Diclofenac sodium is a benzene-acetic acid derivative. Diclofenac sodium delayed-released tablets USP are available as delayed-release tablets of 25 mg, 50 mg and 75 mg for oral administration. Diclofenac sodium is a white or slightly yellowish crystalline powder and is sparingly soluble in water at 25°C. The chemical name is 2-[(2,6-dichlorophenyl)amino] benzeneacetic acid, monosodium salt. The molecular weight is 318.14 g/mol. Its molecular formula is C 14H 10Cl 12NNaO 2, and it has the following structural formula

The inactive ingredients in diclofenac sodium delayed-release tablets USP include: croscarmellose sodium, hydroxypropyl methylcellulose, iron oxide red, lactose monohydrate, magnesium stearate, methacrylic acid copolymer, microcrystalline cellulose, polyethylene glycol, povidone, talc and titanium dioxide.

Mechanism of Action

Diclofenac has analgesic, anti-inflammatory, and antipyretic properties.

The mechanism of action of diclofenac sodium delayed-release tablets, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2).

Diclofenac is a potent inhibitor of prostaglandin synthesis in vitro. Diclofenac concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because diclofenac is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues.

Pharmacokinetics

Absorption

Diclofenac is 100% absorbed after oral administration compared to intravenous (IV) administration as measured by urine recovery. However, due to first-pass metabolism, only about 50% of the absorbed dose is systemically available (see Table 1). Food has no significant effect on the extent of diclofenac absorption. However, there is usually a delay in the onset of absorption of 1 to 4.5 hours and a reduction in peak plasma levels of less than 20%.

Distribution

The apparent volume of distribution (V/F) of diclofenac sodium is 1.4 L/kg.

Diclofenac is more than 99% bound to human serum proteins, primarily to albumin. Serum protein binding is constant over the concentration range (0.15 to 105 mcg/mL) achieved with recommended doses.

Diclofenac diffuses into and out of the synovial fluid. Diffusion into the joint occurs when plasma levels are higher than those in the synovial fluid, after which the process reverses and synovial fluid levels are higher than plasma levels. It is not known whether diffusion into the joint plays a role in the effectiveness of diclofenac.

Elimination

Metabolism

Five diclofenac metabolites have been identified in human plasma and urine. The metabolites include 4'- hydroxy-, 5-hydroxy-, 3'-hydroxy-, 4',5-dihydroxy- and 3'-hydroxy-4'-methoxy-diclofenac. The major diclofenac metabolite, 4'-hydroxy-diclofenac, has very weak pharmacologic activity. The formation of 4’- hydroxy- diclofenac is primarily mediated by CYP2C9. Both diclofenac and its oxidative metabolites undergo glucuronidation or sulfation followed by biliary excretion. Acyl glucuronidation mediated by UGT2B7 and oxidation mediated by CYP2C8 may also play a role in diclofenac metabolism. CYP3A4 is responsible for the formation of minor metabolites, 5-hydroxy- and 3’-hydroxy-diclofenac. In patients with renal dysfunction, peak concentrations of metabolites 4'-hydroxy- and 5-hydroxy-diclofenac were approximately 50% and 4% of the parent compound after single oral dosing compared to 27% and 1% in normal healthy subjects.

Excretion

Diclofenac is eliminated through metabolism and subsequent urinary and biliary excretion of the glucuronide and the sulfate conjugates of the metabolites. Little or no free unchanged diclofenac is excreted in the urine. Approximately 65% of the dose is excreted in the urine and approximately 35% in the bile as conjugates of unchanged diclofenac plus metabolites. Because renal elimination is not a significant pathway of elimination for unchanged diclofenac, dosing adjustment in patients with mild to moderate renal dysfunction is not necessary. The terminal half-life of unchanged diclofenac is approximately 2 hours.

Special Populations

Pediatric:The pharmacokinetics of diclofenac sodium has not been investigated in pediatric patients.

