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Duexis

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Duexis

Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Cardiovascular Thrombotic Events

Clinical trials of several COX-2 selective and nonselective NSAIDs, including ibuprofen, which is a component of DUEXIS tablets, of up to 3 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, the lowest effective dose should be used 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. Patients should be informed about the signs and/or 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 does increase the risk of serious GI events.

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 [see CONTRAINDICATIONS].

Hypertension

NSAIDs, including ibuprofen, which is a component of DUEXIS tablets, can lead to onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including DUEXIS, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy [see DRUG INTERACTIONS].

Congestive Heart Failure and Edema

Fluid retention and edema have been observed in some patients taking NSAIDs. DUEXIS should be used with caution in patients with fluid retention or heart failure.

Risk of Gastrointestinal Ulceration, Bleeding, and Perforation

NSAIDs, including ibuprofen, which is a component of DUEXIS tablets, can cause serious gastrointestinal (GI) adverse reactions including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse reactions 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 1 year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk. NSAIDs, including DUEXIS, should be prescribed with extreme caution in those with a prior history of ulcer disease or GI bleeding. Patients with a prior history of peptic ulcer disease and/or GI bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients treated with neither of these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs, including DUEXIS, include concomitant use of oral corticosteroids, anticoagulants, antiplatelet drugs (including low-dose aspirin), longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI reactions are in elderly or debilitated patients, and, therefore, special care should be taken in treating this population with DUEXIS.

To minimize the potential risk for an adverse GI reaction in patients treated with an NSAID, the shortest possible duration should be used. Patients and physicians should remain alert for signs and symptoms of GI ulcers and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse reaction is suspected. This should include discontinuation of the NSAID until a serious GI adverse reaction is ruled out. For high-risk patients, alternate therapies that do not involve NSAIDs should be considered.

Epidemiological studies of the case-control and cohort design have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. In two studies, concurrent use of concurrent use of an NSAID, COX-2 inhibitor, or aspirin potentiated the risk of bleeding [see DRUG INTERACTIONS]. Although these studies focused on upper gastrointestinal bleeding, bleeding at other sites cannot be ruled out.

NSAIDs should be given with care to patients with a history of inflammatory bowel disease (ulcerative colitis, Crohn's disease) as their condition may be exacerbated.

Because serious GI tract ulcers and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs should have their complete blood count (CBC) and chemistry profile checked periodically.

Symptomatic response to therapy with DUEXIS does not preclude the presence of gastric malignancy.

Active Bleeding

When active and clinically significant bleeding from any source occurs in patients receiving DUEXIS, the treatment should be withdrawn. Patients with initial hemoglobin values of 10 g or less who are to receive long-term therapy should have hemoglobin values determined periodically.

Renal Injury

Long-term administration of NSAIDs, including ibuprofen, which is a component of DUEXIS tablets, 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 and angiotensin-converting enzyme (ACE) inhibitors, and the elderly. If clinical signs (e.g., azotemia, hypertension, and/or proteinuria) and symptoms consistent with renal disease develop, DUEXIS should be discontinued. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state [see ADVERSE REACTIONS and Use In Specific Populations].

Seizures

Central nervous system (CNS) adverse effects including seizures, delirium, and coma have been reported with famotidine in patients with moderate (creatinine clearance < 50 mL/min) and severe renal insufficiency (creatinine clearance < 10 mL/min), and the dosage of the famotidine component in DUEXIS is fixed. Therefore, DUEXIS is not recommended in patients with creatinine clearance < 50 mL/min.

Anaphylaxis

Anaphylaxis may occur in patients without known prior exposure to ibuprofen, which is a component of DUEXIS tablets. DUEXIS should not be given to 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]. Emergency help should be sought in cases where anaphylaxis, which may have a fatal outcome, occurs.

Skin Reactions

NSAIDs, including ibuprofen, which is a component of DUEXIS tablets, 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. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity [see CONTRAINDICATIONS and ADVERSE REACTIONS].

