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DICLOFENAC SODIUM DELAYED RELEASE
diclofenac sodium tablet, delayed release
Diclofenac sodium delayed-release is a benzene-acetic acid derivative. The chemical name is 2-[(2,6-dichlorophenyl)amino] benzeneacetic acid, monosodium salt. The molecular weight is 318.13. Its molecular formula is C14H10Cl2NNaO2, and it has the following structural formula
Each enteric-coated tablet for oral administration contains 50 mg or 75 mg of diclofenac sodium. In addition, each tablet contains the following inactive ingredients: aluminum hydrate, colloidal silicon dioxide, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, polyvinyl acetate phthalate, propylene glycol, silica, sodium alginate, sodium starch glycolate (Type A), stearic acid, synthetic black iron oxide, talc, and titanium dioxide.
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, like that of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition.
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 (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%.
Table 1. Pharmacokinetic Parameters for DiclofenacPK Parameter Normal PK Parameter Normal Healthy Adults (20-48 yrs.)
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 ?g/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.
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.
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.
Pediatric: The pharmacokinetics of diclofenac sodium delayed-release 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 elimination, so patients with hepatic disease may require reduced doses of diclofenac sodium delayed-release 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 AND USAGE
Carefully consider the potential benefits and risks of diclofenac sodium delayed-release and other treatment options before deciding to use diclofenac sodium delayed-release. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS).
Diclofenac sodium delayed-release tablets are indicated:
Diclofenac sodium delayed-release tablets are contraindicated in patients with known hypersensitivity to diclofenac. Diclofenac sodium delayed-release 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 is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).
Cardiovascular Thrombotic Events
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, GI Effects).
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).
Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy.
Fluid retention and edema have been observed in some patients taking NSAIDs. Diclofenac sodium delayed-release 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, 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.
Emergency help should be sought in cases where an anaphylactoid reaction occurs.
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.
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.
pharmacological activity of diclofenac sodium delayed-release in
reducing fever and inflammation may diminish the utility of these
diagnostic signs in detecting complications of presumed noninfectious,
elevations of one or more liver tests may occur in up to 15% of
patients taking NSAIDs including diclofenac sodium delayed-release.
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,
periodic monitoring of transaminases is recommende. (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
If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), diclofenac sodium delayed-release should be discontinued.
is sometimes seen in patients receiving NSAIDs, including diclofenac
sodium delayed-release. 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, should have their hemoglobin or
hematocrit checked if they exhibit any signs or symptoms of anemia.
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 should not be administered to patients with this
form of aspirin sensitivity and should be used with caution in patients
with preexisting asthma.
Information for Patients
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, 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 should be discontinued.
Aspirin:When diclofenac sodium delayed-release is 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, like other NSAIDs, may affect renal prostaglandins and increase the toxicity of certain drugs. Therefore, concomitant therapy with diclofenac sodium delayed-release may increase cyclosporine’s nephrotoxicity.
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 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.
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 on labor and delivery in pregnant women are unknown.
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, 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.
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:
Abnormal renal function, anemia, dizziness, edema, elevated liver enzymes, headaches, increased bleeding time, pruritus, rashes and tinnitus.
Additional adverse experiences reported occasionally include:
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:
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
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 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. 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 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.
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Med-Health Pharma, LLC
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Revised — January 2008
MHP LB-60006 rev00
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:
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:
The chance of a person getting an ulcer or bleeding increases with:
NSAID medicines should only be used:
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:
Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)?
Do not take an NSAID medicine:
Tell your healthcare provider:
Serious side effects include: Other side effects include:
·heart attack ·stomach pain
·high blood pressure ·diarrhea
·heart failure from body swelling (fluid retention) ·gas
·kidney problems including kidney failure ·heartburn
·bleeding and ulcers in the stomach and intestine ·nausea
·low red blood cells (anemia) ·vomiting
·life-threatening skin reactions ·dizziness
·life-threatening allergic reactions
·liver problems including
·asthma attacks in people who have asthma
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 your NSAID medicine and call your healthcare provider right away if you have any
of the following symptoms:
·nausea ·there is blood in your bowel movement or it is
·more tired or weaker than usual black and sticky like tar
·itching ·skin rash or blisters with fever
·your skin or eyes look yellow ·unusual weight gain
·stomach pain ·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.
Call your doctor for medical advice about side effects. You may report side effects to FDA at
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.
NSAID medicines that need a prescription
Generic Name Tradename
Diclofenac Cataflam, Voltaren, Arthrotec (combined with misoprostol)
Etodolac Lodine, Lodine XL
Fenoprofen Nalfon, Nalfon 200
Ibuprofen Motrin, Tab-Profen, Vicoprofen* (combined with hydrocodone),Combunox (combined with oxycodone)
Indomethacin Indocin, Indocin SR, Indo-Lemmon, Indomethagan
Mefenamic Acid Ponstel
Naproxen Naprosyn, Anaprox, Anaprox DS, EC-Naproxyn, Naprelan,
Naprapac (copackaged with lansoprazole)
Tolmetin Tolectin, Tolectin DS, Tolectin 600
*Vicoprofen contains the same dose of ibuprofen as over-the-counter (OTC) NSAIDs, and is usually used for less than 10 days to treat pain. The OTC label warns that long term continuous use may increase the risk of heart attack or stroke.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Revised: 03/2008 Distributed by: Med-Health Pharma, LLC
MHP LB-60006 rev00
Revised: 01/2011 Med Health Pharma, LLC
Reproduced with permission of U.S. National Library of Medicine
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