DICLOFENAC SODIUM tablet, delayed release

Drug Details [pdf]

DESCRIPTION

DESCRIPTION
Diclofenac sodium is a benzeneacetic acid derivative, designated chemically as 2-[(2,6-dichlorophenyl)amino] benzeneacetic acid, monosodium salt. The structural formula is:

soluble in methanol, soluble in ethanol, sparingly soluble in water and practically insoluble in chloroform and in dilute acid. The n-octanol/water partition coefficient is 13.4 at pH 7.4 and 1545 at pH 5.2. Diclofenac sodium has a dissociation constant (pKa) of 4.0 ± 0.2 at 25°C in water.

Each enteric-coated tablet for oral administration contains 25 mg, 50 mg, or 75 mg of diclofenac sodium. In addition, each tablet contains the following inactive ingredients. Inactive ingredients: Black iron oxide, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose (monohydrate), magnesium stearate, methacrylic acid copolymer, microcrystalline cellulose, polyethylene glycol, povidone, red iron oxide, and titanium dioxide. The 25 mg also contains: D and C Yellow #10 Aluminum Lake and pharmaceutical glaze shellac. The 50 mg also contains: Pharmaceutical glaze shellac and yellow iron oxide. The 75 mg also contains: carnauba wax, glycerol monostearate, shellac, and yellow iron oxide.
CLINICAL PHARMACOLOGY

CLINICAL PHARMACOLOGY Pharmacodynamics
Diclofenac sodium delayed-release tablets are a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of diclofenac sodium delayed-release tablets, like that of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition.
Pharmacokinetics Absorption
Diclofenac is 100% absorbed after oral administration compared to IV administration as measured by urine recovery. However, due to first-pass metabolism, only about 50% of the absorbed dose is systemically available. 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 (0.15-105 µg/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.
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. 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. However, diclofenac metabolites undergo further glucuronidation and sulfation followed by biliary excretion.

One diclofenac metabolite 4’-hydroxy-diclofenac has very weak pharmacologic activity.
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 delayed-release tablets has not been investigated in pediatric patients.
Race
Pharmacokinetics differences due to race have not been identified.
Hepatic Insufficiency
Hepatic metabolism accounts for almost 100% of diclofenac sodium delayed-release tablets elimination, so patients with hepatic disease may require reduced doses of diclofenac sodium delayed-release tablets compared to patients with normal hepatic function.
Renal Insufficiency
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 60-90, 30-60, and less than 30 mL/min; N=6 in each group), AUC values and elimination rate were comparable to those in healthy subjects.
INDICATIONS & USAGE
INDICATIONS AND USAGE
Carefully consider the potential benefits and risks of diclofenac sodium delayed-release tablets and other treatment options before deciding to use diclofenac sodium delayed-release tablets. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS).

Diclofenac sodium delayed-release tablets, are indicated:
- For relief of signs and symptoms of osteoarthritis
- For relief of signs and symptoms of rheumatoid arthritis
- For acute or long-term use in the relief of signs and symptoms of ankylosing spondylitis
CONTRAINDICATIONS

CONTRAINDICATIONS
Diclofenac sodium delayed-release tablets, are contraindicated in patients with known hypersensitivity to diclofenac.

Diclofenac sodium delayed-release tablets should not be given to patients who have experienced asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients (see WARNINGS: Anaphylactoid Reactions and PRECAUTIONS: Preexisting Asthma).

Diclofenac sodium delayed-release tablets are contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).
WARNINGS

WARNINGS CARDIOVASCULAR EFFECTS Cardiovascular Thrombotic Events
Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, 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 (see WARNINGS: Gastrointestinal (GI) Effects).

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 can lead to onset of new hypertension or worsening of pre-existing 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 diclofenac sodium delayed-release tablets, 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.
Congestive Heart Failure and Edema Renal Effects
Fluid retention and edema have been observed in some patients taking NSAIDs. Diclofenac sodium delayed-release tablets should be used with caution in patients with fluid retention or heart failure.
Gastrointestinal (GI) Effects Risk of GI Ulceration, Bleeding, and Perforation
NSAIDs, including diclofenac sodium delayed-release tablets, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. These trends continue with longer duration of use, 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 should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population.

