DICLOFENAC POTASSIUM TABLETS clinical aspects

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 potassium 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 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).
1 Throughout this package insert, the term NSAID refers to a non-aspirin non-steroidal anti-inflammatory drug.
DESCRIPTION
Diclofenac potassium is a benzeneacetic acid derivative. Diclofenac potassium tablets, 50 mg are available as orange, film-coated tablets for oral administration. The chemical name is 2-[(2,6-dichlorophenyl)amino]benzeneacetic acid, monopotassium salt. The structural formula is:


C14H10Cl2KNO2 M.W. 334.25

Diclofenac potassium is a faintly yellowish white to light beige, virtually odorless, slightly hygroscopic crystalline powder. It is freely soluble in methanol, soluble in ethanol and 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. It has a single dissociation constant (pKa) of 4.0 ± 0.2 at 25°C in water.

Each tablet, for oral administration, contains 50 mg of diclofenac potassium. In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, corn starch, FD&C Blue No. 2, FD&C Red No. 40, FD&C Yellow No. 6, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol 4000, povidone, sodium starch glycolate, titanium dioxide, and tricalcium phosphate.

CLINICAL PHARMACOLOGY
Pharmacodynamics
Diclofenac potassium tablets are a non-steroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of diclofenac potassium tablets, like that of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition.

Pharmacokinetics
Special Populations
INDICATIONS AND USAGE
Carefully consider the potential benefits and risks of diclofenac potassium tablets and other treatment options before deciding to use diclofenac potassium tablets. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS).

Diclofenac potassium tablets are indicated:

For treatment of primary dysmenorrhea
For relief of mild to moderate pain
For relief of the signs and symptoms of osteoarthritis
For relief of the signs and symptoms of rheumatoid arthritis
CONTRAINDICATIONS
Diclofenac potassium tablets are contraindicated in patients with known hypersensitivity to diclofenac. Diclofenac potassium 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 potassium tablets are contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).

WARNINGS
Cardiovascular Effects
Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation
NSAIDs, including diclofenac potassium 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 to 6 months, and in about 2 to 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 potassium 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 non-steroidal 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 non-steroidal anti-inflammatory drug 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 in patients with advanced renal disease. Therefore, treatment with diclofenac potassium tablets is not recommended in these patients with advanced renal disease. If diclofenac potassium tablet 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 potassium tablets. Diclofenac potassium 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 potassium 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 potassium tablets should be avoided because they may cause premature closure of the ductus arteriosus.

PRECAUTIONS
General
Diclofenac potassium 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 potassium 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 potassium 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 potassium 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% to 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 potassium tablets. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), diclofenac potassium tablets should be discontinued.

Hematological Effects
Anemia is sometimes seen in patients receiving NSAIDs, including diclofenac potassium tablets. This may be due to fluid retention, occult or gross GI loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including diclofenac potassium 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 potassium 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 non-steroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, diclofenac potassium tablets should not be administered to patients with this form of aspirin sensitivity and should be used with caution in all patients with preexisting asthma.

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.

Diclofenac potassium 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 signs or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS, Cardiovascular Effects).
Diclofenac potassium 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 signs or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS, Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation).
Diclofenac potassium tablets, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalization and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and bulers, 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.
Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians.
Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy.
Patients should be informed of the signs of 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).
In late pregnancy, as with other NSAIDs, diclofenac potassium tablets should be avoided because they 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 potassium 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 potassium tablets should be discontinued.

Drug Interactions
Pregnancy
Teratogenic Effects
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 potassium 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, 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).

ADVERSE REACTIONS
In 718 patients treated for shorter periods, i.e., 2 weeks or less, with diclofenac potassium tablets, adverse reactions were reported one-half to one-tenth as frequently as by patients treated for longer periods. In a 6 month, double-blind trial comparing diclofenac potassium tablets (N = 196) versus diclofenac sodium delayed-release tablets) (N = 197) versus ibuprofen (N = 197), adverse reactions were similar in nature and frequency.

In patients taking diclofenac potassium 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.

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
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 an 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 potassium tablets and other treatment options before deciding to use diclofenac potassium 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 potassium tablets, the dose and frequency should be adjusted to suit an individual patient's needs.

For treatment of pain or primary dysmenorrhea the recommended dosage is 50 mg t.i.d. With experience, physicians may find that in some patients an initial dose of 100 mg of diclofenac potassium tablets, followed by 50 mg doses, will provide better relief.

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

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

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

HOW SUPPLIED
Diclofenac potassium tablets, 50 mg are available as orange, round, unscored, biconvex, film- coated tablets debossed with the numbers “93” and “948” on one face of the tablet and plain on the other, in bottles of 100 and 500.

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Protect from moisture.

Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).

Medication Guide for Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
(See the end of this Medication Guide for a ul 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 of 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 ul 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: Other side effects include:
• heart attack • stomach pain
• stroke • constipation
• 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 liver failure
• 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
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 bulers 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.
NSAID medicines that need a prescription

Generic Name Tradename
Celecoxib Celebrex
Diclofenac Cataflam, Voltaren, Arthrotec (combined with misoprostol)
Diflunisal Dolobid
Etodolac Lodine, Lodine XL
Fenoprofen Nalfon, Nalfon 200
Flurbiprofen Ansaid
Ibuprofen Motrin, Tab-Profen, Vicoprofen (combined with hydrocodone), Combunox (combined with oxycodone)
Indomethacin Indocin, Indocin SR, Indo-Lemmon, Indomethagan
Ketoprofen Oruvail
Ketorolac Toradol
Mefenamic Acid Ponstel
Meloxicam Mobic
Nabumetone Relafen
Naproxen Naprosyn, Anaprox, Anaprox DS, EC-Naproxyn, Naprelan, Naprapac (copackaged with lansoprazole)
Oxaprozin Daypro
Piroxicam Feldene
Sulindac Clinoril
Tolmetin Tolectin, Tolectin DS, Tolectin 600

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