PENNSAID Topical solution Ref.[50794] Active ingredients: Diclofenac

Please see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX.

Carcinogenesis and Mutagenesis

See 16 NON-CLINICAL TOXICOLOGY.

Cardiovascular

PENNSAID is a non-steroidal anti-inflammatory drug (NSAID). Use of some NSAIDs is associated with an increased incidence of cardiovascular adverse events (such as myocardial infarction, stroke or thrombotic events) which can be fatal. Large population-based observational studies, meta-analyses and systematic reviews suggest an increased risk of myocardial infarction and stroke also in association with the use of diclofenac. The risk may increase with the dose and duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk.

Caution should be exercised in prescribing PENNSAID to patients with risk factors for cardiovascular disease, cerebrovascular disease or renal disease, such as any of the following (NOT an exhaustive list):

• Hypertension
• Dyslipidemia/Hyperlipidemia
• Diabetes Mellitus
• Congestive Heart Failure (NYHA I)
• Coronary Artery Disease (Atherosclerosis)
• Peripheral Arterial Disease
• Smoking
• Creatinine Clearance <60 mL/min or 1 mL/sec

Use of NSAIDs, such as PENNSAID, can lead to new hypertension or can worsen pre-existing hypertension, either of which may increase the risk of cardiovascular events as described above. Thus blood pressure should be monitored regularly. Consideration should be given to discontinuing PENNSAID should hypertension either develop or worsen with its use.

Use of NSAIDs, such as PENNSAID, can induce fluid retention and edema, and may exacerbate congestive heart failure, through a renally-mediated mechanism.

For patients with a high risk of developing an adverse CV event, other management strategies that do NOT include the use of NSAIDs should be considered first. To minimize the potential risk for an adverse CV event, the lowest effective dose should be used for the shortest possible duration.

Driving and Operating Machinery

Some patients may experience drowsiness, dizziness, vertigo, insomnia or depression with the use of PENNSAID. If patients experience these side effects, they should exercise caution in carrying out activities that require alertness.

Gastrointestinal

In clinical studies, PENNSAID has not been associated with serious gastrointestinal (GI) toxicity, such as peptic ulceration, perforation and GI bleeding commonly associated with NSAIDS.

Serious GI 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 diclofenac sodium.

Gastrointestinal symptoms, such as dyspepsia, are common, usually developing early in therapy. Healthcare professionals should remain alert for the signs and symptoms of ulceration and bleeding in patients treated with NSAIDs, even in the absence of previous GI tract symptoms.

In patients observed in clinical trials of NSAIDs given orally, symptomatic upper GI ulcers, gross bleeding, or perforation appear to occur in approximately 1% of patients treated for 3-6 months and in about 2-4% of patients treated for one year. The incidence of these complications is related to dose, past history of known ulcer disease, and advanced age.

PENNSAID should be given under close medical supervision to patients with a history of ulcer of the gastrointestinal tract, or inflammatory disease of the gastrointestinal tract, such as ulcerative colitis or Crohn’s disease. In these cases the healthcare professionals must weigh the benefits of treatment against the possible hazards.

Patients should be informed about the signs and/or symptoms of serious GI toxicity and instructed to contact a healthcare professional immediately if they experience persistent dyspepsia or other symptoms or signs suggestive of gastrointestinal ulceration or bleeding.

Because serious GI tract ulceration and bleeding can occur without warning symptoms, healthcare professionals should follow patients for signs and symptoms of ulceration and bleeding and should inform the patients of the importance of this follow-up.

If ulceration is suspected or confirmed, or if GI bleeding occurs, PENNSAID 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. The major risk factors are a prior history of serious GI events and increasing age. Possible risk factors include Helicobacter pylori infection, excess alcohol intake, smoking, concomitant oral steroids, anticoagulants, anti-platelet agents (including ASA) and selective serotonin reuptake inhibitors (SSRIs).