To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered.
Renal Effects
Caution should be used when initiating treatment with diclofenac sodium delayed-release tablets in patients with considerable dehydration.

Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-inflammatory drug 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 ACE inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.
Advanced Renal Disease
No information is available from controlled clinical studies regarding the use of diclofenac sodium delayed-release tablets in patients with advanced renal disease. Therefore, treatment with diclofenac sodium delayed-release tablets are not recommended in these patients with advanced renal disease. If diclofenac sodium delayed-release tablets therapy must be initiated, close monitoring of the patient’s renal function is advisable.
Anaphylactoid Reactions
As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to diclofenac sodium delayed-release tablets. Diclofenac sodium delayed-release tablets 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 and PRECAUTIONS: Preexisting Asthma.) Emergency help should be sought in cases where an anaphylactoid reaction occurs.
Skin Reactions
NSAIDs, including diclofenac sodium delayed-release tablets, can cause serious skin adverse events 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.
Pregnancy
In late pregnancy, as with other NSAIDs, diclofenac sodium delayed-release tablets should be avoided because it may cause premature closure of the ductus arteriosus.
PRECAUTIONS

PRECAUTIONS 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.

The pharmacological activity of diclofenac sodium delayed-release tablets in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.
Hepatic Effects
Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including diclofenac sodium delayed-release tablets. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Based on this experience, in patients on chronic treatment with diclofenac sodium delayed-release tablets, periodic monitoring of transaminases is recommended (see PRECAUTIONS: Laboratory Tests). Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 2%-4% of patients, including marked elevations (eight or more times the upper limit of normal) in about 1% of patients in clinical trials with diclofenac. In addition, rare cases of severe hepatic reactions, including jaundice and fatal 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 in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with diclofenac sodium delayed-release tablets. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), diclofenac sodium delayed-release tablets should be discontinued.
Hematological Effects
Anemia is sometimes seen in patients receiving NSAIDs, including diclofenac sodium delayed-release 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 diclofenac sodium delayed-release tablets, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia.

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 diclofenac sodium delayed-release tablets who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.
Preexisting 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 other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, diclofenac sodium delayed-release tablets should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.
ADVERSE REACTIONS

ADVERSE REACTIONS
In patients taking diclofenac sodium delayed-release tablets, or other NSAIDs, the most frequently reported adverse experiences occurring in approximately 1%-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, liver failure, pancreatitis
Hemic and Lymphatic System
agranulocytosis, hemolytic anemia, aplastic anemia, lymphadenopathy, pancytopenia
Metabolic and Nutritional
hyperglycemia
Nervous System
convulsions, coma, hallucinations, meningitis
Respiratory System
respiratory depression, pneumonia
Skin and Appendages
angioedema, toxic epidermal necrolysis, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, urticaria
Special Senses
conjunctivitis, hearing impairment
OVERDOSAGE

OVERDOSAGE
Symptoms following acute NSAID overdoses are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression and coma may occur, but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose.

Patients should be managed by symptomatic and supportive care following a NSAID overdose. There are no specific antidotes. Emesis and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children) and/or osmotic cathartic may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large overdose (5 to 10 times the usual dose). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.
DOSAGE & ADMINISTRATION

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

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

For the relief of osteoarthritis, the recommended dosage is 100-150 mg/day in divided doses (50 mg b.i.d. or t.i.d., or 75 mg b.i.d.).

For the relief of rheumatoid arthritis, the recommended dosage is 150-200 mg/day in divided doses (50 mg t.i.d. or q.i.d., or 75 mg b.i.d.).