Race:Pharmacokinetic differences due to race have not been identified.

Hepatic Impairment:Hepatic metabolism accounts for almost 100% of diclofenac sodium elimination, so patients with hepatic disease may require reduced doses of diclofenac sodium delayed-release tablets compared to patients with normal hepatic function.

Renal Impairment:Diclofenac pharmacokinetics has been investigated in subjects with renal insufficiency. No differences in the pharmacokinetics of diclofenac have been detected in studies of patients with renal impairment. In patients with renal impairment (inulin clearance 60 to 90, 30 to 60, and less than 30 mL/min; N = 6 in each group), area under the curve (AUC) values and elimination rate were comparable to those in healthy subjects.

Drug Interactions Studies

Voriconazole:When coadministered with voriconazole (inhibitor of CYP2C9, 2C19, and 3A4 enzyme), the Cmax and AUC of diclofenac increased by 114% and 78%, respectively (see PRECAUTIONS ; Drug Interactions).

Aspirin:When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 2 for clinically significant drug interactions of NSAIDs with aspirin (see PRECAUTIONS ; Drug Interactions).

Carefully consider the potential benefits and risks of diclofenac sodium delayed-release tablets and other treatment options before deciding to use diclofenac sodium. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS; Gastrointestinal Bleeding, Ulceration, and Perforation).

Diclofenac sodium delayed-release tablets are indicated:

• for relief of the signs and symptoms of osteoarthritis
• for relief of the signs and symptoms of rheumatoid arthritis
• for acute or long-term use in the relief of signs and symptoms of ankylosing spondylitis

Diclofenac sodium delayed-release tablets are contraindicated in the following patients:

• Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to diclofenac or any components of the drug product (see WARNINGS; Anaphylactic Reactions, Serious Skin Reactions).

• History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients (see WARNINGS; Anaphylactic Reaction, Exacerbation of Asthma Related to Aspirin Sensitivity).

• In the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS; Cardiovascular Thrombotic Events).

Cardiovascular Thrombotic Events

Clinical trials of several COX-2 selective and nonselective NSAIDs of up to 3 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 WARNING; 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 to 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 diclofenac sodium in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If diclofenac sodium 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 to 6 months, and in about 2% to 4% of patients treated for one year. However, even short-term 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 use NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of 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 (SSRIs); 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 Risks 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 such 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 diclofenac sodium delayed-release tablets 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 PRECAUTIONS; Drug Interactions).

Hepatotoxicity

In clinical trials of diclofenac-containing products, meaningful elevations (i.e., more than 3 times the upper limit of normal [ULN]) of aspartate aminotransferase (AST) (also known as SGOT) were observed in about 2% of approximately 5700 patients at some time during diclofenac treatment (alanine aminotransferase [ALT] was not measured in all studies).

In a large, open-label, controlled trial of 3700 patients treated with oral diclofenac sodium for 2 to 6 months, patients were monitored first at 8 weeks and 1200 patients were monitored again at 24 weeks. Meaningful elevations of ALT and/or AST occurred in about 4% of patients and included marked elevations (greater than 8 times the ULN) in about 1% of the 3700 patients. In that open-label study, a higher incidence of borderline (less than 3 times the ULN), moderate (3 to 8 times the ULN), and marked (greater than 8 times the ULN) elevations of ALT or AST was observed in patients receiving diclofenac when compared to other NSAIDs. Elevations in transaminases were seen more frequently in patients with osteoarthritis than in those with rheumatoid arthritis.

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 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.

In a European retrospective population-based, case-controlled study, 10 cases of diclofenac associated drug- induced liver injury with current use compared with non-use of diclofenac were associated with a statistically significant 4-fold adjusted odds ratio of liver injury. In this particular study, based on an overall number of 10 cases of liver injury associated with diclofenac, the adjusted odds ratio increased further with female gender, doses of 150 mg or more, and duration of use for more than 90 days.

