Included as part of the PRECAUTIONS section.
Cardiovascular Thrombotic Events
Clinical trials of several COX-2 selective and
nonselective NSAIDs of up to three years duration have shown an increased risk
of serious cardiovascular (CV) thrombotic events, including myocardial
infarction(MI) and stroke, which can be fatal. Based on available data, it is
unclear that the risk for CV thrombotic events is similar for all NSAIDs. The
relative increase in serious CV thrombotic events over baseline conferred by
NSAID use appears to be similar in those with and without known CV disease or
risk factors for CV disease. However, patients with known CV disease or risk factors
had a higher absolute incidence of excess serious CV thrombotic events, due to
their increased baseline rate. Some observational studies found that this
increased risk of serious CV thrombotic events began as early as the first
weeks of treatment. The increase in CV thrombotic risk has been observed most
consistently at higher doses.
To minimize the potential risk for an adverse CV event in
NSAID-treated patients, use the lowest effective dose for the shortest duration
possible. Physicians and patients should remain alert for the development of
such events, throughout the entire treatment course, even in the absence of
previous CV symptoms. Patients should be informed about the symptoms of serious
CV events and the steps to take if they occur.
There is no consistent evidence that concurrent use of
aspirin mitigates the increased risk of serious CV thrombotic events associated
with NSAID use. The concurrent use of aspirin and an NSAID, such as diclofenac,
increases the risk of serious gastrointestinal (GI) events [see Gastrointestinal Bleeding, Ulceration, and Perforation].
Status Post Coronary Artery Bypass Graft (CABG) Surgery
Two large, controlled clinical trials of a COX-2
selective NSAID for the treatment of pain in the first 10-14 days following
CABG surgery found an increased incidence of myocardial infarction and stroke.
NSAIDs are contraindicated in the setting of CABG [see CONTRAINDICATIONS].
Observational studies conducted in the Danish National
Registry have demonstrated that patients treated with NSAIDs in the post-MI
period were at increased risk of reinfarction, CV-related death, and all-cause
mortality beginning in the first week of treatment. In this same cohort, the
incidence of death in the first year post-MI was 20 per 100 person years in
NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed
patients. Although the absolute rate of death declined somewhat after the first
year post-MI, the increased relative risk of death in NSAID users persisted
over at least the next four years of follow-up.
Avoid the use of CAMBIA in patients with a recent MI
unless the benefits are expected to outweigh the risk of recurrent CV
thrombotic events. If CAMBIA is used in patients with a recent MI, monitor
patients for signs of cardiac ischemia.
Gastrointestinal Bleeding, Ulceration, And Perforation
NSAIDs, including diclofenac, cause serious
gastrointestinal (GI) adverse events including inflammation, bleeding,
ulceration, and perforation of the esophagus, stomach, small intestine, or
large intestine, which can be fatal. These serious adverse events can occur at
any time, with or without warning symptoms, in patients treated with NSAIDs.
Only one in five patients who develop a serious upper GI adverse event on NSAID
therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused
by NSAIDs occurred in approximately 1% of patients treated for 3-6 months, and
in about 2%-4% of patients treated for one year. However, even short-term NSAID
therapy is not without risk.
Risk Factors For GI Bleeding, Ulceration, And Perforation
Patients with a prior history of peptic ulcer disease
and/or GI bleeding who used NSAIDs had a greater than 10fold increased risk for
developing a GI bleed compared to patients without these risk factors. Other
factors that increase the risk for GI bleeding in patients treated with NSAIDs
include longer duration of NSAID therapy; concomitant use of oral
corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake
inhibitors (SSRI); smoking; use of alcohol; older age; and poor general health
status. Most postmarketing reports of fatal GI events occurred in elderly or
debilitated patients. Additionally, patients with advanced liver disease and/or
coagulopathy are at increased risk for GI bleeding.
Strategies to Minimize the GI Risk in NSAID-treated
- Use the lowest effective dosage for the shortest possible
- Avoid administration of more than one NSAID at a time.