Pregnancy

Starting at 30 weeks gestation, DUEXIS should be avoided by pregnant women because it may cause premature closure of the ductus arteriosus [see CONTRAINDICATIONS and Use in Specific Population].

Hepatic Injury

Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs, including ibuprofen, which is a component of DUEXIS tablets. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice, fulminant hepatitis, liver necrosis, and hepatic failure, some of them with fatal outcomes have been reported.

A patient with symptoms and/or signs suggesting liver dysfunction, or with abnormal liver test values, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with DUEXIS. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), DUEXIS should be discontinued.

Anemia

Anemia is sometimes seen in patients receiving NSAIDs, including ibuprofen which is a component of DUEXIS tablets. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including DUEXIS, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia.

Inhibition of Platelet Aggregation

NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving DUEXIS who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.

Pre-existing Asthma

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 NSAIDs has been reported in such aspirin-sensitive patients, DUEXIS should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with pre-existing asthma.

Concomitant NSAID Use

DUEXIS contains ibuprofen as one of its active ingredients. It should not be used with other ibuprofen-containing products.

The concomitant use of NSAIDs, including aspirin, with DUEXIS may increase the risk of adverse events [see ADVERSE REACTIONS, DRUG INTERACTIONS, and Clinical Studies].

Aseptic Meningitis

Aseptic meningitis with fever and coma has been observed on rare occasions in patients on ibuprofen, which is a component of DUEXIS. Although it is probably more likely to occur in patients with systemic lupus erythematosus (SLE) and related connective tissue diseases, it has been reported in patients who do not have an underlying chronic disease. If signs or symptoms of meningitis develop in a patient on DUEXIS, the possibility of its being related to ibuprofen should be considered.

Corticosteroid Treatment

DUEXIS cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids and the patient should be observed closely for any evidence of adverse effects, including adrenal insufficiency and exacerbation of symptoms of arthritis.

Masking of Inflammation and Fever

The pharmacological activity of DUEXIS in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, noninflammatory painful conditions.

Visual Disturbances

Blurred and/or diminished vision, scotomata, and/or changes in color vision have been reported. If a patient develops such complaints while receiving DUEXIS, the drug should be discontinued, and the patient should have an ophthalmologic examination which includes central visual fields and color vision testing.

Patient Counseling Information

“See FDA-approved patient labeling (Medication Guide)

Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide.

  • DUEXIS, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death [see WARNINGS AND PRECAUTIONS].
  • DUEXIS, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death [see WARNINGS AND PRECAUTIONS].
  • DUEXIS, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, Stevens Johnson Syndrome, and Toxic epidermal necrolysis, which may result in hospitalization and even death. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible.
  • Patients should be monitored for development of nephrotoxicity (e.g., azotemia, hypertension, and/or proteinuria). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy.
  • DUEXIS is not recommended in patients with creatinine clearance < 50 mL/min because of the seizures, delirium, coma and other CNS effect.
  • Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians.
  • Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy.
  • Patients should be informed of the signs of anaphylaxis (e.g. difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help [see WARNINGS AND PRECAUTIONS].
  • Patients should be informed that in late pregnancy, as with other NSAIDs, DUEXIS should be avoided because it may cause premature closure of the ductus arteriosus.
  • DUEXIS tablets should be swallowed whole, and should not be cut to supply a lower dose. Do not chew, divide, or crush tablets [see DOSAGE AND ADMINISTRATION].
  • Patients should be instructed that if a dose is missed, it should be taken as soon possible. However, if the next schedule dose is due, the patient should not take the missed dose, and should be instructed to take the next dose on time. Patients should be instructed not to take 2 doses at one time to make up for a missed dose.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies to evaluate the potential effects of DUEXIS on carcinogenicity, mutagenicity, or impairment of fertility have not been conducted.

In a 106-week study in rats and a 92-week study in mice, famotidine was given at oral doses of up to 2000 mg/kg/day (approximately 122 and 243 times the recommended human dose, respectively, based on body surface area). There was no evidence of carcinogenic potential for famotidine.

