Source: FDA, National Drug Code (US) Revision Year: 2019
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, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Inform patients about the signs and 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 increases the risk of serious GI events [see Warnings and Precautions (5.2)].
Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following coronary artery bypass graft (CABG) surgery found an increased incidence of myocardial infarction and stroke [see Contraindications (4)].
NSAIDs, including CAMBIA, can cause serious gastrointestinal (GI) adverse events such as inflammation, bleeding, ulceration, and perforation of the 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 occur in approximately 1% of patients treated for 3-6 months, and in about 2%-4% of patients treated for one year. These trends continue with longer duration of use, thus increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term NSAID therapy is not without risk.
Prescribe NSAIDs, including CAMBIA, with extreme caution in patients with a prior history of ulcer disease or GI bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold risk for developing a GI bleed than patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients, and therefore special care should be taken in treating this population.
To minimize the potential risk for an adverse GI event in patients treated with an NSAID, use the lowest effective dose for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during CAMBIA therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of the CAMBIA until a serious GI adverse event is ruled out. For high risk patients, alternative therapies that do not include NSAIDs should be considered.
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 liver injury.
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.
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 with diclofenac.
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.
Measure transaminases (ALT and AST) periodically in patients receiving long-term therapy with diclofenac because severe hepatotoxicity may develop without a prodrome of distinguishing symptoms. The optimum times for making the first and subsequent transaminase measurements are not known. Based on clinical trial data and postmarketing experiences, transaminases should be monitored within 4 to 8 weeks after initiating treatment with diclofenac. However, severe hepatic reactions can occur at any time during treatment with diclofenac. If abnormal liver tests persist or worsen, if clinical signs and/or symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, abdominal pain, diarrhea, dark urine, etc.), discontinue CAMBIA immediately.
To minimize the possibility that hepatic injury will become severe between transaminase measurements, 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), and the appropriate action patients should take if these signs and symptoms appear.
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 CAMBIA.
NSAIDs, including CAMBIA, can lead to new onset 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 therapy.
Patients taking ACE inhibitors, thiazides, or loop diuretics may have impaired response to these therapies when taking NSAIDs.
Fluid retention and edema have been observed in some patients taking NSAIDs. Use CAMBIA with caution in patients with fluid retention or heart failure.
Use caution when initiating treatment with CAMBIA in patients with considerable dehydration.
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, heart failure, liver dysfunction, those taking diuretics or ACE inhibitors, 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. 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.
As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to CAMBIA. CAMBIA is contraindicated in patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs. [see Contraindications (4)].
NSAIDs, including CAMBIA, 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 manifestations and to discontinue CAMBIA at the first appearance of skin rash or any other sign of hypersensitivity.
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 Special Populations (8.1)].
The pharmacological activity of NSAIDs in reducing inflammation and possibly fever may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.
Anemia may occur in patients receiving NSAIDs. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. In patients on long-term therapy with NSAIDs, including CAMBIA, check hemoglobin or hematocrit if they exhibit any signs or symptoms of anemia or blood loss.
NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, the NSAID effect on platelet function is quantitatively less, of shorter duration, and reversible. Carefully monitor patients treated with CAMBIA who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants.
Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross-reactivity, including bronchospasm, between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, CAMBIA is contraindicated in patients with this form of aspirin sensitivity and should be used with caution in all patients with pre-existing asthma.
Because serious GI ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding.
For patients on long-term treatment with NSAIDs, including CAMBIA, periodically perform a CBC and chemistry profile. Discontinue CAMBIA if abnormal liver tests or renal tests persist or worsen.
CAMBIA contains aspartame equivalent to phenylalanine 25 mg per packet.
The following serious adverse reactions are discussed elsewhere in the labeling:
The most common adverse reactions reported with CAMBIA are nausea and dizziness.
The most common adverse events resulting in discontinuation of patients following CAMBIA dosing in controlled clinical trials were urticaria (0.2%) and flushing (0.2%).
In patients taking diclofenac or other NSAIDs, the most frequently reported adverse reactions occurring in approximately 1%-10% of patients are: GI reactions (including abdominal pain, constipation, diarrhea, dyspepsia, flatulence, gross bleeding/perforation, heartburn, nausea, GI ulcers [gastric/duodenal], and vomiting), abnormal renal function, anemia, dizziness, edema, elevated liver enzymes, headaches, increased bleeding time, pruritus, rashes, and tinnitus.