Physicians should measure transaminases at baseline and 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.), diclofenac sodium delayed-release tablets should be discontinued immediately.

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 diclofenac sodium delayed-release tablets immediately, and perform a clinical evaluation of the patient.

To minimize the potential risk for an adverse liver related event in patients treated with diclofenac sodium delayed-release tablets, use the lowest effective dose for the shortest duration possible. Exercise caution when prescribing diclofenac sodium delayed-release tablets with concomitant drugs that are known to be potentially hepatotoxic (e.g., acetaminophen, antibiotics, anti- epileptics).

Hypertension

NSAIDs, including diclofenac sodium, can lead to new onset of hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazides diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs (see PRECAUTIONS; Drug Interactions).

Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy.

Heart Failure and Edema

The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately 2-fold increase in hospitalization 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 PRECAUTIONS; Drug Interactions).

Avoid the use of diclofenac sodium delayed-release tablets in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If diclofenac sodium delayed-release tablets are 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 diclofenac sodium in patients with advanced renal disease. The renal effects of diclofenac sodium may hasten the progression of renal dysfunction in patients with preexisting renal disease.

Correct volume status in dehydrated or hypovolemic patients prior to initiating diclofenac sodium delayed-release tablets. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of diclofenac sodium (see PRECAUTIONS; Drug Interactions). Avoid the use of diclofenac sodium delayed-release tablets in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If diclofenac sodium delayed-release tablets are 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, WARNINGS; Exacerbation of Asthma Related to Aspirin Sensitivity).

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, diclofenac sodium is contraindicated in patients with this form of aspirin sensitivity (see CONTRAINDICATIONS). When diclofenac sodium delayed-release tablets are 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 diclofenac sodium delayed-release tablets at the first appearance of skin rash or any other sign of hypersensitivity. Diclofenac sodium delayed-release tablets are contraindicated in patients with previous serious skin reactions to NSAIDs (see CONTRAINDICATIONS).

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs, such as diclofenac sodium. Some of these events have been fatal or life-threatening. 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. 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. If such signs or symptoms are present, discontinue diclofenac sodium delayed-release tablets and evaluate the patient immediately.

Fetal Toxicity

Premature Closure of Fetal Ductus Arteriosus
Avoid use of NSAIDs, including diclofenac sodium, in pregnant women at about 30-weeks’ gestation and later. NSAIDs, including diclofenac sodium, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age.

Oligohydramnios/Neonatal Renal Impairment

Use of NSAIDs, including diclofenac sodium, at about 20-weeks’ gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. 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. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures, such as exchange transfusion or dialysis were required.

If NSAID treatment is necessary between about 20 weeks and 30-weeks’ gestation, limit diclofenac sodium use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if diclofenac sodium treatment extends beyond 48 hours. Discontinue diclofenac sodium delayed-release tablets if oligohydramnios occurs and follow up according to clinical practice (see PRECAUTIONS; Pregnancy).

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 on erythropoiesis. If a patient treated with diclofenac sodium delayed-release tablets, has any signs or symptoms of anemia, monitor hemoglobin or hematocrit.

NSAIDs, including diclofenac sodium, may increase the risk of bleeding events. Co-morbid conditions, such as coagulation disorders, concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding (see PRECAUTIONS; Drug Interactions).

General

Diclofenac sodium delayed-release tablets 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.

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

Information for Patients

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 diclofenac sodium delayed-release tablets 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 healthcare provider immediately (see WARNING; Cardiovascular Thrombotic Events).

Gastrointestinal Bleeding, Ulceration, and Perforation

Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for the signs and symptoms of GI bleeding (see WARNINGS; Gastrointestinal Bleeding, Ulceration, and Perforation).

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 diclofenac sodium delayed-release tablets and seek immediate medical therapy (see WARNINGS; Hepatotoxicity).

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 WARNING; Heart Failure and Edema).

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 WARNING; Anaphylactic Reactions).