- Avoid use in patients at higher risk unless benefits are
expected to outweigh the increased risk of bleeding. For high risk patients, as
well as those with active GI bleeding, consider alternate therapies other than
- Remain alert for signs and symptoms of GI ulceration and
bleeding during NSAID therapy.
- If a serious GI adverse event is suspected, promptly
initiate evaluation and treatment, and discontinue CAMBIA until a serious GI
adverse event is ruled out.
- In the setting of concomitant use of low-dose aspirin for
cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding
[see DRUG INTERACTIONS].
Elevations of one or more liver tests may occur during
therapy with CAMBIA. These laboratory abnormalities may progress, may persist,
or may only be transient with continued therapy. Borderline elevations (less
than 3 times the upper limit of the normal [ULN] range) or greater elevations of
transaminases occurred in about 15% of diclofenac-treated patients. Of the
markers of hepatic function, ALT (SGPT) is recommended for the monitoring of
In clinical trials, meaningful elevations (i.e., more
than 3 times the ULN) of AST (SGOT) occurred in about 2% of approximately 5,700
patients at some time during treatment (ALT was not measured in all studies). In
an open-label, controlled trial of 3,700 patients treated for 2-6 months,
patients were monitored at 8 weeks and 1,200 patients were monitored again at
24 weeks. Meaningful elevations of ALT and/or AST occurred in about 4% of the
3,700 patients and included marked elevations ( > 8 times the ULN) in about 1%
of the 3,700 patients. In this open-label study, a higher incidence of borderline
(less than 3 times the ULN), moderate (3-8 times the ULN), and marked ( > 8
times the ULN) elevations of ALT or AST was observed in patients receiving diclofenac
when compared to other NSAIDs. Almost all meaningful elevations in
transaminases were detected before patients became symptomatic [see Laboratory Monitoring].
Abnormal tests occurred during the first 2 months of
therapy with diclofenac in 42 of the 51 patients in all trials who developed
marked transaminase elevations. In postmarketing reports, cases of drug-induced
hepatotoxicity have been reported in the first month, and in some cases, the
first 2 months of NSAID therapy, but can occur at any time during treatment
Postmarketing surveillance has reported cases of severe
hepatic reactions, including liver necrosis, jaundice, fulminant hepatitis with
and without jaundice, and liver failure. Some of these reported cases resulted
in fatalities or liver transplantation.
Inform patients of the warning signs and symptoms of
hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice,
right upper quadrant tenderness, and “flu-like” symptoms). If
clinical signs and symptoms consistent with liver disease develop, or if
systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue
CAMBIA immediately, and perform a clinical evaluation of the patient.
To minimize the potential risk for an adverse
liver-related event in patients treated with CAMBIA, use the lowest effective
dose for the shortest duration possible. Exercise caution when prescribing
CAMBIA with concomitant drugs that are known to be potentially hepatotoxic
(e.g., acetaminophen, certain antibiotics, antiepileptics). Caution patients to
avoid taking nonprescription acetaminophen-containing products while using
NSAIDs, including CAMBIA, can lead to new onset of
hypertension or worsening of pre-existing hypertension, either of which may
contribute to the increased incidence of CV events. Use NSAIDs, including
CAMBIA, with caution in patients with hypertension. Monitor blood pressure
closely during the initiation of NSAID treatment and throughout the course of
Patients taking angiotensin converting enzyme (ACE)
inhibitors, thiazides, or loop diuretics may have impaired response to these
therapies when taking NSAIDs [see DRUG INTERACTIONS].
Heart Failure And Edema
The Coxib and traditional NSAID Trialists' Collaboration
meta-analysis of randomized controlled trials demonstrated an approximately
two-fold increase in hospitalizations for heart failure in COX-2
selective-treated patients and nonselective NSAID-treated patients compared to
placebo-treated patients. In a Danish National Registry study of patients with
heart failure, NSAID use increased the risk of MI, hospitalization for heart
failure, and death.
