due to the
possibility of additive side effects.
Antacids: The concomitant administration of
aluminum hydroxide or magnesium hydroxide antacids may delay the absorption of
diclofenac but does not affect the total amount of the drug absorbed. The total
availability of misoprostol acid is reduced by antacids in large doses. Only
aluminum-based antacids should be used with Arthrotec as magnesium-based
antacids may increase the potential for diarrhea (see Adverse Effects).
Digoxin: Diclofenac may increase the plasma
concentration of digoxin. Dosage adjustment of the digoxin may be required with
Arthrotec. Serum digoxin levels should be monitored.
Diuretics/Antihypertensives: NSAIDs have been
reported to inhibit the activity of diuretics. Concomitant treatment of
Arthrotec with potassium-sparing diuretics may be associated with increased
serum potassium levels, thus making it necessary to monitor the latter. The
antihypertensive effect of hydrochlorothiazide and other agents may be
decreased by diclofenac in patients with essential hypertension.
Anticoagulants: Numerous studies have shown that
concomitant use of NSAIDs and anticoagulants increases the risk of
gastrointestinal adverse events such as ulceration and bleeding.
Pharmacodynamic studies have shown no potentiation of anticoagulant drugs due
to concurrent administration with diclofenac. However, other NSAIDs have been
shown to interact with anticoagulant agents. Although clinical investigations
would appear to indicate that diclofenac has no influence on the effect of
anticoagulants, there are isolated reports of an increased risk of hemorrhage
with the combined use of diclofenac and nicoumalone anticoagulant therapy. Special
caution is therefore recommended and frequent laboratory tests should be
performed to check that the desired response to the anticoagulant is being
maintained. Because prostaglandins play an important role in hemostasis and
NSAIDs affect platelet function as well, concurrent therapy of Arthrotec with
warfarin requires close monitoring to be certain no change in anticoagulant
dosage is necessary.
Oral Hypoglycemic Agents: Diclofenac does not
alter glucose metabolism in normal subjects, and pharmacodynamic studies have
shown no potentiation of oral hypoglycemic drugs due to concurrent
administration with diclofenac. However, other NSAIDs have been shown to
interact with oral hypoglycemic agents. Therefore, Arthrotec should be
administered with caution in patients receiving insulin or oral hypoglycemic
agents.
Methotrexate: Concurrent administration of
methotrexate and diclofenac may result in increased plasma levels of
methotrexate and rare cases of fatal renal toxicity have been reported. Thus,
caution should be taken when administering Arthrotec and methotrexate.
Lithium: Diclofenac, when administered
concomitantly with lithium, increases the lithium plasma concentration through
an effect on lithium renal clearance. Lithium toxicity may develop in these patients.
Dosage adjustment of lithium may be required with Arthrotec.
Glucocorticoids: Numerous studies have shown
that the concomitant use of NSAIDs and oral glucocorticoids increases the risk
of gastrointestinal side effects such as ulceration and bleeding. This is
especially the case in older (>65 years old) individuals.
Clinical Laboratory Tests: Diclofenac increases
platelet aggregation time but does not affect bleeding time, plasma prothrombin
clotting time, plasma fibrinogens, or factors V and VII to XII. Statistically
significant changes in prothrombin and partial thromboplastin times have been
reported in normal volunteers. The mean changes were observed to be less than 1
second in both instances, and are unlikely to be clinically important.
Laboratory
abnormalities included increased alkaline phosphatase, decreased hematocrit and
elevated ALT.
Persistently abnormal
or worsening renal, hepatic or hematological test values should be followed up
carefully since they may be related to therapy.
Adverse Effects
The most common adverse reactions encountered
with NSAIDs are gastrointestinal, of which peptic ulcer, with or without
bleeding, is the most severe. Fatalities have occurred, particularly in the
elderly.
In clinical trials,
3549 arthritic patients have been treated with Arthrotec, 506 of whom received
Arthrotec for more than 1 year. A total of 285 patients have been
treated with Arthrotec 75 in clinical trials for a duration of up to
12 weeks.
The following adverse
reactions occurred with an incidence of 1% or greater with at least one of the
Arthrotec dosing regimens presented in Table 2.
CPS:Arthrotec_t2Click here for Table 2
Table 2: Arthrotec
Adverse Reactions Reported in ≥ 1% of
Patients
|
|
A50
b.i.d.
N=391
|
A50
t.i.d.
N=692
|
A50
b.i.d./t.i.d.
N=750
|
D50
b.i.d./t.i.d.
N=754
|
A75
b.i.d.a
N=285
|
D75
b.i.d.a
N=260
|
|
|
Gastrointestinal
|
|
Abdominal Pain
|
19.4
|
19.4
|
23.2
|
19.5
|
24.6
|
24.2
|
|
|
Diarrhea
|
15.9
|
17.8
|
19.9
|
11.3
|
20.4
|
16.2
|
|
|
Dyspepsia
|
7.2
|
14.5
|
11.3
|
7.8
|
33.3
|
34.6
|
|
|
Nausea
|
10.2
|
10.0
|
11.7
|
6.5
|
14.0
|
9.2
|
|
|
Flatulence
|
6.1
|
8.7
|
8.0
|
3.1
|
18.2
|
9.2
|
|
|
Gastritis
|
2.8
|
2.3
|
3.6
|
6.8
|
7.4
|
13.1
|
|
|
Vomiting
|
2.6
|
3.3
|
3.1
|
1.3
|
3.9
|
5.4
|
|
|
Constipation
|
1.8
|
2.6
|
2.1
|
2.9
|
4.9
|
6.9
|
|
|
Eructation
|
2.6
|
0.3
|
2.0
|
0.8
|
2.1
|
0.4
|
|
|
Esophagitis
|
0.8
|
1.7
|
1.1
|
0.8
|
3.9
|
1.9
|
|
|
Duodenitis
|
2.3
|
0.9
|
0.9
|
2.3
|
3.5
|
5.0
|
|
|
Gastroesophageal Reflux
|
0.0
|
1.0
|
0.4
|
1.7
|
1.1
|
1.2
|
|
|
Duodenal Ulcer
|
0.0
|
1.2
|
0.1
|
0.4
|
0.7
|
2.7
|
|
|
Gastric Ulcer
|
0.8
|
0.6
|
0.7
|
1.7
|
3.2
|
6.9
|
|
|
Tooth Disorder
|
0.3
|
0.6
|
0.0
|
0.0
|
1.1
|
0.8
|
|
|
CNS
|
|
Headache
|
9.2
|
6.4
|
7.3
|
9.2
|
12.3
|
15.8
|
|
|
Dizziness
|
2.6
|
2.0
|
3.5
|
5.3
|
3.9
|
4.2
|
|
|
Migraine
|
1.3
|
0.6
|
0.4
|
0.9
|
1.4
|
0.8
|
|
|
Paresthesia
|
0.3
|
0.3
|
0.7
|
0.7
|
1.1
|
0.4
|
|
|
|