Serious Skin Reactions, Including DRESS

Advise patients to stop diclofenac sodium delayed-release tablets immediately if they develop any type of rash or fever and contact their healthcare provider as soon as possible (see WARNINGS; Serious Skin Reactions).

Female Fertility

Advise females of reproductive potential who desire pregnancy that NSAIDs, including diclofenac sodium, may be associated with a reversible delay in ovulation (see PRECAUTIONS; Carcinogenesis, Mutagenesis, Impairment of Fertility).

Fetal Toxicity

Inform pregnant women to avoid use of diclofenac sodium and other NSAIDs, starting at 30 weeks gestation because of the risk of the premature closure of the fetal ductus arteriosus. If treatment with diclofenac sodium is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours. (see WARNING; Fetal Toxicity, PRECAUTIONS, Pregnancy).

Avoid Concomitant Use of NSAIDs

Inform patients that the concomitant use of diclofenac sodium 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; Gastrointestinal Bleeding, Ulceration, and Perforation 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 diclofenac sodium until they talk to their healthcare provider (see PRECAUTIONS; Drug Interactions).

Masking of Inflammation and Fever

The pharmacological activity of diclofenac sodium 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 (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation, and Hepatotoxicity).

Drug Interactions

See Table 2 for clinically significant drug interactions with diclofenac.

Table 2. Clinically Significant Drug Interactions with Diclofenac

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Long-term carcinogenicity studies in rats given diclofenac sodium up to 2 mg/kg/day (approximately 0.1 times maximum recommended human dose (MRHD) of diclofenac sodium, 200 mg/day, based on body surface area (BSA) comparison ) have revealed no significant increases in tumor incidence. A 2-year carcinogenicity study conducted in mice employing diclofenac sodium at doses up to 0.3 mg/kg/day (approximately 0.007 times the MRHD based on BSA comparison) in males and 1 mg/kg/day (approximately 0.02 times the MRHD based on BSA comparison) in females did not reveal any oncogenic potential.

Mutagenesis

Diclofenac sodium did not show mutagenic activity in in vitropoint mutation assays in mammalian (mouse lymphoma) and microbial (yeast, Ames) test systems and was nonmutagenic in several mammalian in vitroand in vivotests, including dominant lethal and male germinal epithelial chromosomal studies in mice, and nucleus anomaly and chromosomal aberration studies in Chinese hamsters.

Impairment of Fertility

Diclofenac sodium administered to male and female rats at 4 mg/kg/day (approximately 0.2 times the MRHD based on BSA comparison) did not affect fertility.

Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including diclofenac sodium, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including diclofenac sodium, in women who have difficulties conceiving or who are undergoing investigation of infertility.

Pregnancy

Risk Summary

Use of NSAIDs, including diclofenac sodium, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of diclofenac sodium use between about 20 and 30 weeks of gestation, and avoid diclofenac sodium use at about 30 weeks of gestation and later in pregnancy (see WARNINGS; Fetal Toxicity).

Premature Closure of Fetal Ductus Arteriosus

Use of NSAIDs, including diclofenac sodium, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus.

Oligohydramnios/Neonatal Renal Impairment

Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment.

There are no adequate and well-controlled studies of diclofenac sodium in pregnant women.

Data from observational studies regarding potential embryo-fetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive.

In animal reproduction studies, no evidence of teratogenicity was observed in mice, rats, or rabbits given diclofenac during the period of organogenesis at doses up to approximately 0.5, 0.5, and 1 times, respectively, the maximum recommended human dose (MRHD) of diclofenac sodium, 200 mg/day, despite the presence of maternal and fetal toxicity at these doses (see Data).

Based on published animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors, such as diclofenac, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses.

The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Premature Closure of Fetal Ductus Arteriosus:

Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including diclofenac sodium, can cause premature closure of the fetal ductus arteriosus (see WARNINGS; Fetal Toxicity).