Additionally, fluid retention and edema have been
observed in some patients treated with NSAIDs. Use of diclofenac may blunt the
CV effects of several therapeutic agents used to treat these medical conditions
(e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see
Avoid the use of CAMBIA in patients with severe heart
failure unless the benefits are expected to outweigh the risk of worsening
heart failure. If CAMBIA is used in patients with severe heart failure, monitor
patients for signs of worsening heart failure.
Renal Toxicity And Hyperkalemia
Long-term administration of NSAIDs has resulted in renal
papillary necrosis and other renal injury. Renal toxicity has also been seen in
patients in whom renal prostaglandins have a compensatory role in the
maintenance of renal perfusion. In these patients, administration of an NSAID
may cause a dose-dependent reduction in prostaglandin formation and,
secondarily, in renal blood flow, which may precipitate overt renal decompensation.
Patients at greatest risk of this reaction are those with impaired renal
function, dehydration, hypovolemia, heart failure, liver dysfunction, those
taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation
of NSAID therapy is usually followed by recovery to the pretreatment state.
No information is available from controlled clinical
studies regarding the use of CAMBIA in patients with advanced renal disease.
The renal effects of CAMBIA may hasten the progression of renal dysfunction in
patients with pre-existing renal disease.
Correct volume status in dehydrated or hypovolemic
patients prior to initiating CAMBIA. Monitor renal function in patients with
renal or hepatic impairment, heart failure, dehydration, or hypovolemia during
use of CAMBIA [see DRUG INTERACTIONS]. Avoid the use of CAMBIA in
patients with advanced renal disease unless the benefits are expected to
outweigh the risk of worsening renal function. If CAMBIA is used in patients
with advanced renal disease, monitor patients for signs of worsening renal
Increases in serum potassium concentration, including
hyperkalemia, have been reported with use of NSAIDs, even in some patients
without renal impairment. In patients with normal renal function, these effects
have been attributed to a hyporeninemic-hypoaldosteronism state.
Diclofenac has been associated with anaphylactic
reactions in patients with and without known hypersensitivity to diclofenac and
in patients with aspirin-sensitive asthma [see CONTRAINDICATIONS and Exacerbation Of Asthma Related To Aspirin Sensitivity].
Seek emergency help if an anaphylactic reaction occurs.
Exacerbation Of Asthma Related To Aspirin Sensitivity
A subpopulation of patients with asthma may have
aspirin-sensitive asthma which may include chronic rhinosinusitis complicated
by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to
aspirin and other NSAIDs. Because cross-reactivity between aspirin and other
NSAIDs has been reported in such aspirin-sensitive patients, CAMBIA is contraindicated
in patients with this form of aspirin sensitivity [see CONTRAINDICATIONS].
When CAMBIA is used in patients with preexisting asthma (without known aspirin
sensitivity), monitor patients for changes in the signs and symptoms of asthma.
Serious Skin Reactions
NSAIDs, including diclofenac, can cause serious skin
adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome
(SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious
events may occur without warning. Inform patients about the signs and symptoms
of serious skin reactions, and to discontinue the use of CAMBIA at the first
appearance of skin rash or any other sign of hypersensitivity. CAMBIA is
contraindicated in patients with previous serious skin reactions to NSAIDs [see
Medication Overuse Headache
Overuse of acute migraine drugs (e.g., ergotamine,
triptans, opioids, nonsteroidal anti-inflammatory drugs or combination of these
drugs for 10 or more days per month) may lead to exacerbation of headache
(medication overuse headache). Medication overuse headache may present as
migraine-like daily headaches or as a marked increase in frequency of migraine
attacks. Detoxification of patients, including withdrawal of the overused drugs
and treatment of withdrawal symptoms (which often includes a transient
worsening of headache) may be necessary.
Premature Closure Of Fetal Ductus Arteriosus
CAMBIA can cause fetal harm when administered to a pregnant
woman. Starting at 30 weeks gestation, CAMBIA and other NSAIDs should be
avoided by pregnant women as premature closure of the ductus arteriosus in the
fetus may occur. If this drug is used during this time period in pregnancy, the
patient should be apprised of the potential hazard to a fetus [see Use in
Anemia has occurred in NSAID-treated patients. This may
be due to occult or gross blood loss, fluid retention, or an incompletely
described effect upon erythropoiesis. If a patient treated with CAMBIA has any
signs or symptoms of anemia, monitor hemoglobin or hematocrit.