Famotidine was negative in the microbial mutagen test (Ames test) using Salmonella typhimurium and Escherichia coli with or without rat liver enzyme activation at concentrations up to 10,000 μg/plate. In in vivo mouse micronucleus test and a chromosomal aberration test with famotidine, no evidence of a mutagenic effect was observed.

In studies of famotidine in rats at oral doses of up to 2000 mg/kg/day (approximately 243 times the recommended human dose, based on body surface area), fertility and reproductive performance were not affected.

Use In Specific Populations

Pregnancy

Teratogenic Effects - Pregnancy Category C

Animal reproduction studies have not been conducted with DUEXIS. Reproductive studies conducted with ibuprofen in rats and rabbits have not demonstrated evidence of developmental abnormalities. Reproductive studies with famotidine have been performed in rats and rabbits at oral doses of up to 2000 and 500 mg/kg/day (approximately 243 and 122 times the recommended human dose, respectively, based on body surface area) and in both species at intravenous (I.V.) doses of up to 200 mg/kg/day, and have revealed no significant evidence of impaired fertility or harm to the fetus due to famotidine. While no direct fetotoxic effects have been observed, sporadic abortions occurring only in mothers displaying marked decreased food intake were seen in some rabbits at oral doses of 200 mg/kg/day (approximately 49 times the recommended human dose based on body surface area) or higher. There are no adequate and well-controlled studies in pregnant women. Animal reproduction studies are not always predictive of human response. DUEXIS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects

Because of the known effects of NSAIDs on the fetal cardiovascular system (closure of ductus arteriosus), use during late pregnancy should be avoided [see WARNINGS AND PRECAUTIONS].

Labor and Delivery

In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of DUEXIS on labor and delivery in pregnant women are unknown.

Nursing Mothers

It is not known whether ibuprofen is excreted in human milk.

Famotidine is secreted into breast milk of lactating rats. Transient growth depression was observed in young rats suckling from mothers treated with maternotoxic doses of at least 300 times the usual human dose of famotidine. Famotidine is detectable in human milk. Because of the potential for serious adverse reactions in nursing infants from DUEXIS, a decision should be made whether to discontinue nursing or 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

The clinical trials primarily enrolled patients less than 65 years of age. Of the 1022 subjects in clinical studies of DUEXIS, 18% (249 subjects) were 65 years of age or older. Efficacy results in patients who are greater than or equal to 65 years of age are summarized in the CLINICAL STUDIES section [see Clinical Studies].

Famotidine is known to be substantially excreted by the kidney, and the risk of toxic 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 in dose selection and adjusting dose interval, and it may be useful to monitor renal function [see WARNINGS AND PRECAUTIONS].

As with any NSAIDs, caution should be exercised in treating the elderly (65 years old and older). Experience indicates that geriatric patients may be particularly sensitive to certain adverse effects of NSAIDs. Elderly or debilitated patients seem to tolerate peptic ulceration or bleeding less well when these events do occur. Most spontaneous reports of fatal GI events are in the geriatric population [see WARNINGS AND PRECAUTIONS].

Ibuprofen is known to be substantially excreted by the kidney, and the risk of toxic 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 in dose selection, and it may be useful to monitor renal function. Geriatric patients may be at a greater risk for the development of a form of renal toxicity precipitated by reduced prostaglandin formation during administration of NSAIDs [see WARNINGS AND PRECAUTIONS].

Renal Insufficiency

In adult patients with renal insufficiency (creatinine clearance < 50 mL/min), the elimination half-life of famotidine is increased. Since CNS adverse effects have been reported in patients with creatinine clearance < 50 mL/min and the dosage of the famotidine component in DUEXIS is fixed, DUEXIS is not recommended in these patients [see WARNINGS AND PRECAUTIONS].

Last reviewed on RxList: 1/31/2013
This monograph has been modified to include the generic and brand name in many instances.

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