There is no definitive evidence that the concomitant administration of histamine H2-receptor antagonists and/or antacids will either prevent the occurrence of gastrointestinal side effects or allow the continuation of PENNSAID therapy when, and if, these adverse reactions appear.

Genitourinary

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 PENNSAID must be stopped immediately to obtain recovery. This should be done before any urological investigation or treatment is carried out.

Hematologic

In clinical studies with PENNSAID, abnormal hemoglobin, white blood cell (WBC) or platelet counts have not been observed.

The effect of PENNSAID on platelet function was studied in 10 healthy patients randomly selected to participate in a sub-study of multiple-dose pharmacokinetic study where 40 drops of PENNSAID were applied to each knee four times a day for 7 days. Following 7-day treatment with PENNSAID, the mean change in % aggregation for ADP-collagen-, epinephrine- and arachidonic acid-induced aggregation was 1.31%, -0.19%, 9.85% and -0.95%, respectively. These results indicate that there was no marked effect on platelet aggregation after application of the maximum clinical dose for 7 days.

Diclofenac sodium increases platelet aggregation time but does not affect bleeding time, plasma thrombin clotting time, plasma fibrinogen, 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.

Drugs inhibiting prostaglandin biosynthesis interfere with platelet function to varying degrees; therefore, patients who may be adversely affected by such an action, such as those on anti-coagulants or suffering from haemophilia or platelet disorders, should be carefully observed when PENNSAID is administered.

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. Patients on long-term diclofenac sodium treatment should have their hematopoietic system evaluated periodically.

Hepatic / Biliary / Pancreatic

As with other NSAIDs, including PENNSAID, borderline elevations of one or more liver enzyme tests (AST, ALT, alkaline phosphatase) may occur in up to 15% of patients. These abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy. Toxicity studies in animals with high doses of DMSO have shown occasional, transient elevation of liver function tests.

In two clinical trials with PENNSAID, a mild elevation of AST was seen in 4 of 117 (3.4%) patients using PENNSAID, 2 of 109 (1.8%) using vehicle-control (both of these solutions contained DMSO 45.5%) and 1 of 110 (0.9%) using Placebo. A mild elevation of ALT was seen in 4 of 117 (3.4%) patients using PENNSAID, 6 of 111 (5.4%) using vehicle-control and 2 of 108 (1.9%) using placebo. In most cases the increase was minimal and in two patients (one treated with PENNSAID, one treated with vehiclecontrol) the increase was 2.5 times normal.

In post-marketing reports of patients receiving diclofenac, cases of drug-induced hepatotoxicity have been reported in the first month, and in some cases, the first 2 months of therapy, but can occur at any time during treatment. 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 PENNSAID. Post-marketing surveillance has reported cases of severe hepatic reactions including jaundice, fulminant hepatitis with and without jaundice, liver necrosis and hepatic failure. Some of these cases have resulted in fatalities or liver transplantation.

Transaminases should be measured periodically in patients receiving PENNSAID because severe hepatotoxicity may develop without a prodrome of distinguishing symptoms. Severe hepatic reactions can occur at any time during treatment with diclofenac. Although such reactions are rare, if abnormal liver function tests persist or worsen, if clinical signs and symptoms consistent with liver disease develop (e.g. jaundice), or if systemic manifestations occur (e.g. eosinophilia, rash, etc.), this drug should be discontinued immediately.

To minimize the possibility that hepatic injury will become severe between transaminase measurements, patients should be informed of 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 they should take if these signs and symptoms appear. Use of diclofenac is contraindicated in patients with significant hepatic impairment or active liver disease. If there is a need to prescribe this drug to patients with liver impairment, it must be done under strict observation.

Caution is advised when using diclofenac sodium in patients with hepatic porphyria, since diclofenac sodium may trigger an attack.

Immune

In common with other NSAIDs, diclofenac sodium may mask the usual signs of infection (i.e. fever).

Aseptic Meningitis

In rare 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 tissue diseases, etc.) seem to be pre-disposed. Therefore, in such patients, the healthcare professional must be vigilant to the development of this complication.