Oligohydramnios/Neonatal Renal Impairment:

If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If diclofenac sodium treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue diclofenac sodium and follow up according to clinical practice (see WARNINGS; Fetal Toxicity).

Data

Human Data

Premature Closure of Fetal Ductus Arteriosus:

Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus.

Oligohydramnios/Neonatal Renal Impairment:

Published studies and post-marketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. 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. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis.

Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain.

Animal Data

Reproductive and developmental studies in animals demonstrated that diclofenac sodium administration during organogenesis did not produce teratogenicity despite the induction of maternal toxicity and fetal toxicity in mice at oral doses up to 20 mg/kg/day (approximately 0.5 times the maximum recommended human dose [MRHD] of diclofenac sodium, 200 mg/day, based on body surface area (BSA) comparison), and in rats and rabbits at oral doses up to 10 mg/kg/day (approximately 0.5 and 1 times, respectively, the MRHD based on BSA comparison). In a study in which pregnant rats were orally administered 2 or 4 mg/kg diclofenac (0.1 and 0.2 times the MRHD based on BSA) from Gestation Day 15 through Lactation Day 21, significant maternal toxicity (peritonitis, mortality) was noted. These maternally toxic doses were associated with dystocia, prolonged gestation, reduced fetal weights and growth, and reduced fetal survival. Diclofenac has been shown to cross the placental barrier in mice, rats, and humans.

Labor or Delivery

There are no studies on the effects of diclofenac sodium during labor or delivery. In animal studies, NSAIDS, including diclofenac, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth.

Nursing Mothers

Risk Summary

Based on available data, diclofenac may be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for diclofenac sodium and any potential adverse effects on the breastfed infant from the diclofenac sodium or from the underlying maternal condition.

Data

One woman treated orally with a diclofenac salt, 150 mg/day, had a milk diclofenac level of 100 mcg/L, equivalent to an infant dose of about 0.03 mg/kg/day. Diclofenac was not detectable in breast milk in 12 women using diclofenac (after either 100 mg/day orally for 7 days or a single 50 mg intramuscular dose administered in the immediate postpartum period).

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, start dosing at the low end of the dosing range, and monitor patients for adverse effects (see WARNINGS; Cardiovascular Thrombotic Events, Gastrointestinal Bleeding, Ulceration, and Perforation, Hepatotoxicity, Renal Toxicity and Hyperkalemia, PRECAUTIONS; Laboratory Monitoring).

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 in dose selection, and it may be useful to monitor renal function (see CLINICAL PHARMACOLOGY, ADVERSE REACTIONS).

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• Cardiovascular Thrombotic Events (see WARNINGS)

• GI Bleeding, Ulceration and Perforation (see WARNING)

• Hepatotoxicity (see WARNINGS)

• Hypertension (see WARNINGS)

• Heart Failure and Edema (see WARNINGS)

• Renal Toxicity and Hyperkalemia (see WARNINGS)

• Anaphylactic Reactions (see WARNINGS)

• Serious Skin Reactions (see WARNINGS)

• Hematologic Toxicity (see WARNINGS)

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In patients taking diclofenac sodium delayed-release tablets, or other NSAIDs, the most frequently reported adverse experiences occurring in approximately 1% to 10% of patients are:

Gastrointestinal experiences, 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 experiences reported occasionally include:

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, 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, fulminant hepatitis with and without jaundice, liver failure, liver necrosis, 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

Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression and coma have occurred, but were rare (see WARNINGS; Cardiovascular Thrombotic Events, Gastrointestinal Bleeding, Ulceration, and Perforation, Hypertension, Renal Toxicity and Hyperkalemia).

Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdose (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.

For additional information about overdosage treatment, contact a poison control center (1-800-222-1222).

Carefully consider the potential benefits and risks of diclofenac sodium delayed release tablets and other treatment options before deciding to use diclofenac sodium. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNING; Gastrointestinal Bleeding, Ulceration, and Perforation).