NSAIDs, including CAMBIA, may increase the risk of
bleeding events. Concomitant use of warfarin and other anticoagulants,
antiplatelet agents (e.g., aspirin), and serotonin reuptake inhibitors (SSRIs)
and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this
risk. Monitor these patients and any patient who may be adversely affected by
alterations in platelet function for signs of bleeding [see DRUG
Masking Of Inflammation And Fever
The pharmacological activity of CAMBIA in reducing
inflammation, and possibly fever, may diminish the utility of diagnostic signs
in detecting infections.
Because serious GI bleeding, hepatotoxicity, and renal
injury can occur without warning symptoms or signs, consider monitoring
patients on long-term NSAID treatment with a CBC and a chemistry profile
periodically [see sections above].
Discontinue CAMBIA if abnormal liver tests or renal tests
persist or worsen.
Patient Counseling Information
Advise the patient to read the
FDA-approved patient labeling (Medication Guide) that accompanies each
prescription dispensed. Inform patients, families, or their caregivers of the
following information before initiating therapy with CAMBIA and periodically
during the course of ongoing therapy.
Advise patients to be alert for
the symptoms of cardiovascular thrombotic events, including chest pain,
shortness of breath, weakness, or slurring of speech, and to report any of
these symptoms to their health care provider immediately [see WARNINGS
Ulceration, And Perforation
ICAMBIA, like other NSAIDS, can
cause GI discomfort and more serious GI adverse events such as ulcers and
bleeding, which may result in hospitalization and even death. Inform patients
of the increased risk, and advise patients to report symptoms of ulcerations
and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to
their health care provider. Inform patients of the importance of follow-up in
the setting of concomitant use of low-dose aspirin for cardiac prophylaxis [see
WARNINGS AND PRECAUTIONS].
Medication Overuse Headache
Inform patients that use of
acute migraine drugs for 10 or more days per month may lead to an exacerbation of
headache and encourage patients to record headache frequency and drug use
(e.g., by keeping a headache diary) [see WARNINGS AND PRECAUTIONS].
Inform patients of the warning
signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy,
pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like”
symptoms). If these occur, instruct patients to stop CAMBIA and seek immediate
medical therapy [see WARNINGS AND PRECAUTIONS].
Heart Failure And Edema
Advise patients to be alert for
the symptoms of congestive heart failure including shortness of breath,
unexplained weight gain, or edema and to contact their healthcare provider if
such symptoms occur [see WARNINGS AND PRECAUTIONS].
Inform patients of the signs of
an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or
throat). Instruct patients to seek immediate emergency help if these occur [see
CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS].
Serious Skin Reactions
Advise patients to stop CAMBIA immediately if they
develop any type of rash, blisters, fever or other signs of hypersensitivity
such as itching and to contact their healthcare provider as soon as possible [see
WARNINGS AND PRECAUTIONS]. CAMBIA, like other NSAIDS, can cause serious
skin reactions such as exfoliative dermatitis, Stevens-Johnson syndrome (SJS),
and toxic epidermal necrosis (TEN), which may result in hospitalizations and
Effects During Pregnancy
Inform patients that starting at 30 weeks gestation,
CAMBIA and other NSAIDs should be avoided by pregnant women as premature
closure of the ductus arteriosus in the fetus may occur [see WARNINGS AND
PRECAUTIONS and Use in Specific Populations].
Avoid Concomitant Use Of NSAIDs
Inform patients that the concomitant use of CAMBIA with
other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended
due to the increased risk of gastrointestinal toxicity, and little or no increase
in efficacy [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].
Alert patients that NSAIDs may be present in “over the counter” medications for
treatment of colds, fever, or insomnia.