Monitoring and Laboratory Tests

The following testing or monitoring should be considered (note: this is not an exhaustive list):

Cardiovascular: Blood pressure monitoring should be considered. See 2 CONTRAINDICATIONS, 3 SERIOUS WARNINGS AND PRECAUTIONS BOX, 7 WARNINGS AND PRECAUTIONS, Cardiovascular.

Hematology: Concurrent therapy with anticoagulants may require monitoring of the international normalized ratio (INR). Hemoglobin, hematocrit, red blood cells (RBCs), white blood cells (WBCs), and platelets may require monitoring. See 7 WARNINGS AND PRECAUTIONS, Hematologic and 9 DRUG INTERACTIONS.

Lithium plasma concentration (in case of lithium co-prescription) should be monitored. See 9 DRUG INTERACTIONS.

Hepatic: Serum transaminase and bilirubin may require monitoring. See 7 WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic.

Ophthalmologic: If ophthalmological symptoms develop, PENNSAID should be discontinued and an ophthalmologic examination performed. See 7 WARNINGS AND PRECAUTIONS, Ophthalmologic.

Renal: Serum creatinine, creatinine clearance, serum urea and electrolytes including serum potassium may require monitoring. See 2 CONTRAINDICATIONS, 3 SERIOUS WARNINGS AND PRECAUTIONS BOX, 4.2 Recommended Dose and Dosage Adjustment, 7 WARNINGS AND PRECAUTIONS, Renal and 9 DRUG INTERACTIONS.

Pregnancy: PENNSAID is contraindicated for use in pregnancy. See 2 CONTRAINDICATIONS.

Ophthalmologic

Blurred and/or diminished vision has been reported with the use of NSAIDs. Changes in the refractive index and lens opacities have been seen in non-primate animals with chronic administration of dimethyl sulfoxide, in doses far in excess of those used in humans. If ophthalmological symptoms develop, PENNSAID should be discontinued and an ophthalmologic examination performed.

Peri-operative Considerations

See 2 CONTRAINDICATIONS.

Renal

In clinical studies with PENNSAID, increase in urea or creatinine, or any other renal toxicity has not been observed.

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 pre-renal conditions leading to 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 an NSAID may cause a dosedependent 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 NSAID therapy is usually followed by recovery to the pretreatment state.

Diclofenac sodium and its metabolites are eliminated primarily (60%) by the kidneys; therefore, PENNSAID should be used with great caution in patients with impaired renal function. In these cases, utilization of lower doses of PENNSAID should be considered and patients carefully monitored.

Fluid and Electrolyte Balance

In clinical studies with PENNSAID, fluid or electrolyte abnormalities have not been observed.

Fluid retention and edema have been observed in patients treated with diclofenac sodium. 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. PENNSAID 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 β-adrenergic blockers, angiotensin-converting enzyme inhibitors, angiotensin-II receptor antagonists or some diuretics. Patients at risk should be monitored periodically.

Sensitivity / Resistance

Dimethyl sulfoxide may initiate the liberation of histamine and occasional hypersensitivity reactions have occurred with topical administration. If anaphylactoid symptoms develop, appropriate therapy should be instituted and further use of PENNSAID immediately discontinued.

As with other NSAIDs, allergic reactions, including anaphylactic/anaphylactoid reactions, can occur without prior exposure to the drug. Careful questioning for patient history of asthma, nasal polyps, urticaria, and hypotension associated with NSAIDs is important before starting therapy. Because hypersensitivity reactions may occur even at a low systemic level, the possibility of such adverse effects with PENNSAID cannot be completely excluded.

These reactions are potentially life-threatening, but may be reversible if the causative agent is discontinued and appropriate treatment instituted. Patients should be advised that if they experience a generalized skin rash they should discontinue PENNSAID and contact their healthcare professional for assessment and advice, including which additional therapies to discontinue.

