June 27, 2016
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Cambia

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Cambia




Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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].

Post-MI Patients

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 patients:

  • Use the lowest effective dosage for the shortest possible duration.
  • 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 NSAIDs.
  • 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].

Hepatotoxicity

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 [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 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.

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 CAMBIA.

Hypertension

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 therapy.

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 DRUG INTERACTIONS].

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

Renal Toxicity

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 function.

Hyperkalemia 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.

Anaphylactic Reactions

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 CONTRAINDICATIONS].

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 Special Populations].

Hematologic Toxicity

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 INTERACTIONS].

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.

Laboratory Monitoring

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.

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.

Cardiovascular Thrombotic Events

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 AND PRECAUTIONS].

Gastrointestinal Bleeding, 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].

Hepatotoxicity

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].

Anaphylactic Reactions

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 even death. [See WARNINGS AND PRECAUTIONS]

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 INTERACTIONS].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, And Impairment Of Fertility

Carcinogenesis

Long term carcinogenicity studies in rats given 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.

Mutagenesis

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 hamster) assays.

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.

Use In Specific Populations

Pregnancy

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 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.

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 survival.

Nursing Mothers

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.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

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.

Hepatic Impairment

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].

Renal Impairment

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.

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 5/23/2016

Warnings
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