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

Different formulations of diclofenac (diclofenac sodium enteric-coated tablets; diclofenac sodium extended-release tablets; diclofenac potassium immediate-release tablets) are not necessarily bioequivalent even if the milligram strength is the same.
HOW SUPPLIED

HOW SUPPLIED
Diclofenac sodium delayed-release tablets, USP, for oral administration, are available as:

25 mg: round, yellow, enteric-coated tablets imprinted GG 737 on one side in black ink and plain on the reverse side are supplied as:

NDC: 0781-1785-60 bottles of 60 tablets

NDC: 0781-1785-01 bottles of 100 tablets

NDC: 0781-1785-10 bottles of 1000 tablets

NDC: 0781-1785-13 unit dose packages of 100 tablets

50 mg: round, brown, enteric-coated tablets imprinted GG 738 on one side in black ink and plain on the reverse side are supplied as:

NDC: 0781-1787-60 bottles of 60 tablets

NDC: 0781-1787-01 bottles of 100 tablets

NDC: 0781-1787-10 bottles of 1000 tablets

NDC: 0781-1787-13 unit dose packages of 100 tablets

75 mg: round, pink, enteric-coated tablets imprinted GG 739 on one side in black ink and plain on the reverse side are supplied as:

NDC: 0781-1789-60 bottles of 60 tablets

NDC: 0781-1789-01 bottles of 100 tablets

NDC: 0781-1789-10 bottles of 1000 tablets

Store at 20°-25°C (68°-77°F) (see USP Controlled Room Temperature). Protect from moisture.

Dispense in a tight, light-resistant container.
INFORMATION FOR PATIENTS
Information for Patients
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 that accompanies each prescription dispensed.
1. Diclofenac sodium delayed-release tablets, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS: CARDIOVASCULAR EFFECTS).
2. Diclofenac sodium delayed-release tablets, like other NSAIDs, can cause GI discomfort and, rarely, more serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS: Gastrointestinal (GI) Effects: Risk of GI Ulceration, Bleeding, and Perforation).
3. Diclofenac sodium delayed-release tablets, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible.
4. Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians.
5. 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.
6. Patients should be informed of the signs of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS).
7. In late pregnancy, as with other NSAIDs, diclofenac sodium delayed-release tablets should be avoided because it may cause premature closure of the ductus arteriosus.
Laboratory Tests
Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. In patients on long-term treatment with NSAIDs, including diclofenac sodium delayed-release tablets, the CBC and a chemistry profile (including transaminase levels) should be checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, diclofenac sodium delayed-release tablets should be discontinued.
Drug InteractionsAspirin
When diclofenac sodium delayed-release tablets are administered with aspirin, its protein binding is reduced. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of diclofenac and aspirin is not generally recommended because of the potential of increased adverse effects.
Methotrexate
NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate.
Cyclosporine
Diclofenac sodium delayed-release tablets, like other NSAIDs, may affect renal prostaglandins and increase the toxicity of certain drugs. Therefore, concomitant therapy with diclofenac sodium delayed-release tablets may increase cyclosporine’s nephrotoxicity. Caution should be used when diclofenac sodium delayed-release tablets are administered concomitantly with cyclosporine.
ACE-inhibitors
Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors.
Furosemide
Clinical studies, as well as post-marketing observations, have shown that diclofenac sodium delayed-release tablets can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see WARNINGS: Renal Effects), as well as to assure diuretic efficacy.
Lithium
NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity.
Warfarin
The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone.
PregnancyTeratogenic EffectsPregnancy Category C
Reproductive studies conducted in rats and rabbits have not demonstrated evidence of developmental abnormalities. However, animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies in pregnant women.
Nonteratogenic Effects
Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided.
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 diclofenac sodium delayed-release tablets on labor and delivery in pregnant women are unknown.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from diclofenac sodium delayed-release tablets, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
As with any NSAIDs, caution should be exercised in treating the elderly (65 years and older).
BOXED WARNING (What is this?)
Cardiovascular Risk
- NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk (see WARNINGS).
- Diclofenac sodium delayed-release tablets are contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).
Gastrointestinal Risk
- NSAIDs cause an increased risk of serious gastrointestinal adverse events including inflammation, bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events (see WARNINGS).

MEDICATION GUIDE

DICLOFENAC SODIUM - diclofenac sodium tablet
Sandoz Inc.