Skin

PENNSAID should not be applied to open, abraded or infected skin, and it should not be used under occlusive dressings. Contact with the eyes or mucous membranes should be avoided.

Patients should be warned against excessive exposure to sunlight in order to reduce the incidence of photosensitivity.

Serious skin reactions

Use of some NSAIDs, such as PENNSAID, have been associated with rare post-market cases of serious, fatal or otherwise life-threatening skin reactions, including:

• drug reaction with eosinophilia and systemic symptoms (DRESS)
• Stevens-Johnson syndrome (SJS)
• toxic epidermal necrolysis (TEN)
• exfoliative dermatitis
• erythema multiforme

Patients appear to be at higher risk for these events early in the course of therapy, with the onset of cases usually occurring within the first month of treatment. These reactions may be reversible if the causative agent is discontinued and appropriate treatment instituted. Patients should be advised that they should discontinue their NSAID at the first appearance of a skin rash, mucosal lesions or any other sign of hypersensitivity, and contact their physician immediately for assessment and advice, including which therapies to discontinue.

DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection, and eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident.

7.1 Special Populations

7.1.1 Pregnant Women

PENNSAID is contraindicated for use during pregnancy because of risks of premature closure of the ductus arteriosus and the potential to prolong parturition (see 2 CONTRAINDICATIONS and 16 NONCLINICAL TOXICOLOGY).

Published studies and post-marketing reports describe maternal NSAID use at approximately 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment or failure. NSAIDs were shown to cause significant reduction in fetal urine production prior to reduction of amniotic fluid volume. There have also been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction and renal impairment without oligohydramnios, some of which were irreversible, even after treatment discontinuation.

These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Complications of prolonged oligohydramnios may for example, include limb contractures and delayed lung maturation. In some post-marketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required.

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryo-fetal development. Data from epidemiological studies suggest an increased risk of miscarriage and of cardiac malformation after use of a prostaglandin synthesis inhibitor in early pregnancy.

In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in increased pre- and post-implantation loss and embryo-fetal lethality. In addition, increased incidences of various malformations, including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenesis period.

7.1.2 Breast-feeding

PENNSAID is contraindicated in breast-feeding women (see 2 CONTRAINDICATIONS).

7.1.3 Pediatrics

Pediatrics (<18 years of age): No data are available to Health Canada, therefore PENNSAID is contraindicated in the pediatric population (see 2 CONTRAINDICATIONS).

7.1.4 Geriatrics

Geriatrics (≥65 years of age): Evidence from clinical studies and experience suggests that use in the geriatric population is associated with differences in safety (see 4.2 Recommended Dose and Dosage Adjustment).

8.1 Adverse Reaction Overview

Adverse reaction reporting is based on double-blind, controlled clinical studies in which 446 patients were exposed to PENNSAID. Mean drop-out rates were: PENNSAID, 22.0%; vehicle-control (C), 28.3%; diclofenac control, 19.2%; placebo, 20.6%.

Application-site, dermatological reactions are the most commonly seen adverse events with PENNSAID (see Table 3).

The most common adverse reactions encountered with oral NSAIDs are gastrointestinal, of which peptic ulcer, with or without bleeding, is the most severe. Fatalities have occurred, particularly in the elderly. The most severe, albeit rare, dermatological reactions observed were erythema multiforme (Stevens-Johnson syndrome and Lyell’s syndrome).

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

The following table lists all adverse events, regardless of causality, occurring in >2% of patients receiving PENNSAID from five controlled studies conducted in patients with osteoarthritis that included a vehicle-control, active-control and/or placebo-control group.