Additional adverse reactions reported in patients taking NSAIDs include occasionally:
Body as a Whole: Fever, infection, sepsis
Cardiovascular System: Congestive heart failure, hypertension, tachycardia, syncope
Digestive System: Dry mouth, esophagitis, gastric/peptic ulcers, gastritis, gastrointestinal bleeding, glossitis, hematemesis, hepatitis, jaundice
Hemic and Lymphatic System: Ecchymosis, eosinophilia, leukopenia, melena, purpura, rectal bleeding, stomatitis, thrombocytopenia
Metabolic and Nutritional: Weight changes
Nervous System: Anxiety, asthenia, confusion, depression, dream abnormalities, drowsiness, insomnia, malaise, nervousness, paresthesia, somnolence, tremors, vertigo
Respiratory System: Asthma, dyspnea
Skin and Appendages: Alopecia, photosensitivity, sweating increased
Special Senses: Blurred vision
Urogenital System: Cystitis, dysuria, hematuria, interstitial nephritis, oliguria/polyuria, proteinuria, renal failure
Other adverse reactions in patients taking NSAIDs, which occur rarely, are:Body as a Whole: Anaphylactic reactions, appetite changes, death
Cardiovascular System: Arrhythmia, hypotension, myocardial infarction, palpitations, vasculitis
Digestive System: Colitis, eructation, liver failure, pancreatitis
Hemic and Lymphatic System: Agranulocytosis, hemolytic anemia, aplastic anemia, lymphadenopathy, pancytopenia
Metabolic and Nutritional: Hyperglycemia
Nervous System: Convulsions, coma, hallucinations, meningitis
Respiratory System: Respiratory depression, pneumonia
Skin and Appendages: Angioedema, toxic epidermal necrolysis, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, urticaria
Special Senses: Conjunctivitis, hearing impairment
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety of a single dose of CAMBIA was evaluated in 2 placebo-controlled trials with a total of 634 migraine patients treated with CAMBIA for a single migraine headache. Following treatment with diclofenac potassium (either CAMBIA or diclofenac potassium immediate-release tablets [as a control]), 5 subjects (0.8%) withdrew from the studies; following placebo exposure, 1 subject (0.2%) withdrew. No withdrawals were due to a serious reaction.
The most common adverse reactions (i.e., that occurred in 1% or more of CAMBIA-treated patients) and more frequent with CAMBIA than with placebo were nausea and dizziness (see Table 1).
Table 1. Treatment-Related Adverse Reactions With Incidence >1% and Greater Than Placebo in Studies 1 and 2 Combined:
| Disorder | CAMBIA | Placebo |
|---|---|---|
| Event | N=634 | N=646 |
| Gastrointestinal | ||
| Nausea | 3% | 2% |
| Nervous System | ||
| Dizziness | 1% | 0.5% |
When administered with aspirin, diclofenac potassium’s protein binding is reduced. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of CAMBIA and aspirin is not generally recommended because of the potential of increased adverse effects.
The effects of anticoagulants such as warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than that with use of either drug alone.
NSAIDs may diminish the antihypertensive effect of ACE inhibitors. This interaction should be given consideration in patients taking CAMBIA concomitantly with ACE inhibitors.
Clinical studies, as well as post-marketing observations, have shown that diclofenac potassium can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, observe patients closely for signs of renal failure as well as to assure diuretic efficacy [see Warnings and Precautions (5.6)].
NSAIDs have produced elevations of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. When CAMBIA and lithium are administered concurrently, observe patients carefully for signs of lithium toxicity.
NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This indicates that NSAIDs may enhance the toxicity of methotrexate. Use caution when NSAIDs are administered concomitantly with methotrexate.
CAMBIA, like other NSAIDs, may affect renal prostaglandins and increase the toxicity of certain drugs. Therefore, concomitant therapy with CAMBIA may increase cyclosporine’s nephrotoxicity. Use caution when CAMBIA is administered concomitantly with cyclosporine.
Diclofenac is metabolized predominantly by Cytochrome P-450 CYP2C9. Co-administration of medications that inhibit CYP2C9 may affect the pharmacokinetics of diclofenac [see Clinical Pharmacology (12.3)].
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 (5.9)]. 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 fetus.
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.
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 survival.
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 mother.
Safety and effectiveness in pediatric patients have not been established.
Clinical studies of CAMBIA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
Elderly patients are at increased risk for serious GI adverse events.
Diclofenac is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken when using CAMBIA in the elderly.
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.
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 Clinical Pharmacology (12.3)].
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