After observing the response to initial therapy with diclofenac sodium, the dose and frequency should be adjusted to suit an individual patient’s needs.

For the relief of osteoarthritis, the recommended dosage is 100 to 150 mg/day in divided doses (50 mg twice a day or three times a day, or 75 mg twice a day).

For the relief of rheumatoid arthritis, the recommended dosage is 150 to 200 mg/day in divided doses (50 mg three times a day. or four times a day, or 75 mg twice a day.).

For the relief of ankylosing spondylitis, the recommended dosage is 100 to 125 mg/day, administered as 25 mg four times a day, with an extra 25-mg dose at bedtime if necessary.

Different formulations of diclofenac [diclofenac sodium delayed-release tablets; diclofenac sodium extended-release tablets); diclofenac potassium immediate-release tablets] are not necessarily bioequivalent even if the milligram strength is the same.

Diclofenac sodium delayed-release tablets, USP are supplied as follows:

25 mg:

Round, light brown to brown, enteric-coated tablets, imprinted with ‘Λ10’ in black ink on one side and plain on other side.

Bottles of 30 tablets NDC 72888-109-30

Bottles of 60 tablets NDC 72888-109-60

Bottles of 100 tablets NDC 72888-109-01

Bottles of 500 tablets NDC 72888-109-05

Bottles of 1000 tablets NDC 72888-109-00

50 mg:

Round, light brown to brown, enteric-coated tablets, imprinted with ‘Λ11’ in black ink on one side and plain on other side.

Bottles of 30 tablets NDC 72888-110-30

Bottles of 60 tablets NDC 72888-110-60

Bottles of 100 tablets NDC 72888-110-01

Bottles of 500 tablets NDC 72888-110-05

Bottles of 1000 tablets NDC 72888-110-00

75 mg:

Round, light brown to brown, enteric-coated tablets, imprinted with ‘Λ12’ in black ink on one side and plain on other side.

Bottles of 30 tablets NDC 72888-111-30

Bottles of 60 tablets NDC 72888-111-60

Bottles of 100 tablets NDC 72888-111-01

Bottles of 500 tablets NDC 72888-111-05

Bottles of 1000 tablets NDC 72888-111-00

Store at room temperature 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature].

Dispense in tight container(USP). Protect from moisture.

Dispense with Medication Guide available at:

www.advagenpharma.com/medguide/diclofenacsodiumdelayedreleasetablets

Distributed By:
Advagen Pharma Ltd.,
666 Plainsboro Road,
Suite 605, Plainsboro,
NJ 08536, USA.

Manufactured by:
Rubicon Research Private Limited
Ambernath, Dist: Thane, 421506
India.
Rev. 01, 08/2023

Medication Guide

Diclofenac Sodium (dye kloe’ fen ak soe’ dee um)

Delayed-Release Tablets, USP

25 mg, 50 mg and 75 mg

What is the most important information I should know about medicines called Non-Steroidal Anti- Inflammatory Drugs (NSAIDs)?

NSAIDs can cause serious side effects, including:

• Increased risk of a heart attack or stroke that can lead to death.This risk may happen early in treatment and may increase:

o with increasing doses of NSAIDs

o with longer use of NSAIDs

Do not take NSAIDs right before or after a heart surgery called a “coronary artery bypass graft (CABG).” Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack.

• Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines:

o any time during use

o without warning symptoms

o that may cause death

The risk of getting an ulcer or bleeding increases with:

o past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs

o taking medicines called “corticosteroids”, “anticoagulants”, “SSRIs”, or “SNRIs”

o increasing doses of NSAIDs o older age

o longer use of NSAIDs o poor health

o smoking o advanced liver disease

o drinking alcohol o bleeding problems

NSAIDs should only be used:

o exactly as prescribed

o at the lowest dose possible for your treatment

o for the shortest time needed

What are NSAIDs?

NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps, and other types of short-term pain.