Table 3. Adverse Events Occurring in >2% of PENNSAID Patients in Five Vehicle-Controlled Studies:

¹ Contains the full carrier with DMSO, no diclofenac sodium
² Contains negligible DMSO with the full dose of diclofenac sodium
³ Contains negligible DMSO with no diclofenac sodium

8.3 Less Common Clinical Trial Adverse Reactions

The following spontaneous adverse events occurred in 0.2 to 1.8% of patients treated with PENNSAID regardless of causality:

Gastrointestinal: colitis, constipation, diarrhea, dry mouth, flatulence, gastritis, gastroenteritis, gingivitis, periodontal abscess, rectal disorder, thirst, tooth caries, vomiting;

Central and Peripheral Nervous System: aphasia, confusion, dizziness, depression, dysthymia, hypertonia, insomnia, migraine, nervousness, neuritis, sleep disorder, speech disorder, thinking abnormal, vertigo;

Skin and Appendages: acne, acne (application site), contact dermatitis, dry skin, furunculosis, hair disorder, maculopapular rash, nail disorder, pruritus, pustular rash, skin nodule, urticaria, vesiculobullous rash;

Cardiovascular: arrhythmia, arteriosclerosis, bradycardia, cardiovascular disorder, hypertension, myocardial infarction, palpitation, vasodilation, vasodilation (application site);

Special Senses: amblyopia, cataract, ear pain, eye pain, lacrimation disorder;

Hemic and Lymphatic: ecchymosis;

Urogenital: dysmenorrhea, prostatic specific antigen increase, testis disorder, vaginal hemorrhage;

Metabolic and Nutritional: edema, gout, hypercholesterolemia, peripheral edema;

Respiratory: asthma, bronchitis, congestion, cough increased, dyspnea, epistaxis, rhinitis, sinusitis;

Musculoskeletal: abnormal gait, arthritis, bone pain, leg cramps, myasthenia;

Body as a Whole: accidental injury, allergic reaction, asthenia, body odour, carcinoma, chest pain, chills, face edema, fever, halitosis, hernia, malaise, neck pain, neck rigidity.

In a controlled clinical trial conducted to assess the alternative dose regimen of 50 drops t.i.d, a total of 311 patients received at least one dose of PENNSAID for mean treatment duration of 66 days. The safety profile observed in this study was consistent with that reported in previous studies, the primary adverse events experienced by PENNSAID patients being application-site reactions.

In a long-term, uncontrolled clinical trial (approximately 800 patients were treated with PENNSAID for one year or longer), the adverse event profile was similar to that observed in the controlled clinical trials.

8.5 Post-Market Adverse Reactions

In post-marketing surveillance for PENNSAID and other diclofenac containing products, the following adverse reactions have been reported:

Body as a whole: Abdominal pain, Accidental injury, Allergic reaction, Asthenia, Back pain, Body odor, Chest pain, Edema, Face edema, Halitosis, Headache, lack of drug effect, Neck rigidity, Pain;

Cardiovascular: Cardiovascular disorder, Palpitation;

Digestive: Diarrhea, Dry mouth, Dyspepsia, Mouth ulceration, Nausea, Rectal hemorrhage, Ulcerative stomatitis;

Hepatic: Hepatotoxicity, severe hepatic reactions including liver necrosis, jaundice, fulminant hepatitis with and without jaundice and liver failure, with a fatal outcome or requiring liver transplantation (see 7 WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic); Metabolic and nutritional: Creatinine increased;

Musculoskeletal: Leg cramps, Myalgia;

Nervous: Depression, Dizziness, Drowsiness, Paresthesia, Paresthesia, app. site;

Respiratory: Asthma, Dyspnea, Laryngismus, Laryngitis, Pharyngitis;

Skin and appendages: At the Application site: Contact dermatitis, Contact dermatitis with vesicles, Dry skin, Pruritus, Rash. Other skin adverse reaction: Rash, Skin discoloration, Urticaria;

Special senses: Abnormal vision, Blurred vision, Cataract, Ear pain, Eye disorder, Eye pain, Taste perversion.