Use Of NSAIDS And Low-Dose Aspirin
Inform patients not to use low-dose aspirin concomitantly
with CAMBIA until they talk to their healthcare provider [see DRUG
Carcinogenesis, Mutagenesis, And Impairment Of Fertility
Long term carcinogenicity studies in rats given
Use In Specific Populations
Pregnancy Category C prior to
30 weeks gestation; Category D starting at 30 weeks gestation.
Starting at 30 weeks gestation,
CAMBIA, and other NSAIDS, should be avoided by pregnant women as premature
closure of the ductus arteriosus in the fetus may occur [see WARNINGS
AND PRECAUTIONS]. There are no adequate and well
controlled studies in pregnant women.
Prior to 30 weeks gestation, CAMBIA should be used during
pregnancy only if the potential benefit justifies the potential risk to the
Reproductive studies have been performed in mice given
diclofenac sodium (up to 20 mg/kg/day, 2 times the recommended human dose [RHD]
of 50 mg/day on a body surface area [mg/m² basis), and in rats and rabbits
given diclofenac sodium (up to 10 mg/kg/day; 2 [rats] and 4 [rabbits] times the
RHD on a mg/m² basis) and have revealed no evidence of teratogenicity despite
the induction of maternal toxicity and fetal toxicity. In rats, maternally
toxic doses were associated with dystocia, prolonged gestation, reduced fetal
weights and growth, and reduced fetal survival.
Labor And Delivery
The effects of CAMBIA on labor
and delivery in pregnant women are unknown. In rat studies, maternal exposure
to NSAIDs, as with other drugs known to inhibit prostaglandin synthesis,
increased the incidence of dystocia, delayed parturition, and decreased pup
It is not known whether this
drug is excreted in human milk. Because many drugs are excreted in human milk
and because of the potential for serious adverse reactions in nursing infants
from CAMBIA, a decision should be made whether to discontinue nursing or to
discontinue the drug, taking into account the importance of the drug to the
Safety and effectiveness in
pediatric patients have not been established.
Elderly patients, compared to
younger patients, are at greater risk for NSAID-associated serious
cardiovascular, gastrointestinal, and/or renal adverse reactions. If the
anticipated benefit for the elderly patient outweighs these potential risks,
monitor patients for adverse effects [see WARNINGS AND PRECAUTIONS].
Clinical studies of CAMBIA did
not include sufficient numbers of subjects aged 65 and over to determine
whether they respond differently from younger subjects.
Because hepatic metabolism
accounts for almost 100% of diclofenac elimination, patients with hepatic
impairment should be considered for treatment with CAMBIA only if the benefits
outweigh the risks. There is insufficient information available to support
dosing recommendations for CAMBIA in patients with hepatic insufficiency [see
No information is available
from controlled clinical studies regarding the use of CAMBIA in patients with
advanced renal disease. Therefore, treatment with CAMBIA is not recommended in
patients with advanced renal disease. If CAMBIA therapy must be initiated,
close monitoring of the patient's renal function is advisable.
diclofenac sodium up to 2 mg/kg/day (less than the recommended human dose [RHD]
of 50 mg/day on a body surface area [mg/m²] basis) have revealed no significant
increases in tumor incidence. There was a slight increase in benign mammary
fibroadenomas in mid-dose treated (0.5 mg/kg/day or 3 mg/m²/day) female rats
(high-dose females had excessive mortality), but the increase was not
significant for this common rat tumor. A 2-year carcinogenicity study conducted
in mice employing diclofenac sodium at doses up to 0.3 mg/kg/day (less than the
RHD on a mg/m² basis) in males and 1 m/kg/day (less than the RHD on a mg/m² basis)
in females did not reveal any oncogenic potential.
Diclofenac sodium was not genotoxic in in vitro (reverse
mutation in bacteria [Ames], mouse lymphoma tk) or in in vivo (including
dominant lethal and male germinal epithelial chromosomal aberration in Chinese
Impairment Of Fertility
Diclofenac sodium administered to male and female rats at
4 mg/kg/day (less than the RHD on a mg/m² basis) did not affect fertility.