Who should not take NSAIDs?

Do not take NSAIDs:

• if you had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs.

• right before or after heart bypass surgery.

Before taking NSAIDs, tell your healthcare provider about all of your medical conditions, including if you:

• have liver or kidney problems

• have high blood pressure

• have asthma

• are pregnant or plan to become pregnant. Taking NSAIDs at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to take NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. You should not take NSAIDs after about 30 weeks of pregnancy.

• are breastfeeding or plan to breastfeed.

Tell your healthcare provider about all of the medicines you take, including prescription or over the-counter medicines, vitamins, or herbal supplements. NSAIDs and some other medicines can interact with each other and cause serious side effects. Do not start taking any new medicine without talking to your healthcare provider first.

What are the possible side effects of NSAIDs?

NSAIDs can cause serious side effects, including:

See "What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)?"

• new or worse high blood pressure

• heart failure

• liver problems, including liver failure

• kidney problems, including kidney failure

• low red blood cells (anemia)

• life-threatening skin reactions

• life-threatening allergic reactions

Other side effects of NSAIDs include:stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness

Get emergency help right away if you have any of the following symptoms:

• shortness of breath or trouble breathing • slurred speech

• chest pain • swelling of the face or throat

• weakness in one part or side of your body

Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms:

• nausea • vomit blood

• more tired or weaker than usual • there is blood in your bowel movement or it is black and sticky like tar

• diarrhea • unusual weight gain

• itching • skin rash or blisters with fever

• your skin or eyes look yellow • swelling of the arms and legs, hands and feet

• indigestion or stomach pain

• flu-like symptoms

If you take too much of your NSAID, call your healthcare provider or get medical help right away.

These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Other information about NSAIDs.

• Aspirin is an NSAID medicine but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines.

• Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days.

General information about the safe and effective use of NSAIDs.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them.

If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals.

For more information, contact Advagen Pharma Ltd, at 866-488-0312.

Distributed by:

Advagen Pharma Ltd.,

666 Plainsboro Road,

Suite 605, Plainsboro,

NJ 08536, USA.

Manufactured by:

Rubicon Research Private Limited

Ambernath, Dist: Thane, 421506

India.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Revised: August 2023

Diclofenac Sodium DR Tablets USP 25mg - NDC 72888-109-30 - 30 Tablets Label

Diclofenac Sodium DR Tablets USP 25mg - NDC 72888-109-60 - 60 Tablets Label

Diclofenac Sodium DR Tablets USP 25mg - NDC 72888-109-01 - 100 Tablets Label

Diclofenac Sodium DR Tablets USP 25mg - NDC 72888-109-05 - 500 Tablets Label

Diclofenac Sodium DR Tablets USP 25mg - NDC 72888-109-00 - 1000 Tablets Label

Diclofenac Sodium DR Tablets USP 50mg - NDC 72888-110-30 - 30 Tablets Label

Diclofenac Sodium DR Tablets USP 50mg - NDC 72888-110-60 - 60 Tablets Label

Diclofenac Sodium DR Tablets USP 50mg - NDC 72888-110-01 - 100 Tablets Label

Diclofenac Sodium DR Tablets USP 50mg - NDC 72888-110-05 - 500 Tablets Label

Diclofenac Sodium DR Tablets USP 50mg - NDC 72888-110-00 - 1000 Tablets Label

Diclofenac Sodium DR Tablets USP 75mg - NDC 72888-111-30 - 30 Tablets Label

Diclofenac Sodium DR Tablets USP 75mg - NDC 72888-111-60 - 60 Tablets Label

Diclofenac Sodium DR Tablets USP 75mg - NDC 72888-111-01 - 100 Tablets Label

Diclofenac Sodium DR Tablets USP 75mg - NDC 72888-111-05 - 500 Tablets Label

Diclofenac Sodium DR Tablets USP 75mg - NDC 72888-111-00 - 1000 Tablets Label