9.2 Drug Interactions Overview

Diclofenac metabolism is predominantly mediated via cytochrome P450 CYP 2C9 in the liver. Patients who are known or suspected to be poor CYP2C9 metabolizers based on previous history/experience with other CYP2C9 substrates should be administered diclofenac with caution as they may have abnormally high plasma levels due to reduced metabolic clearance. Caution is recommended when coprescribing diclofenac with potent CYP2C9 inhibitors (such as sulfinpyrazone and voriconazole), which could result in a significant increase in peak plasma concentrations and exposure to diclofenac due to inhibition of diclofenac metabolism.

9.3 Drug-Behavioural Interaction

Alcohol: There may be an increased risk of GI side effects, including ulceration or hemorrhage, when taken concomitantly with NSAIDs.

9.4 Drug-Drug Interactions

The drugs listed below are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction (i.e., those identified as contraindicated).

Acetylsalicylic Acid (ASA) or other NSAIDs: The use of PENNSAID in addition to any other NSAID, including those over-the-counter ones (such as ASA and ibuprofen) is not recommended due to the possibility of additive side effects. Low dose ASA (<325 mg/day) for cardiovascular prophylaxis, is permitted.

Digoxin: Diclofenac sodium may increase the plasma concentration of digoxin. Dosage adjustment of digoxin may be required.

Anticoagulants, Heparin, Thrombolytic Agents and Other Platelet Aggregation Inhibitors: Numerous studies have shown that the concomitant use of NSAIDs and anticoagulants increases the risk of GI adverse events such as ulceration and bleeding.

Because prostaglandins play an important role in hemostasis, and NSAIDs affect platelet function, concurrent therapy of PENNSAID with warfarin requires close monitoring to be certain that no change in anticoagulant dosage is necessary.

Oral Hypoglycemics: Pharmacodynamic studies have shown no potentiation of effect with concurrent administration with diclofenac sodium; however, there are isolated reports of both hypoglycemic and hyperglycemic effects in the presence of diclofenac sodium, which necessitated changes in the dosage of hypoglycemic agents.

Diuretics: NSAIDs have been reported to decrease the activity of diuretics. Concomitant treatment with potassium-sparing diuretics may be associated with increased serum potassium, thus making it necessary to monitor levels.

Antihypertensives: Like other NSAIDs, diclofenac sodium can reduce the antihypertensive effects of propranolol and other beta-blockers, as well as other antihypertensive agents.

Glucocorticoids: Numerous studies have shown that concomitant use of NSAIDs and oral glucocorticoids increases the risk of GI side effects such as ulceration and bleeding. This is especially the case in older individuals (>65 years of age).

Methotrexate: Caution should be exercised when NSAIDs are administered less than 24 hours before or after treatment with methotrexate. Elevated blood concentrations of methotrexate may occur, increasing its toxicity.

Acetaminophen: There may be an increased risk of adverse renal effects when administered concomitantly with NSAIDs.

Cyclosporine: The nephrotoxicity of cyclosporine may be increased because of the effects of NSAIDs on renal prostaglandins.

Lithium: Lithium plasma concentrations will increase when administered concomitantly with diclofenac sodium (which affects lithium renal clearance). Dosage adjustment of lithium may be required.

Probenecid: May decrease the excretion and increase serum concentration of NSAIDs, possibly enhancing effectiveness and/or increasing the potential for toxicity. Concurrent therapy of NSAIDs with probenecid requires close monitoring of dosage.

Quinolone Antibacterials: There have been isolated reports of convulsions, which may have been due to concomitant use of quinolones and NSAIDs.

Phenytoin: When using phenytoin concomitantly with diclofenac, monitoring of phenytoin plasma concentrations is recommended due to an expected increase in exposure to phenytoin.

Sulfinpyrazone: Concomitant administration of diclofenac and sulfinpyrazone could result in a significant increase in peak plasma concentrations and exposure to diclofenac due to inhibition of diclofenac metabolism.

Voriconazole: Concomitant administration of diclofenac and voriconazole could result in a significant increase in peak plasma concentrations and exposure to diclofenac due to inhibition of diclofenac metabolism.