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Diclofenac Sodium Delayed-release Tablets, USP MEDICATION GUIDE for Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

(See the end of this Medication Guide for a list of prescription NSAID medicines.)

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

NSAID medicines may increase the chance of a heart attack or stroke that can lead to death. This chance increases:

with longer use of NSAID medicines
in people who have heart disease

NSAID medicines should never be used right before or after a heart surgery called a “coronary artery bypass graft (CABG).”

NSAID medicines can cause ulcers and bleeding in the stomach and intestines at any time during treatment. Ulcers and bleeding:

can happen without warning symptoms
may cause death

The chance of a person getting an ulcer or bleeding increases with:

taking medicines called “corticosteroids” and “anticoagulants”
longer use
smoking
drinking alcohol
older age
having poor health

NSAID medicines should only be used:

exactly as prescribed
at the lowest dose possible for your treatment
for the shortest time needed

What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?

NSAID medicines 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 a Non-Steroidal Anti-Inflammatory Drug (NSAID)?

Do not take an NSAID medicine:

if you had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAID medicine
for pain right before or after heart bypass surgery

Tell your healthcare provider:

about all your medical conditions.
about all of the medicines you take. NSAIDs and some other medicines can interact with each other and cause serious side effects. Keep a list of your medicines to show to your healthcare provider and pharmacist.
if you are pregnant. NSAID medicines should not be used by pregnant women late in their pregnancy.
if you are breastfeeding. Talk to your doctor.

What are the possible side effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?

Serious side effects include:

heart attack
stroke
high blood pressure
heart failure from body swelling (fluid retention)
kidney problems including kidney failure
bleeding and ulcers in the stomach and intestine
low red blood cells (anemia)
life-threatening skin reactions
life-threatening allergic reactions
liver problems including liver failure
asthma attacks in people who have asthma

Other side effects include:

stomach
pain
constipation
diarrhea
gas
heartburn
nausea
vomiting
dizziness

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

shortness of breath or trouble breathing
chest pain
weakness in one part or side of your body
slurred speech
swelling of the face or throat

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

nausea
more tired or weaker than usual
itching
your skin or eyes look yellow
stomach pain
flu-like symptoms
vomit blood
there is blood in your bowel movement or it is black and sticky like tar
unusual weight gain
skin rash or blisters with fever
swelling of the arms and legs, hands and feet

These are not all the side effects with NSAID medicines. Talk to your healthcare provider or pharmacist for more information about NSAID medicines.

Other information about Non-Steroidal Anti-Inflammatory Drugs (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 of these NSAID medicines 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.

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

07-2007

7365

Sandoz Inc.

Princeton, NJ 08540

Revised: 01/2008Sandoz Inc.

PRINCIPAL DISPLAY PANEL

Label Image

INGREDIENTS AND APPEARANCE

DICLOFENAC SODIUM
diclofenac sodium tablet, delayed release

Product Information
Product Type	HUMAN PRESCRIPTION DRUG	Item Code (Source)	NDC: 16590-074(NDC: 0781-1787)
Route of Administration	ORAL

Ingredient Name	Basis of Strength	Strength
Active Ingredient/Active Moiety
Diclofenac Sodium (UNII: QTG126297Q) (diclofenac - UNII:144O8QL0L1)	Diclofenac Sodium	50 mg

Product Characteristics
Color	brown	Score	2 pieces
Shape	ROUND	Size	10mm
Flavor		Imprint Code	GG;738
Contains

#	Item Code	Package Description
Packaging
1	NDC: 16590-074-20	20 in 1 BOTTLE
2	NDC: 16590-074-30	30 in 1 BOTTLE
3	NDC: 16590-074-60	60 in 1 BOTTLE
4	NDC: 16590-074-90	90 in 1 BOTTLE

Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
Marketing Information
ANDA	ANDA074376	09/28/1995

Labeler - Stat Rx USA (786036330)

DICLOFENAC SODIUM tablet, delayed release

Diclofenac Sodium by

Drug Labeling and Warnings

Drug Details [pdf]