Diclofenac Potassium 50 MG Oral Tablet
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 , GI Effects ).
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 (see CONTRAINDICATIONS ).
Hypertension NSAIDs can lead to onset of new hypertension or worsening of preexisting 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 potassium 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 Fluid retention and edema have been observed in some patients taking NSAIDs.
Diclofenac potassium 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 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 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 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.
Hepatic Effects Elevations of one or more liver tests may occur during therapy with diclofenac potassium.
These laboratory abnormalities may progress, may remain unchanged, or may be transient with continued therapy.
Borderline elevations (i.e., less than 3 times the ULN [ULN = the upper limit of the normal range]) or greater elevations of transaminases occurred in about 15% of diclofenac-treated patients.
Of the markers of hepatic function, ALT (SGPT) is recommended for the monitoring of liver injury.
In clinical trials, meaningful elevations (i.e., more than 3 times the ULN) of AST (GOT) (ALT was not measured in all studies) occurred in about 2% of approximately 5,700 patients at some time during diclofenac treatment.
In a large, open-label, controlled trial of 3,700 patients treated for 2 to 6 months, patients were monitored first at 8 weeks and 1,200 patients were monitored again at 24 weeks.
Meaningful elevations of ALT and/or AST occurred in about 4% of patients and included marked elevations (i.e., more than 8 times the ULN) in about 1% of the 3,700 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 (> 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.
Physicians should measure transaminases 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 potassium should be discontinued immediately.
To minimize the possibility that hepatic injury will become severe between transaminase measurements, physicians should 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), and the appropriate action patients should take if these signs and symptoms appear.
To minimize the potential risk for an adverse liver related event in patients treated with diclofenac potassium, the lowest effective dose should be used for the shortest duration possible.
Caution should be exercised in prescribing diclofenac potassium with concomitant drugs that are known to be potentially hepatotoxic (e.g., antibiotics, anti-epileptics).
Anaphylactic Reactions As with other NSAIDs, anaphylactic reactions may occur both in patients with the aspirin triad and in patients without known sensitivity to NSAIDs or 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 ).
Anaphylaxis-type reactions have been reported with NSAID products, including with diclofenac products, such as diclofenac potassium tablets.
Emergency help should be sought in cases where an anaphylactic 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.
DRUG INTERACTIONS
Drug Interactions Aspirin: When diclofenac 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 potassium tablets, like other NSAIDs, may affect renal prostaglandins and increase the toxicity of certain drugs.
Therefore, concomitant therapy with diclofenac potassium tablets may increase cyclosporine’s nephrotoxicity.
Caution should be used when diclofenac potassium 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 postmarketing observations, have shown that diclofenac 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.
CYP2C9 Inhibitors or Inducers: Diclofenac is metabolized by cytochrome P450 enzymes, predominantly by CYP2C9.
Coadministration of diclofenac with CYP2C9 inhibitors (e.g., voriconazole) may enhance the exposure and toxicity of diclofenac whereas coadministration with CYP2C9 inducers (e.g., rifampin) may lead to compromised efficacy of diclofenac.
Use caution when dosing diclofenac with CYP2C9 inhibitors or inducers, a dosage adjustment may be warranted (see CLINICAL PHARMACOLOGY , Pharmacokinetics , Drug Interactions ).
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.
DESCRIPTION
Diclofenac potassium tablets USP are a benzeneacetic acid derivative.
Diclofenac potassium tablets USP, 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: C 14 H 10 Cl 2 KNO 2 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.
diclofenac potassium structural formula
HOW SUPPLIED
Diclofenac potassium tablets USP, 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).
Manufactured In Israel By: TEVA PHARMACEUTICAL IND.
LTD.
Jerusalem, 91010, Israel Manufactured For: TEVA PHARMACEUTICALS USA Sellersville, PA 18960 Rev.
J 3/2011
GERIATRIC USE
Geriatric Use As with any NSAIDs, caution should be exercised in treating the elderly (65 years and older).
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
PEDIATRIC USE
Pediatric Use Safety and effectiveness in pediatric patients have not been established.
PREGNANCY
Pregnancy Teratogenic Effects Pregnancy 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 non-steroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided.
NUSRING MOTHERS
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.
BOXED WARNING
CARDIOVASCULAR RISK NSAIDs 1 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 perioperative 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 ).
1 Throughout this package insert, the term NSAID refers to a non-aspirin non-steroidal anti-inflammatory drug.
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.
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 sign 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 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 ).
Diclofenac potassium 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.
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 (see WARNINGS , Hepatic Effects ).
Patients should be informed of the signs of an anaphylactic 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 , Anaphylactic Reactions ).
In late pregnancy, as with other NSAIDs, diclofenac potassium tablets should be avoided because they will cause premature closure of the ductus arteriosus.
DOSAGE AND ADMINISTRATION
Carefully consider the potential benefits and risks of diclofenac potassium tablets USP and other treatment options before deciding to use diclofenac potassium tablets USP.
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 USP, 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 USP, 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 sodium enteric-coated tablets; diclofenac sodium extended-release tablets; diclofenac potassium tablets USP] are not necessarily bioequivalent even if the milligram strength is the same.